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  • 1.
    Berhan, Yonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Impact of Parental Socioeconomic Status on Excess Mortality in a Population-Based Cohort of Subjects With Childhood-Onset Type 1 Diabetes2015In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 38, no 5, p. 827-832Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to analyze the possible impact of parental and individual socioeconomic status (SES) on all-cause mortality in a population-based cohort of patients with childhood-onset type 1 diabetes.

    RESEARCH DESIGN AND METHODS: Subjects recorded in the Swedish Childhood Diabetes Registry (SCDR) from 1 January 1978 to 31 December 2008 were included (n =14,647). The SCDR was linked to the Swedish Cause of Death Registry (CDR) and the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA).

    RESULTS: At a mean follow-up of 23.9 years (maximum 46.5 years), 238 deaths occurred in a total of 349,762 person-years at risk. In crude analyses, low maternal education predicted mortality for male patients only (P = 0.046), whereas parental income support predicted mortality in both sexes (P < 0.001 for both). In Cox models stratified by age-at-death group and adjusted for age at onset and sex, parental income support predicted mortality among young adults (≥18 years of age) but not for children. Including the adult patient’s own SES in a Cox model showed that individual income support to the patient predicted mortality occurring at ≥24 years of age when adjusting for age at onset, sex, and parental SES.

    CONCLUSIONS: Exposure to low SES, mirrored by the need for income support, increases mortality risk in patients with childhood-onset type 1 diabetes who died after the age of 18 years.

  • 2.
    Berhan, Yonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Impact of parental socioeconomic status on excess mortality in subjects with childhood onset type-1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    Aims/Hypothesis: The aim of this study was to analyze the possible impact of parental and individual socioeconomic status (SES) on all cause mortality in a population based cohort of childhood onset T1D.

    Methods: Subjects recorded in the Swedish Childhood Diabetes Registry (SCDR) January 1 1978 to December 31 2008 were included (n=14 409). The SCDR was linked to the Swedish Cause of Death Register (CDR) and the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA). SES measures (education and income support) wtypeere retrieved from the LISA for the years 1990-2010. Mortality data were retrieved from the CDR as of December 31, 2010.

    Results: At a mean follow-up of 24.4 years (maximum 47.5), 238 deaths occurred in a total of 357 048 person-years at risk. In crude analyses, low maternal education predicted mortality for male cases only (p=0.046), while parental income support predicted mortality in both sexes (p<0.001 for both). In Cox models stratified by age at death groups and adjusted for age at onset and sex, parental income support predicted mortality among young adults ( ≥18 years of age) but not for children. Including the adult patient´s own SES in a Cox model showed that individual income support to the patient predicted mortality occurring at ≥ 24 years of age when adjusting for age at onset, sex and parental SES.

    Conclusions/Interpretation: Low parental SES, mirrored by the need of income support, increases mortality risk in childhood onset type-1 diabetics who died after the age of 18 years.

  • 3.
    Berhan, Yonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Lund Univ, Dept Clin Sci, Lund, Sweden.
    Högberg, Lotta
    Linköping Univ, Dept Clin & Expt Med, Div Pediat, Linköping, Sweden.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Five-region study finds no evidence of undiagnosed type 2 diabetes in Swedish 11- to 13-year-olds2014In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 103, no 10, p. 1078-1082Article in journal (Refereed)
    Abstract [en]

    AIM: Childhood obesity is now an established public health problem in most developed countries, and there is concern about a parallel increase of type 2 diabetes. The aim of this study was to estimate the prevalence of undiagnosed type 2 diabetes in overweight Swedish school children from 11 to 13 years of age.

    METHODS: Body mass index (BMI) was measured in 5528 schoolchildren in the 6th grade, from 11 to 13 years of age, in five different regions in Sweden. Overweight was defined by international age- and sex-specific BMI cut-offs, corresponding to adult BMI cut-offs of 25 kg/m(2) at 18 years of age (ISO-BMI ≥25, n = 1275). Haemoglobin A1c (HbA1c) was measured in 1126 children with ISO-BMI ≥25. Children with a Diabetes Control and Complications Trial aligned HbA1c ≥6.1% on two occasions underwent an oral glucose tolerance test (OGTT) to establish the diabetes diagnosis.

    RESULTS: Of 1126 children with ISO-BMI ≥25, 24 (2.1%) had at least one HbA1c value ≥6.1%. Three of them had HbA1c ≥6.1% on two occasions, and all of them had a normal OGTT.

    CONCLUSION: In this cross-sectional, population-based screening study of a high-risk group of 11- to 13-year-old Swedish school children, we found no indication of undiagnosed diabetes or impaired glucose tolerance.

  • 4.
    Berhan, Yonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, Annelie
    Högberg, Lotta
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Screening for undiagnosed type-2 diabetes in Swedish 6th grade school childrenManuscript (preprint) (Other academic)
    Abstract [en]

    Aims: To estimate the prevalence of undiagnosed type-2 diabetes in overweight Swedish school children 11-13 years old.

    Methods: BMI was measured in 5 528 school-children (11-13 years of age) attending the 6th grade, in five different regions in Sweden. Overweight was defined by international age-sex specific BMI cut-offs, corresponding to adult BMI cut-offs of 25 kg/m² at 18 years of age (ISO-BMI ≥25, n=1 275). Haemoglobin A1c (HbA1c) was measured in 1 126 children with ISO-BMI ≥25. Children with a DCCT-aligned HbA1c ≥ 6.1% on two occasions underwent an oral glucose-tolerance test (OGTT) to establish diabetes diagnosis.

    Results: Twenty four children (2.1%) had at least one HbA1c-value ≥6.1%. Three of them had HbA1c ≥6.1% on two occasions and all of them had a normal OGTT.

    Conclusion: In this cross-sectional population-based screening study of a high risk group of 11-13 years old Swedish school children we found no indication of undiagnosed diabetes or impaired glucose tolerance.Key

  • 5.
    Berhan, Yonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Department of Statistics.
    Lind, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlqvist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden.2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 2, p. 577-81Article in journal (Refereed)
    Abstract [en]

    Childhood T1D increased dramatically and shifted to a younger age at onset the first 22 years of the study period. We report a reversed trend, starting in 2000, indicating a change in nongenetic risk factors affecting specifically young children.

  • 6.
    Dahlquist, Gisela
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Källén, B
    Hospitalization for vascular complications in childhood onset type 1 diabetes--effects of gender and age at onset.2008In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 97, no 4, p. 483-8Article in journal (Refereed)
    Abstract [en]

    AIMS: To study the cumulative incidence of hospitalization for severe diabetic vascular complications in childhood onset type 1 diabetes patients with special regards to age at onset and gender. METHODS: The Swedish Childhood Diabetes Register (SCDR) was linked to the Swedish Hospital Discharge Register up to 31 December 2004. The following diagnoses were traced: diabetic kidney disease, myocardial infarction, stroke, lower limb arterial disease and diabetes with multiple complications. Cox proportional hazards survival method was applied with the following covariates: maternal age, birthweight deviation from gestational week standard, age at onset and gender. RESULTS: Until 31 December 9974 children had been followed for at least 10 years corresponding to 141 839 person years at risk and 103 (7.3 per 1000 person years) had been hospitalized at least once at the maximum duration of follow-up of 26 years. Diabetic kidney disease was the most common cause of hospitalization and 63 patients had more than one diabetic complication. Female gender (RR=2.02, 95% CI=1.05-3.89) and age at onset of diabetes (RR=1.37, 95% CI=1.20-1.56) were significant risk factors for severe complication. CONCLUSIONS: Hospitalization for severe diabetic complications at a maximum follow-up of 26 years is rather low in Sweden. There is a higher hospitalization rate among females than among males, and also among patients diagnosed with diabetes after 10 years of age than among patients diagnosed before the age of 10 years.

  • 7.
    Fredriksson, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Persson, Emma
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lind, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Risk of cancer in young and middle-aged adults with childhood-onset type 1 diabetes in Sweden - A prospective cohort study2022In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, article id e14771Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: In persons with type 1 diabetes, the risk of cancer remains controversial. We wanted to examine the excess risk of cancer in a large population-based cohort diagnosed with type 1 diabetes before 15 years of age.

    Study population and methods: From 1 July 1977 to 31 December 2013, we prospectively and on a national scale included 18,724 persons (53% men) with childhood-onset type 1 diabetes. For each person with type 1 diabetes, we selected four referents, matched for the date at birth and municipality of living at the time when the case developed diabetes. Cases and referents were linked to national registers of cancer and of the cause of death.

    Results: A total of 125 persons (61% women) with diabetes had 135 different cancers, all diagnosed after the diabetes diagnosis. The median duration from diabetes diagnosis to first cancer diagnosis was 19 years (interquartile range 10-26). The median age at cancer diagnosis in the diabetes group was 28 years (interquartile range 20-35). The overall standardized incidence ratio (95%), using the Swedish general population as referents for women with diabetes was 1.28 (1.02, 1.58) and when comparing women with diabetes with matched referents, we found a hazard ratio of 1.42 (1.10, 1.85). No elevated risk was seen for men. Cancers of the breast and testis were the most common types in women and men respectively.

    Conclusions: Women with childhood-onset type 1 diabetes had a small but significantly elevated risk of cancer. No such tendency was seen for men. The reason behind this is unclear.

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  • 8. Gu, Tianwei
    et al.
    Horova, Eva
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Abu Seman, Norhashimah
    Falhammar, Henrik
    Prazny, Martin
    Brismar, Kerstin
    Gu, Harvest F.
    IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy2012In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 26, no 5, p. 393-398Article in journal (Refereed)
    Abstract [en]

    Objective: The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (120) and diabetic nephropathy (ON). Its protein functionally binds to 5'-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN. Materials and Methods: Three cohorts including T1D with and without DN (n = 1139) of European descents from the GoKinD study, Swedish T1D with and without ON (n = 303) and Czech control subjects without diabetes, T1D, T2D with and without ON (n = 1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot. Results: An association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P = 0.037, OR = 0.69 95% CI 0.49-0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and ON in male patients with T1D was still significant (P = 0.030, OR = 0.73, 95% CI 0.54-0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P = 0.038, OR = 0.67 95% CI 0.46-0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P = 0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5 weeks but not at 26 weeks. Conclusions: The present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D. (C) 2012 Elsevier Inc. All rights reserved.

  • 9. Ma, J
    et al.
    Möllsten, A
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Prázny, M
    Falhammar, H
    Brismar, K
    Dahlquist, G
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Efendic, S
    Gu, H F
    Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.2006In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 23, no 10, p. 1093-1099Article in journal (Refereed)
    Abstract [en]

    AIM: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM-1 gene polymorphisms on the development of T1D and diabetic nephropathy. METHODS: Five valid single nucleotide polymorphisms (SNPs) were genotyped in 432 T1D patients (196 patients had diabetic nephropathy) and 187 non-diabetic control subjects by using dynamic allele-specific hybridization (DASH) and pyrosequencing. RESULTS: SNPs rs281432(C/G) and rs5498 E469K(A/G) had high heterozygous indexes. They were significantly associated with T1D [P = 0.026, OR = 1.644 (95% CI 1.138-2.376) and P < 0.001, OR = 2.456 (1.588-3.8)]. Frequencies of the C allele in SNP rs281432(C/G) and the A allele in SNP rs5498 E469K(A/G) increased stepwise from non-diabetic control subjects to T1D patients without diabetic nephropathy and T1D patients with diabetic nephropathy. Further analysis for these two SNPs indicated that T1D patients had increased frequency of the common haplotype C-A, in comparison with non-diabetic control subjects (38.1 vs. 32.1%, P = 0.035). CONCLUSION: The present study provided evidence that SNPs rs281432(C/G) and rs5498 E469K(A/G) in the ICAM-1 gene confer susceptibility to the development of T1D and might also be associated with diabetic nephropathy in Swedish Caucasians.

  • 10. Ma, Jun
    et al.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Falhammar, Henrik
    Brismar, Kerstin
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Efendic, Suad
    Gu, Harvest F
    Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy.2007In: J Diabetes Complications, ISSN 1056-8727, Vol. 21, no 1, p. 28-33Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Adiponectin [adipocyte C1q and collagen domain containing (ACDC)] is the most abundant adipose-specific protein. It is beneficial in that it improves insulin sensitivity and mitigates vascular damage, in addition to the possibility of it having anti-inflammatory properties. Clinical evidences demonstrate that serum adiponectin concentrations are increased in patients with type 1 diabetes (T1D) as well as in patients with microvascular complications. However, the genetic influence of the ACDC gene in T1D and diabetic microvascular complications is still unclear. The present study aims to evaluate the association of the ACDC genetic variation in T1D and diabetic nephropathy (DN). MATERIALS AND METHODS: Ten single nucleotide polymorphisms (SNPs) of the ACDC gene were genotyped in 432 T1D patients (of which, 196 had DN) and 187 nondiabetic control subjects, who were all Swedish Caucasians, by using dynamic allele specific hybridization. RESULTS: Single-marker association analysis demonstrated that SNPs +45G15G(T/G) and +276(G/T) were strongly associated with T1D [P=.002, OR=1.855 (1.266-2.717) and P=.001, OR=1.694 (1.337-2.147)]. Further analysis for haplotypes of these two SNPs indicated that one of the common haplotype (T_G) was strongly associated with T1D [P<.001, OR=1.769 (1.430-2.188)]. However, there was no significant difference in the allele frequencies of these two SNPs between the groups of T1D patients with nephropathy and the patients without nephropathy. CONCLUSIONS: The present study thus suggests that SNPs +45G15G(T/G) and +276(G/T) in the ACDC gene are associated with T1D but not with DN among Swedish Caucasians.

  • 11. Ma, Jun
    et al.
    Nordman, Sofia
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Falhammar, Henrik
    Brismar, Kerstin
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Efendic, Suad
    Gu, Harvest F
    Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations.2007In: Eur J Endocrinol, ISSN 1479-683X, Vol. 157, no 5, p. 641-5Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations. DESIGN: One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study. METHODS: Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization. RESULTS: The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249-5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD. CONCLUSIONS: The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

  • 12.
    Mollsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Svensson, M
    Berhan, Yonas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Age at onset and sex influence the risk of developing end-stage renal disease in young patients with type 1 diabetes2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, p. S25-S26Article in journal (Refereed)
  • 13.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Clinical Sciences, Paediatrics.
    Factors influencing the risk of diabetic nephropathy: analyses of genes, smoking and diet2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetic long-term complications, despite intensive treatment, cause serious handicaps at relatively young age in diabetic patients. Diabetic nephropathy (DN) develops in up to 30% of patients with type 1 diabetes (T1D). Besides the eventual loss of kidney function, with need for dialysis treatment and transplantation, this complication also increases the risk of early death from cardiovascular disease. In addition to hyperglycaemia, the risk of developing DN is influenced by a number of life-style related factors, such as smoking and diet, but the mechanisms of action of these factors are largely unknown. The incidence of DN is not linearly related to diabetes duration. There is a peak incidence of DN at 15-20 years and this, together with results from family studies, shows that genetic factors are important contributors. Possible candidate genes are those involved in regulation of intraglomerular pressure and blood pressure, oxidative stress and inflammation.

    The main aims of this thesis were:

    ● To investigate the risk of DN associated with polymorphisms in;

    A) the endothelial NO-synthase gene (NOS3) and genes in the renin-angiotensin-system (RAAS) (all involved in the regulation of intraglomerular pressure).

    B) the manganese superoxide dismutase gene (SOD2) (involved in the regulation of oxidative stress).

    C) the ICAM1 gene (involved in activation and migration of lymphocytes)

    ● To investigate gene-smoking interactions

    ● To investigate the influence of normal diet on risk of microalbuminuria.

    The aims were addressed in different case-control settings, including 347 T1D patients from Sweden and 1163 patients from Finland, with or without DN, defined as; overt DN – having albumin excretion rate (AER) ≥200 μg/min, incipient DN – AER between 20 and 200 μg/min, non-DN controls – having AER <20 μg/min and at least 20 years of diabetes duration. In one study also non-diabetic healthy individuals were included to asses the risk of T1D associated with the ICAM1 gene.

    Results: The RAAS genes were investigated in the Swedish sample set and there was an association between a polymorphism in the angiotensin II type 1 receptor (AGTR1) gene and overt DN, when adjusting for age, duration of diabetes, HbA1c, sex and smoking (adjusted OR=3.04, 99% CI=1.02-9.06). Also a synergistic interaction with smoking was indicated.

    The ICAM1 gene was investigated in the Swedish sample set, but no association with DN was found. There were, however, associations between T1D and two polymorphisms in this gene, rs281432 (OR=1.64, 95% CI=1.14-2.38) and rs5498 (OR=2.46, 95% CI=1.59-3.80).

    In the combined Swedish/Finnish sample set, the Glu/Glu genotype of the Glu298Asp polymorphism in the NOS3 gene was associated with DN when age at diabetes onset, duration of diabetes, HbA1c, blood pressure, sex and smoking were taken into account (adjusted OR=1.46, 95% CI=1.12-1.91). There was also association between a polymorphism in the MnSOD gene and DN in this sample set. Homozygosity for the valine-allele of the Val16Ala polymorphism was associated with increased risk of DN in a model including age at diabetes onset, duration of diabetes, HbA1c, sex and smoking (adjusted OR=1.32, 95% CI=1.00-1.74).

    Smoking was associated with DN (OR=2.00, 95% CI=1.60-2.50) and in the Swedish sample set there were indications of interactions between smoking and the NOS3 and SOD2 genes, but these results could not be confirmed in the Finnish sample set.

    A high protein intake can enhance glomerular filtration rate and accelerate progression to DN, also other dietary components such as fat, fibres, vitamins and the ratio red/white meat have been discussed as important for DN development. In a nested case-control study including young T1D patients, the normal dietary intakes of protein and other nutrients were assessed using a semiquantitative questionnaire. The results showed that T1D patients consuming more than 6.5 g fish protein (>75th percentile) per day were at slightly lower risk to have microalbuminuria in both crude (OR=0.49, 95% CI=0.25-0.97) and adjusted analyses (OR=0.26, 95% CI=0.09-0.76, adjusted for age, duration of diabetes, sex, HbA1c, mean arterial pressure, BMI, region, smoking, energy intake and fish fat intake).

    Conclusions: The risk of having diabetic nephropathy is influenced by at least two genes controlling blood pressure and one gene protecting against oxidative stress. Smoking also increases the risk of DN and our findings indicate that smoking may accentuate the effect of the AGTR1, NOS3 and SOD2 genes. Normal dietary intake of protein was not associated with risk of having microalbuminuria in young T1D patients, on the other hand, an intake of fish protein above the 75th percentile decreased the risk of microalbuminuria.

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  • 14.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rudberg, Susanne
    Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients.2001In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 24, no 5, p. 805-810Article in journal (Refereed)
  • 15.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jorsal, A
    Steno Diabetes Center, Gentofte, Denmark.
    Lajer, M
    Steno Diabetes Center, Gentofte, Denmark.
    Vionnet, N
    INSERM and Université Pierre et Marie Curie-Paris, UMR S 525, Paris, France.
    Tarnow, L
    Steno Diabetes Center, Gentofte, Denmark.
    The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 12, p. 2590-2593Article in journal (Refereed)
    Abstract [en]

    The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.

  • 16.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kockum, Ingrid
    Svensson, Maria
    Rudberg, Susanne
    Ugarph-Morawski, Anna
    Brismar, Kerstin
    Eriksson, Jan
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy riskManuscript (Other academic)
  • 17.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kockum, Ingrid
    Svensson, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rudberg, Susanne
    Ugarph-Morawski, Anna
    Brismar, Kerstin
    Eriksson, Jan W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk2008In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Journal of diabetes and its complications, ISSN 1873-460X, Vol. 22, no 6, p. 377-383Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The risk of diabetic nephropathy (DN) can be increased by elevated intraglomerular pressure and glomerular filtration rate, leading to glomerular damage. This can be controlled by the renin-angiotensin-aldosterone (RAA) system, which has an important function regulating both systemic and intrarenal blood pressure. Smoking increases the risk of DN, but not all diabetic patients who smoke develop DN. There is a possibility that smoking has different effects depending on the different genotypes of the individual. We investigated the association of DN with seven polymorphisms in the RAA system and their possible interaction with smoking. SUBJECTS AND METHODS: In the present case-control study, type 1 diabetic patients with diabetes duration > or =20 years, without albuminuria and without antihypertensive treatment (n=197), were included as controls. An albumin excretion rate (AER) of 20-200 microg/min (n=73) was considered as incipient DN, and an AER >200 microg/min was considered as overt DN (n=48). Smoking habits were obtained from questionnaires. RESULTS: Homozygosity for the A allele, of the angiotensin II type 1 receptor (AGTR1) A1166C polymorphism, was associated with increased risk of overt DN (OR=3.04; 99% CI=1.02-9.06), independently of the other associated variables: age, duration of diabetes, ever smoking, HbA1c, and sex. The effect of the AA genotype was enhanced to a four times risk increase among ever-smoking patients. Two alleles of the microsatellite marker adjacent to the angiotensinogen gene were less common among nephropathy cases than among controls, but this was not significant when controlling for the same variables as above. CONCLUSIONS: The risk of having overt DN was increased in patients homozygous for the A1166 allele, and smoking seemed to enhance the effect of the AGTR1 genotype.

  • 18.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lajer, Maria
    Jorsal, Anders
    Tarnow, Lise
    The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes2009In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 97, no 1, p. 80-84Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion >300 mg/24h) and 319 controls with persistent normoalbuminuria (<30 mg/24h), despite > or =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.

  • 19.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wessman, Maija
    Svensson, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forsblom, Carol
    Parkkonen, Maikki
    Brismar, Kerstin
    Groop, Per-Henrik
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 1, p. 265-269Article in journal (Refereed)
    Abstract [en]

    Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radicals. The demand for antioxidants is increased by smoking, which could disturb the balance between antioxidants and radicals. The present study aimed to determine whether a valine/alanine polymorphism in MnSOD (V16A, rs4880), alone or in combination with smoking, can contribute to development of diabetic nephropathy in 1,510 Finnish and Swedish patients with type 1 diabetes. Overt diabetic nephropathy (n = 619) was defined as having an albumin excretion rate (AER) >200 microg/min or renal replacement therapy; incipient diabetic nephropathy was defined as having an AER of 20-200 microg/min (n = 336). The control subjects had diabetes duration of >or=20 years, without albuminuria (AER <20 microg/min) and without antihypertensive treatment (n = 555). In addition to male sex and elevated A1C, smoking was significantly associated with diabetic nephropathy (overt plus incipient), odds ratio (OR) 2.00 (95% CI 1.60-2.50). When controlling for age at onset, diabetes duration, A1C, smoking, and sex, the Val/Val genotype was associated with an increase in risk of diabetic nephropathy (1.32 [1.00-1.74], P = 0.049). When evaluating the combined effect of genotype and smoking, we used logistic regression with stratification according to smoking status and genotype. The high-risk group (ever smoking plus Val/Val genotype) had 2.52 times increased risk of diabetic nephropathy (95% CI 1.73-3.69) compared with the low-risk group, but no departure from additivity was found. Our results indicate that smoking and homozygosity for the MnSOD Val allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.

  • 20.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study.2008In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 26, no 7, p. 1367-1372Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.

  • 21.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Svensson, Maria
    Department of Nephrology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Department of Statistics.
    Berhan, Yonas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schön, Staffan
    Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Arnqvist, Hans J.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: A nationwide population-based cohort study2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 7, p. 1803-1808Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE—This study aimed to estimate the current cumulativerisk of end-stage renal disease (ESRD) due to diabeticnephropathy in a large, nationwide, population-based prospectivetype 1 diabetes cohort and specifically study the effects ofsex and age at onset.RESEARCH DESIGN AND METHODS—In Sweden, all incidentcases of type 1 diabetes aged 0–14 years and 15–34 years arerecorded in validated research registers since 1977 and 1983,respectively. These registers were linked to the Swedish RenalRegistry, which, since 1991, collects data on patients who receiveactive uremia treatment. Patients with 13 years duration of type1 diabetes were included (n 11,681).RESULTS—During a median time of follow-up of 20 years, 127patients had developed ESRD due to diabetic nephropathy. Thecumulative incidence at 30 years of type 1 diabetes duration waslow, with a male predominance (4.1% [95% CI 3.1–5.3] vs. 2.5%[1.7–3.5]). In both male and female subjects, onset of type 1diabetes before 10 years of age was associated with the lowestrisk of developing ESRD. The highest risk of ESRD was found inmale subjects diagnosed at age 20–34 years (hazard ratio 3.0 [95%CI 1.5–5.7]). In female subjects with onset at age 20–34 years, therisk was similar to patients’ diagnosed before age 10 years.CONCLUSIONS—The cumulative incidence of ESRD is exceptionallylow in young type 1 diabetic patients in Sweden. There isa striking difference in risk for male compared with femalepatients. The different patterns of risk by age at onset and sexsuggest a role for puberty and sex hormones.

  • 22.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Toppe, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Eeg-Olofsson, Katarina
    Lind, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sex Differences in Treatment With ACE Inhibitors and Angiotensin Receptor Blockers in Patients With Type 1 Diabetes2019In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 42, no 5, p. E73-E74Article in journal (Refereed)
  • 23.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Torffvit, Ole
    Tamm-Horsfall protein gene is associated with distal tubular dysfunction in patients with type 1 diabetes.2010In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 44, no 6, p. 438-444Article in journal (Refereed)
    Abstract [en]

    Distal tubular dysfunction was associated with the THP gene and macroalbuminuria in patients with type 1 diabetes.

  • 24.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Vionnet, Nathalie
    Forsblom, Carol
    Parkkonen, Maija
    Tarnow, Lise
    Hadjadj, Samy
    Marre, Michel
    Parving, Hans-Henrik
    Groop, Per-Henrik
    A polymorphism in the angiotensin II type 1 receptor gene has different effects on the risk of diabetic nephropathy in men and women.2011In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 103, no 1, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Background

    The etiology of diabetic nephropathy depends partly on genetic factors. Elevated systemic and intraglomerular blood pressure and glomerular filtration rate, partly regulated by the renin–angiotensin system, increase the risk of diabetic nephropathy.

    Methods

    The present case–control study investigated the association of the rs5186 polymorphism, in the angiotensin II type 1 receptor gene (AGTR1), with diabetic nephropathy. The study included 3561 patients with type 1 diabetes from Denmark, Finland, France and Sweden. Microalbuminuria was defined as albumin excretion rate (AER) ≥ 20 to < 200 μg/min or albumin concentration ≥ 30 to < 300 mg/l (n = 707), macroalbuminuria was defined as AER ≥ 200 μg/min or ≥ 300 mg/l (n = 1546), and patients with renal replacement therapy were also included in this group. The controls had > 15 years diabetes duration, AER < 20 μg/min or < 30 mg/l, and no antihypertensive treatment (n = 1308).

    Results

    AA genotype of the rs5186 polymorphism significantly increased the risk of diabetic nephropathy in male patients, OR = 1.27 (95% CI = 1.02–1.58), P = 0.03, adjusted for age at diabetes onset, HbA1c, diabetes duration, smoking and country of origin. Among the women, there were no significant associations between rs5186 and diabetic nephropathy, OR = 0.89 (0.71–1.11), P = 0.30.

    Conclusion

    We conclude that the AGTR1 gene may be associated with increased risk of diabetic nephropathy in men with type 1 diabetes.

  • 25.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wessman, M
    Svensson, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Forsblom, C
    Parkkonen, M
    Brismar, K
    Groop, PH
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.2006In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 38, no 7, p. 522-528Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    BACKGROUND AND AIMS: The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO-production can be affected by polymorphisms in the endothelial NO-synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients. PATIENTS AND METHODS: A total of 1510 Finnish and Swedish T1D patients were included in a cross-sectional case-control study. Incipient DN was defined as an albumin excretion rate (AER) of 20-200 microg/min (n = 336). Overt DN = AER>200 microg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration 20 years, AER<20 microg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983). RESULTS: Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu-allele of the Glu298Asp-polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12-1.91). The variables smoking (OR = 2.13; 95% CI = 1.63-2.78), male sex (OR = 1.61; 95% CI = 1.23-2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02-1.03), systolic (OR = 1.05; 95% CI = 1.04-1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02-1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a-allele was not associated with DN. CONCLUSIONS: The Glu/Glu-genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.

  • 26.
    Pazzagli, Laura
    et al.
    University of Perugia, Department of Economics, Division of Statistics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Marginal structural model to evaluate the joint effect of socioeconomic exposures on the risk of developing end-stage renal disease in patients with type 1 diabetes: a longitudinal study based on data from the Swedish Childhood Diabetes Study Group2017In: Annals of Epidemiology, ISSN 1047-2797, E-ISSN 1873-2585, Vol. 27, no 8, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Purpose: Diabetic nephropathy is a severe complication of type 1 diabetes (T1D) that may lead to renal failure and end-stage renal disease (ESRD) demanding dialysis and transplantation. The aetiology of diabetic nephropathy is multifactorial and both genes and environmental and life style related factors are involved. In this study we investigate the effect of the socioeconomic exposures unemployment and receiving income support on the development of ESRD in T1D patients, using a marginal structural model in comparison with standard logistic regression models.

    Methods: The study is based on the Swedish Childhood Diabetes Register which in 1977 started to register patients developing T1D before 15 years of age. In the analyses we include patients born between 1965 and 1979, developing diabetes between 1977 and 1994, followed until 2013 (n=4034). A marginal structural model (MSM) was fitted to adjust for both baseline and time-varying confounders.

    Results: The main results of the analysis indicate that being unemployed for more than one year and receiving income support are risk factors for the development of ESRD. Multiple exposure over time to these risk factors increases the risk associated with the disease.

    Conclusions: Using a MSM is an advanced method well suited to investigate the effect of exposures on the risk of complications of a chronic disease with longitudinal data. The results show that socioeconomic disadvantage increases the risk of developing ESRD in patients with type 1 diabetes.

  • 27. Salem, Rany M.
    et al.
    Todd, Jennifer N.
    Sandholm, Niina
    Cole, Joanne B.
    Chen, Wei-Min
    Andrews, Darrell
    Pezzolesi, Marcus G.
    McKeigue, Paul M.
    Hiraki, Linda T.
    Qiu, Chengxiang
    Nair, Viji
    Di Liao, Chen
    Cao, Jing Jing
    Valo, Erkka
    Onengut-Gumuscu, Suna
    Smiles, Adam M.
    McGurnaghan, Stuart J.
    Haukka, Jani K.
    Harjutsalo, Valma
    Brennan, Eoin P.
    van Zuydam, Natalie
    Ahlqvist, Emma
    Doyle, Ross
    Ahluwalia, Tarunveer S.
    Lajer, Maria
    Hughes, Maria F.
    Park, Jihwan
    Skupien, Jan
    Spiliopoulou, Athina
    Liu, Andrew
    Menon, Rajasree
    Boustany-Kari, Carine M.
    Kang, Hyun M.
    Nelson, Robert G.
    Klein, Ronald
    Klein, Barbara E.
    Lee, Kristine E.
    Gao, Xiaoyu
    Mauer, Michael
    Maestroni, Silvia
    Caramori, Maria Luiza
    de Boer, Ian H.
    Miller, Rachel G.
    Guo, Jingchuan
    Boright, Andrew P.
    Tregouet, David
    Gyorgy, Beata
    Snell-Bergeon, Janet K.
    Maahs, David M.
    Bull, Shelley B.
    Canty, Angelo J.
    Palmer, Colin N. A.
    Stechemesser, Lars
    Paulweber, Bernhard
    Weitgasser, Raimund
    Sokolovska, Jelizaveta
    Rovite, Vita
    Pirags, Valdis
    Prakapiene, Edita
    Radzeviciene, Lina
    Verkauskiene, Rasa
    Panduru, Nicolae Mircea
    Groop, Leif C.
    McCarthy, Mark, I
    Gu, Harvest F.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Falhammar, Henrik
    Brismar, Kerstin
    Martin, Finian
    Rossing, Peter
    Costacou, Tina
    Zerbini, Gianpaolo
    Marre, Michel
    Hadjadj, Samy
    McKnight, Amy J.
    Forsblom, Carol
    McKay, Gareth
    Godson, Catherine
    Maxwell, A. Peter
    Kretzler, Matthias
    Susztak, Katalin
    Colhoun, Helen M.
    Krolewski, Andrzej
    Paterson, Andrew D.
    Groop, Per-Henrik
    Rich, Stephen S.
    Hirschhorn, Joel N.
    Florez, Jose C.
    Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen2019In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 30, no 10, p. 2000-2016Article in journal (Refereed)
    Abstract [en]

    Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

    Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

    Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).

    Conclusions: The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

  • 28.
    Sandholm, Niina
    et al.
    Helsinki, Finland.
    Forsblom, Carol
    Helsinki, Finland.
    Mäkinen, Ville-Petteri
    Helsinki, Finland; Los Angeles, CA, USA.
    McKnight, Amy Jayne
    Belfast, UK.
    Österholm, Anne-May
    Stockholm, Sweden.
    He, Bing
    Harjutsalo, Valma
    Helsinki, Finland.
    Lithovius, Raija
    Helsinki, Finland.
    Gordin, Daniel
    Helsinki, Finland.
    Parkkonen, Maija
    Helsinki, Finland.
    Saraheimo, Markku
    Helsinki, Finland.
    Thorn, Lena M.
    Helsinki, Finland.
    Tolonen, Nina
    Helsinki, Finland.
    Waden, Johan
    Helsinki, Finland.
    Tuomilehto, Jaakko
    Helsinki, Finland; Krems, Austria; Jeddah, Saudi Arabia.
    Lajer, Maria
    Gentofte, Denmark.
    Ahlqvist, Emma
    Malmö, Sweden.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcovecchio, M. Loredana
    Cooper, Jason
    Cambridge, UK.
    Dunger, David
    Cambridge, UK.
    Paterson, Andrew D.
    Toronto, ON, Canada.
    Zerbini, Gianpaolo
    Milan, Italy.
    Groop, Leif
    Malmö, Sweden.
    Tarnow, Lise
    Gentofte; Aarhus; Hilleroed, Denmark.
    Maxwell, Alexander P.
    Belfast, UK.
    Tryggvason, Karl
    Stockholm, Sweden.
    Groop, Per-Henrik
    Helsinki, Finland; Melbourne, VIC, Australia.
    Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 6, p. 1143-1153Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.

    METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients withtype 1 diabetes from seven studies.

    RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic associationobserved at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.

    CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

  • 29. Sandholm, Niina
    et al.
    Salem, Rany M.
    McKnight, Amy Jayne
    Brennan, Eoin P.
    Forsblom, Carol
    Isakova, Tamara
    McKay, Gareth J.
    Williams, Winfred W.
    Sadlier, Denise M.
    Makinen, Ville-Petteri
    Swan, Elizabeth J.
    Palmer, Cameron
    Boright, Andrew P.
    Ahlqvist, Emma
    Deshmukh, Harshal A.
    Keller, Benjamin J.
    Huang, Huateng
    Ahola, Aila J.
    Fagerholm, Emma
    Gordin, Daniel
    Harjutsalo, Valma
    He, Bing
    Heikkila, Outi
    Hietala, Kustaa
    Kyto, Janne
    Lahermo, Paivi
    Lehto, Markku
    Lithovius, Raija
    Osterholm, Anne-May
    Parkkonen, Maija
    Pitkaniemi, Janne
    Rosengard-Barlund, Milla
    Saraheimo, Markku
    Sarti, Cinzia
    Soderlund, Jenny
    Soro-Paavonen, Aino
    Syreeni, Anna
    Thorn, Lena M.
    Tikkanen, Heikki
    Tolonen, Nina
    Tryggvason, Karl
    Tuomilehto, Jaakko
    Waden, Johan
    Gill, Geoffrey V.
    Prior, Sarah
    Guiducci, Candace
    Mirel, Daniel B.
    Taylor, Andrew
    Hosseini, S. Mohsen
    Parving, Hans-Henrik
    Rossing, Peter
    Tarnow, Lise
    Ladenvall, Claes
    Alhenc-Gelas, Francois
    Lefebvre, Pierre
    Rigalleau, Vincent
    Roussel, Ronan
    Tregouet, David-Alexandre
    Maestroni, Anna
    Maestroni, Silvia
    Falhammar, Henrik
    Gu, Tianwei
    Mollsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cimponeriu, Danut
    Ioana, Mihai
    Mota, Maria
    Mota, Eugen
    Serafinceanu, Cristian
    Stavarachi, Monica
    Hanson, Robert L.
    Nelson, Robert G.
    Kretzler, Matthias
    Colhoun, Helen M.
    Panduru, Nicolae Mircea
    Gu, Harvest F.
    Brismar, Kerstin
    Zerbini, Gianpaolo
    Hadjadj, Samy
    Marre, Michel
    Groop, Leif
    Lajer, Maria
    Bull, Shelley B.
    Waggott, Daryl
    Paterson, Andrew D.
    Savage, David A.
    Bain, Stephen C.
    Martin, Finian
    Hirschhorn, Joel N.
    Godson, Catherine
    Florez, Jose C.
    Groop, Per-Henrik
    Maxwell, Alexander P.
    New susceptibility loci associated with kidney disease in type 1 diabetes2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 9, p. e1002921-Article in journal (Refereed)
    Abstract [en]

    Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

  • 30.
    Toppe, C.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Jönköping.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Jönköping.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Jönköping.
    Schon, S.
    Swedish Renal Registry, Jönköping.
    Socioeconomic risk factors for developing end stage renal disease in patients with childhood onset type 1 diabetes: a population based register study2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no Supplement: 1, p. S475-S475, Meeting Abstract: 1182Article in journal (Other academic)
  • 31.
    Toppe, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Ryhov City Hospital, Department of Internal Medicin, Jönköping, Sweden.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schon, S.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Socio-economic factors influencing the development of end-stage renal disease in people with Type 1 diabetes: a longitudinal population study2017In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 34, no 5, p. 676-682Article in journal (Refereed)
    Abstract [en]

    Aims: The development of end-stage renal disease (ESRD) in Type 1 diabetes is multifactorial. Familial socio-economic factors may influence adherence to and understanding of diabetes treatment, and also general health behaviour. We investigate how parental and personal education level and exposure to low economic status, indicated by the need for income support, influence the development of ERSD caused by Type 1 diabetes.

    Methods: Participants were retrieved from the nationwide Swedish Childhood Diabetes Registry, which was linked to the Swedish Renal Registry, to find people with ESRD caused by Type 1 diabetes, and to Statistic Sweden to retrieve longitudinal socio-economic data on participants and their parents. Data were analysed using Cox regression modelling.

    Results: Of 9287 people with diabetes of duration longer than 14 years, 154 had developed ESRD due to diabetes. Median diabetes duration (range) for all participants was 24.2 years (14.0-36.7 years). Low maternal education ( 12 years) more than doubled the risk of developing ESRD, hazard ration (HR) = 2.9 [95% confidence interval (95% CI): 1.7-4.8]. For people with a low personal level of education HR was 5.7 (3.4-9.5). In an adjusted model, the person's own education level had the highest impact on the risk of ESRD. If at least one of the parents had ever received income support the HR was 2.6 (1.9-3.6).

    Conclusions: Socio-economic factors, both for the parents and the person with diabetes, have a strong influence on the development of ESRD in Type 1 diabetes. It is important for caregivers to give enough support to more vulnerable people and their families.

  • 32.
    Toppe, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schön, Staffan
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Improved survival in Renal Replacement Therapy for type 1 diabetes patients in Sweden: a national register studyManuscript (preprint) (Other academic)
  • 33.
    Toppe, Cecilia
    et al.
    Lanssjukhuset Ryhov, Dept Internal Med, Jonkoping, Sweden.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schön, Staffan
    Swedish Renal Registry, Jönköping, Sweden; Diaverum Renal Serv Grp, Lund, Sweden.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Low cumulative incidence of end-stage renal disease in young patients with type 1 diabetes in Sweden: a population based study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1 Abstr. 402, p. S201-S202Article in journal (Other academic)
    Abstract [en]

    Background and aims: A previous study from our group showed a low cumulative incidence of end-stage renal disease (ESRD) in a Swedish cohort of type 1 diabetes (T1D) patients with median duration of 20 years. We speculated that a good diabetes health care system might have postponed the peak incidence of ESRD and that young age at onset of T1D can postpone the development of diabetic nephropathy (DN) and ESRD. Moreover, diabetes onset during puberty may promote the development of diabetic complications. Our previous study also indicated differences by sex in ESRD development and a possible interaction with age at onset. Female patients who developed T1D after puberty had similar risk of ESRD as those with onset before 10 years of age. Male patients had the same high risk with onset during puberty and after puberty, those with onset before 10 years had the lowest risk. The aims of the present study are to assess the cumulative incidence of ESRD due to DN in a large prospective population-based cohort of T1D patients at maximum 36 years of diabetes duration and to study the effects of sex and age at onset of T1D.

    Materials andmethods: Since 1977 all incident cases of T1D in the ages 0-14 years are recorded in the Swedish Childhood Diabetes Register (SCDR). The Swedish Renal Registry (SRR) started in 1991 and collects data on all patients with active uraemia treatment, ESRD. We decided to include patients with diabetes duration ≥14 years. In total 9381 patients from the SCDR were included. We have recently received permission to include data from the Swedish National Diabetes Register, a national quality register, and are awaiting data to include patients with age at onset 15-34 years.

    Results: For the childhood onset cases the median diabetes duration was 23.8 years, maximum 36.7 years, and 154 patients had developed ESRD due to diabetes. The cumulative incidence was 4.5%. There was no statistical difference between male and female patients with age at diabetes onset before 15 years of age, males 5.0%, females 3.8%.We confirm that onset of diabetes before 10 years of age postpones the development of ESRD when compared to onset during 10-14 years, HR 2.3 (95% CI= 1.7-3.3). Further analyses will be available for presentation in September.

    Conclusion: The cumulative risk of ESRD due to diabetic nephropathy in Swedish T1D patients at maximum36 years of diabetes duration is still exceptionally low. There is no difference in the development of ESRD between male and female patients with onset of diabetes before 15 years of age.

  • 34.
    Toppe, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schön, Staffan
    Jonsson, Anders
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Renal replacement therapy due to type 1 diabetes; time trends during 1995-2010: a Swedish population based register study2014In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 28, no 2, p. 152-155Article in journal (Refereed)
    Abstract [en]

    Background: End stage renal disease (ESRD), is the most severe complication of diabetes mellitus. This population-based study analysed time trends for start of renal replacement therapy (RRT) due to type 1 diabetes compared to type 2 diabetes and other diagnoses. Material and Methods: We used data on patients who were registered 1995-2010 in the Swedish Renal Registry, a nationwide register covering 95 % of all patients with uraemia. The patients were analysed according to their original kidney disease. The incidence was analysed by calendar year, age at start of RRT and gender. Results: Of 17389 patients who were registered, 1833 had type 1 diabetes; 65% were men. The mean age at onset of RRT for patients with type 1 diabetes was 52.8 years which increased by more than 3 years over the studied period. The number of patients in need of RRT due to type 1 diabetes decreased, while RRT due to type 2 diabetes increased during the period studied. Conclusions: The overall incidence of RRT in Sweden is rather constant over the years but the need for RRT in type 1 diabetes patients decreased and patients with type 1 diabetes tend to become older at onset of RRT. 

  • 35.
    Toppe, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Schön, Staffan
    Swedish Renal Registry, Jönköping, Sweden.
    Gudbjörnsdottir, Soffia
    Swedish National Diabetes Register, Gothenburg, Sweden.
    Landin-Olsson, Mona
    Diabetes Incidence Study in Sweden Department of Clinical Sciences, Lund University, Lund, Sweden.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Decreasing Cumulative Incidence of End-Stage Renal Disease in Young Patients With Type 1 Diabetes in Sweden: a 38-Year Prospective Nationwide Study2019In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 42, no 1, p. 27-31Article in journal (Refereed)
    Abstract [en]

    Objective: Diabetic nephropathy is a serious complication of type 1 diabetes. Recent studies indicate that end-stage renal disease (ESRD) incidence has decreased or that the onset of ESRD has been postponed; therefore, we wanted to analyze the incidence and time trends of ESRD in Sweden.

    Research design and methods: In this study, patients with duration of type 1 diabetes >14 years and age at onset of diabetes 0–34 years were included. Three national diabetes registers were used: the Swedish Childhood Diabetes Register, the Diabetes Incidence Study in Sweden, and the National Diabetes Register. The Swedish Renal Registry, a national register on renal replacement therapy, was used to identify patients who developed ESRD.

    Results: We found that the cumulative incidence of ESRD in Sweden was low after up to 38 years of diabetes duration (5.6%). The incidence of ESRD was lower in patients with type 1 diabetes onset in 1991–2001 compared to onset in 1977–1984 and 1985–1990, independently of diabetes duration.

    Conclusion: The risk of developing ESRD in Sweden in this population is still low and also seems to decrease with time.

  • 36.
    Waernbaum, Ingeborg
    et al.
    Department of Statistics, Uppsala University, Uppsala, Sweden.
    Lind, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Möllsten, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    The incidence of childhood-onset type 1 diabetes, time trends and association with the population composition in sweden: a 40 year follow-up2023In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 66, no 2, p. 346-353Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: During the 1980s and 1990s, the incidence of childhood-onset type 1 diabetes more than doubled in Sweden, followed by a plateau. In the present 40 year follow-up, we investigated if the incidence remained stable and whether this could be explained by increased migration from countries reporting lower incidences.

    Methods: We used 23,143 incident cases of childhood-onset type 1 diabetes reported between 1978 and 2019 to the nationwide, population-based Swedish Childhood Diabetes Registry and population data from Statistics Sweden. Generalised additive models and ANOVA were applied to analyse the effects of onset age, sex, time trends and parental country of birth and interaction effects between these factors.

    Results: The flattening of the incidence increase seems to remain over the period 2005–2019. When comparing the incidence of type 1 diabetes for all children in Sweden with that for children with both parents born in Sweden, the trends were parallel but at a higher level for the latter. A comparison of the incidence trends between individuals with Swedish backgrounds (high diabetes trait) and Asian backgrounds (low diabetes trait) showed that the Asian subpopulation had a stable increase in incidence over time.

    Conclusions/interpretation: In Sweden, the increase in incidence of childhood-onset type 1 diabetes in the late 20th century has been approaching a more stable albeit high level over the last two decades. Increased immigration from countries with lower incidences of childhood-onset type 1 diabetes does not provide a complete explanation for the observed levelling off. Graphical abstract: [Figure not available: see fulltext.]

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