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Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
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2006 (Engelska)Ingår i: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 38, nr 7, s. 522-528Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm)) 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.

Ort, förlag, år, upplaga, sidor
2006. Vol. 38, nr 7, s. 522-528
Identifikatorer
URN: urn:nbn:se:umu:diva-16143DOI: doi:10.1080/07853890600969213PubMedID: 17101543OAI: oai:DiVA.org:umu-16143DiVA, id: diva2:155816
Tillgänglig från: 2007-08-17 Skapad: 2007-08-17 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Factors influencing the risk of diabetic nephropathy: analyses of genes, smoking and diet
Öppna denna publikation i ny flik eller fönster >>Factors influencing the risk of diabetic nephropathy: analyses of genes, smoking and diet
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Klinisk vetenskap, 2006. s. 75
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1053
Nyckelord
type 1 diabetes, diabetic nephropathy, oxidative stress, smoking, diet, blood pressure, renin-angiotensin system, nitric oxide synthase
Nationell ämneskategori
Urologi och njurmedicin
Identifikatorer
urn:nbn:se:umu:diva-911 (URN)91-7264-170-3 (ISBN)
Disputation
2006-11-23, 260, 3A, NUS, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-11-03 Skapad: 2006-11-03 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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