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| 2. |
- Delli, Ahmed, et al.
(författare)
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Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study
- 2012
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:10, s. 2556-2564
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether zinc transporter 8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish patients due to different polymorphisms of SLC30A8, HLA-DQ, or both. Newly diagnosed autoimmune (andgt;= 1 islet autoantibody) type 1 diabetic patients (n = 2,964, andlt;18 years, 55% male) were ascertained in the Better Diabetes Diagnosis study. Two subgroups were identified: Swedes (n = 2,160, 73%) and immigrants (non-Swedes; n = 212, 7%). Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%). ZnT8-RA (57 and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) than Swedes (46%). We tested whether this inconsistency was due to HLA-DQ as 2/X (2/2; 2/y; y is anything but 2 or 8), which was a major genotype in non-Swedes (40%) compared with Swedes (14%). In the non-Swedes only, 2/X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA. Molecular simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lack of tolerance to ZnT8-R. At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC30A8 CC (RR) genotypes.
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| 3. |
- Florez, J. C., et al.
(författare)
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Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:6, s. 1209-1217
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p=0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p=0.059). The combined OR was 1.20 (p=0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. Conclusion/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
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| 4. |
- Melander, Olle, et al.
(författare)
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Association between a variant in the 11 beta-hydroxysteroid dehydrogenase type 2 gene and primary hypertension
- 2000
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Ingår i: Journal of Human Hypertension. - 1476-5527. ; 14:12, s. 819-823
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Tidskriftsartikel (refereegranskat)abstract
- The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A polymorphism was identified in exon 3; G534A (Glu178Glu). This polymorphism and the D16S496 microsatellite were tested for association with primary hypertension in a population consisting of 292 patients with primary hypertension and 263 normotensive control subjects. The frequency of G534G homozygotes was higher in patients with primary hypertension than in normotensive control subjects (92.8% vs 87.8%; P < 0.05). The allele frequencies of the D16S496 microsatellite did not differ between the two groups (chi(2) = 11.0, df = 10; P = 0.36). In conclusion, over-representation of individuals homozygous for the G534 allele in hypertensive patients compared with control subjects suggests that a mutation in linkage disequilibrium with the G534A polymorphism could increase susceptibility to primary hypertension. Journal of Human Hypertension (2000) 14, 819-823
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| 5. |
- Melander, Olle, et al.
(författare)
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Role of the Gly460Trp polymorphism of the alpha-adducin gene in primary hypertension in Scandinavians
- 2000
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Ingår i: Journal of Human Hypertension. - 1476-5527. ; 14:1, s. 43-46
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have suggested that the Trp460 allele of the Gly460Trp polymorphism in the alpha-adducin gene is associated with salt sensitivity and primary hypertension. The present study was undertaken to evaluate if the Trp460 allele of this polymorphism is associated with primary hypertension in Scandinavians. To address this issue, 294 patients with primary hypertension and 265 normotensive control subjects from Sweden were examined and genotyped for the Gly460Trp polymorphism using polymerase chain reaction and restriction fragment length polymorphism methods. We then used a population of 80 patients with primary hypertension and 154 normotensive control subjects from Finland to replicate the findings. The frequency of the Trp460 allele was lower in hypertensive patients than in normotensive controls in the Swedish population (17.7% vs 23.0%; P = 0.03) and in the Finnish population (14.4% vs 19.5%; NS). Therefore we also performed a pooled analysis in which the frequency of the Trp460 allele was significantly lower in hypertensive patients than in normotensive controls (17.0% vs 21. 7%; P = 0.02). In subjects who did not receive antihypertensive medication (n = 447) there was no difference between carriers of the three different codon 460 genotypes (Trp-Trp; Trp-Gly and Gly-Gly) either for systolic (128 +/- 18; 127 +/- 15 and 129 +/- 17 mm Hg, NS) or for diastolic blood pressure (75.6 +/- 12.1; 74.7 +/- 9.3 and 75.0 +/- 10.4 mm Hg, NS). In conclusion, the lower frequency of the Trp460 allele in hypertensive patients than in normotensive controls strongly argues against a pathogenic role of this allele in primary hypertension. The results rather suggest that another variant in linkage disequilibrium with the Gly460Trp polymorphism increases susceptibility for hypertension.Journal of Human Hypertension (2000) 14, 43-46.
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| 6. |
- Prokopenko, Inga, et al.
(författare)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Tidskriftsartikel (refereegranskat)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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| 7. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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