| 1. |
- Campbell, Catarina D., et al.
(författare)
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Association studies of BMI and type 2 diabetes in the neuropeptide y pathway - A possible role for NPY2R as a candidate gene for type 2 diabetes in men
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 56:5, s. 1460-1467
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide Y (NPY) family of peptides and receptors regulate food intake. Inherited variation in this pathway could influence susceptibility to obesity and its complications, including type 2 diabetes. We genotyped a set of 71 single nucleotide polymorphisms (SNPs) that capture the most common variation in NPY, PPY, PYY, NPY1R, NPY2R, and NPY5R in 2,800 individuals of recent European ancestry drawn from the near extremes of BMI distribution. Five SNPs located upstream of NPY2R were nominally associated with BMI in men (P values = 0.001-0.009, odds ratios [ORs] 1.27-1.34). No association with BMI was observed in women, and no consistent associations were observed for other genes in this pathway. We attempted to replicate the association with BMI in 2,500 men and tested these SNPs for association with type 2 diabetes in 8,000 samples. We observed association with BMI in men in only one replica- tion sample and saw no association in the combined replication samples (P = 0.154, OR = 1.09). Finally, a 9% haplotype was associated with type 2 diabetes in men (P = 1.73 x 10(-4), OR = 1.36) and not in women. Variation in this pathway likely does not have a major influence on BMI, although small effects cannot be ruled out; NPY2R should be considered a candidate gene for type 2 diabetes in men.
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| 2. |
- Cervin, Camilla, et al.
(författare)
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Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:5, s. 1433-1437
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS-To accomplish this we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type I diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS-LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 X 10(-6)), with similar frequency as with type I diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type I diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 X 10(-14) and P = 1 X 10(-10), respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes-associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 X 10(-7)), compared with control subjects (44.8%) and type I diabetic subjects (43.39%). CONCLUSIONS-LADA shares genetic features with both type I (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.
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| 3. |
- Florez, Jose C., et al.
(författare)
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The Kruppel-like factor 11 (KLF11) Q62R polymorphism is not associated with type 2 diabetes in 8,676 people
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:12, s. 3620-3624
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Tidskriftsartikel (refereegranskat)abstract
- Kruppel-like factor 11 is a pancreatic transcription factor whose activity induces the insulin gene. A common glutamine-to-arginine change at codon 62 (Q62R) in its gene KLF11 has been recently associated with type 2 diabetes in two independent samples. Q62R and two other rare missense variants (A347S and T220M) were also shown to affect the function of KLF11 in vitro, and insulin levels were lower in carriers of the minor allele at Q62R. We therefore examined their impact on common type 2 diabetes in several family-based and case-control samples of northern-European ancestry, totaling 8,676 individuals. We did not detect the rare A347S and T220M variants in our samples. With respect to Q62R, despite > 99% power to detect an association of the previously published magnitude, Q62R was not associated with type 2 diabetes (pooled odds ratio 0.97 [95% Cl 0.88-1.08], P = 0.63). In a subset of normoglycemic individuals, we did not observe significant differences in various insulin traits according to genotype at KLF11 Q62R. We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk.
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| 4. |
- Holmkvist, Johan, et al.
(författare)
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Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:6, s. 1738-1744
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Mutations in the hepatocyte nuclear factor (HNF)-1 alpha, HNF-4 alpha, glucokinase (GCK), and HNF-1 beta genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. RESEARCH DESIGN AND METHODS-We tested 14 previously associated polymorphisms in HNF-1 alpha, HNF-4 alpha, GCK, and HNF-1 beta for association with type 2 diabetes-related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmo Preventive Project (Sweden) with a total follow-up >360,000 years. RESULTS-The polymorphism rs1169288 in HNF-1 alpha strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4a nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0-1.6], P = 0.03; and 1.1 [1.0-1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 alpha was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp (P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period (P = 0.4; SE 0.004 [-0.003-0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8 -1.0], P = 0.1). Polymorphisms in HNF-1 beta (transcription factor 2 [TCF2]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. CONCLUSIONS-In conclusion, genetic variation in both HNF-1 alpha and HNF-4 alpha predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
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| 5. |
- Jonsson, Anna, et al.
(författare)
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A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion.
- 2009
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:10, s. 2409-2413
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Tidskriftsartikel (refereegranskat)abstract
- Objective- Two independent genome wide association studies for type 2 diabetes in Japanese have recently identified common variants in the KCNQ1 gene to be strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI, insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland. Research design and methods- Risk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetes cases and 3,550 controls from Sweden (Malmö Case-Control) and prospectively in 16,061 individuals from the Malmö Preventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross-sectionally in 3,298 non-diabetic subjects from the PPP-Botnia Study and longitudinally in 2,328 non-diabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n=18) and glucose-stimulated insulin secretion (n=19) was measured in human islets from non-diabetic cadaver donors. Results. The C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the case-control (OR 1.23 [1.12-1.34], p=5.6x10(-6)) and the prospective (OR 1.14 [1.06-1.22], p=4.8x10(-4)) studies. Furthermore, the C-allele was associated with decreased insulin secretion (CIR p=0.013; DI p=0.013) in the PPP-Botnia study and in the BPS at baseline (CIR p=3.6x10(-4); DI p=0.0058) and after follow-up (CIR p=0.0018; DI p=0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (p=2.5x10(-6)). Conclusion. A common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians which partially can be explained by an effect on insulin secretion.
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| 6. |
- Lyon, Helen N., et al.
(författare)
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Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:11, s. 3180-3184
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Tidskriftsartikel (refereegranskat)abstract
- The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.
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| 7. |
- Lyssenko, Valeriya, et al.
(författare)
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Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:1, s. 166-174
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Tidskriftsartikel (refereegranskat)abstract
- Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and β-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in β-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG ≥5.6 mmol/l, BMI ≥30 kg/m2, and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG ≥6.1 mmol/l or 2-h glucose ≥7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in β-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes.
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| 8. |
- Saxena, Richa, et al.
(författare)
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Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:10, s. 2890-2895
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Tidskriftsartikel (refereegranskat)abstract
- Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30-1.50], P = 6.74 x 10(-20)). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.
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| 9. |
- Winckler, Wendy, et al.
(författare)
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Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 56:3, s. 685-693
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Tidskriftsartikel (refereegranskat)abstract
- An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value < 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values < 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value < 10(-6) in > 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.
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