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- Graham, Jinko, et al.
(författare)
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Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset
- 1999
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Ingår i: European Journal of Immunogenetics. - : Wiley. - 0960-7420 .- 1365-2370. ; 26, s. 117-
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Tidskriftsartikel (refereegranskat)abstract
- HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype ether than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.
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| 2. |
- Hagopian, William A., et al.
(författare)
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Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children
- 1995
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 95:4, s. 1505-1511
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Tidskriftsartikel (refereegranskat)abstract
- Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA1*0501/B1*0201 (DQ2; P = 0.007) but not DQA1*0301/B1*0302 (DQ8), and IAA with DQA1*0301/B1*0302 (DQ8; P = 0.03) but not DQA1*0501/B1*0201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population.
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| 3. |
- Kockum, Ingrid, et al.
(författare)
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Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus
- 1996
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 28:7, s. 344-347
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Tidskriftsartikel (refereegranskat)abstract
- Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune markers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recombination frequency within the HLA region. The frequency of the DR3-DQA1 * 0501-DQB1 * 0201 haplotype and the DR3-DQA1 * 0501 DQB1 * 0201 (DQ2)/DR4-DQA1 * 0301-DQB1 * 0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30. The negatively associated haplotype, DR15-DQA1 * 0102-DQB1 * 0602 was absent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tandem repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive but not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onset and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest sensitivity (54%) was in 0-10 year old boys, while age did not affect the sensitivity in girls. In contrast, the sensitivity of IAA was highest (46%) before the age of 15 but decreased thereafter as did the sensitivity for ICA. Classification of patients who develop IDDM above 20-25 years of age was inadequate since many patients classified with NIDDM either had GAD65Ab or ICA or developed these antibodies after 1-2 years of NIDDM. We conclude that not only age but also gender affects the risk for IDDM associated with HLA, other IDDM genes as well as commonly used immunological markers for IDDM.
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| 5. |
- Möllsten, Anna, et al.
(författare)
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The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk
- 2008
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Ingår i: Journal of diabetes and its complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 22:6, s. 377-383
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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