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Factors influencing the risk of diabetic nephropathy: analyses of genes, smoking and diet
Umeå University, Faculty of Medicine, Clinical Sciences, Paediatrics.
2006 (English)Doctoral 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.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap , 2006. , 75 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1053
Keyword [en]
type 1 diabetes, diabetic nephropathy, oxidative stress, smoking, diet, blood pressure, renin-angiotensin system, nitric oxide synthase
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:umu:diva-911ISBN: 91-7264-170-3 (print)OAI: oai:DiVA.org:umu-911DiVA: diva2:145018
Public defence
2006-11-23, 260, 3A, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-11-03 Created: 2006-11-03 Last updated: 2009-10-19Bibliographically approved
List of papers
1. Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients.
Open this publication in new window or tab >>Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients.
2001 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 24, no 5, 805-810 p.Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-5485 (URN)10.2337/diacare.24.5.805 (DOI)11347734 (PubMedID)
Available from: 2006-11-03 Created: 2006-11-03 Last updated: 2017-12-14Bibliographically approved
2. The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk
Open this publication in new window or tab >>The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5486 (URN)
Available from: 2006-11-03 Created: 2006-11-03 Last updated: 2010-10-13Bibliographically approved
3. Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.
Open this publication in new window or tab >>Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.
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2006 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 23, no 10, 1093-1099 p.Article in journal (Refereed) Published
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.

Keyword
Diabetes, Type 1, genetics
Identifiers
urn:nbn:se:umu:diva-16366 (URN)doi:10.1111/j.1464-5491.2006.01948.x (DOI)16978373 (PubMedID)
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2017-12-14Bibliographically approved
4. Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
Open this publication in new window or tab >>Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
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2006 (English)In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 38, no 7, 522-528 p.Article in journal (Other (popular science, discussion, etc.)) Published
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.

Identifiers
urn:nbn:se:umu:diva-16143 (URN)doi:10.1080/07853890600969213 (DOI)17101543 (PubMedID)
Available from: 2007-08-17 Created: 2007-08-17 Last updated: 2017-12-14Bibliographically approved
5. A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.
Open this publication in new window or tab >>A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.
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2007 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 1, 265-269 p.Article in journal (Refereed) Published
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.

Keyword
Diabetes Mellitus, Type 1, Diabetic nephropathy
Identifiers
urn:nbn:se:umu:diva-16381 (URN)10.2337/db06-0698 (DOI)17192491 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved

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