Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations

Aims/hypothesis Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case–control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. Methods Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case–control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. Results In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75–0.96, p = 0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82–0.93, p = 4.5 × 10⁻⁵). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86–0.92; p = 4.9 × 10⁻¹¹). Conclusions/interpretation In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes. An erratum to this article can be found at     

Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China

Aims/hypothesis  Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron 15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China. Methods  Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal controls using the ligase detection reaction method. Results  We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms (SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08–1.31, p = 3.0 × 10⁻⁴); rs2237895 (OR 1.20, 95% CI 1.09–1.32, p = 1.9 × 10⁻⁴); and rs2237897 (OR 1.24, 95% CI 1.13–1.36, p = 3.9 × 10⁻⁵). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and the normal control group (p = 2.6 × 10⁻⁵). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs rs2237892 and rs2237897 were associated with HbA_1c. Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI and waist circumferences. Conclusions/interpretation  Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Y. Liu and D. Z. Zhou contributed equally to this study.     

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians

Aims and hypothesis  Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune. Methods  We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India. Results  We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13–1.40; p = 3 × 10⁻⁵). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01–0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09–0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06–1.37; p = 4.0 × 10⁻³), and also for waist circumference and other anthropometric variables. Conclusions  Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. C. S. Janipalli, S. Bhaskar, S. R. Kulkarni and R. M. Freathy contributed equally to this study.     

Common variants in MODY genes increase the risk of gestational diabetes mellitus

Aims/hypothesis Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM.Subjects and methods We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women).Results The A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM.Conclusions/interpretation The −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.Electronic Supplementary Material Supplementary material is available for this article at An erratum to this article can be found at     

Strong association of common variants in the <Emphasis Type="Italic">CDKN2A/CDKN2B</Emphasis> region with type 2 diabetes in French Europids

Aims/hypothesis Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus. Methods We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort. Results We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs (; OR 1.43 [95% CI 1.24–1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00–1.24]) in the present study. We also obtained several additional nominal association signals (p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04). Conclusions/interpretation Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. K. Duesing and G. Fatemifar contributed equally to this work.     

Variants in the 5′ region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects

Aims/hypothesis The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity.Methods The coding region of NPY2R was analysed for mutations in 48 obese Danish white subjects and two silent substitutions were identified: SNPs 1 and 2 (rs1047214 and rs2880415). SNP1 and additional reported variants (SNPs 3–6 [rs11099992, rs12649641, rs2342676 and rs6857530]) located in the 5′ region were examined in 5,971 Danish white subjects. Since SNPs 1–2 and 4–6, respectively, were in tight linkage disequilibrium large-scale analyses of genetic epidemiology were restricted to SNPs 1, 3 and 4.Results Homozygous carriers of the minor A allele of SNP4 were more common among obese subjects; the AA frequency was 15.9 (95% CI 15.2–16.6) among 4,837 non-obese subjects (BMI <30 kg/m²) vs 19.0 (95% CI 17.2–20.8) among 960 obese subjects (BMI ≥30 kg/m²), odds ratio 1.24 (95% CI 1.04–1.48), p=0.02. SNPs 1–3 were not associated with obesity.Conclusions/interpretation Common variants rs12649641, rs2342676 and rs6857530 in the 5′ region of NPY2R are associated with obesity in Danish white subjects.     

Evaluating the association of common LMNA variants with type 2 diabetes and quantitative metabolic phenotypes in French Europids

Aims/hypothesis In the present study, we sought to examine the evidence that LMNA variants are associated with type 2 diabetes and quantitative metabolic traits in French Europid individuals. Methods We genotyped 24 single nucleotide polymorphisms (SNPs) spanning the LMNA gene in 3,093 case–control participants. The association between LMNA SNPs and quantitative metabolic traits was also examined in the 1,674 normoglycaemic adults who made up the control cohort. Results SNP rs505058, a synonymous SNP (D446D) in exon 7, showed nominal evidence of association with type 2 diabetes [p = 0.003, odds ratio (OR) 1.30 (95% CI 1.09–1.56)] in French Europids. A meta-analysis of available rs505058 genotype data from 7,819 participants provided support for a modest association of rs505058 with type 2 diabetes [p = 0.003, OR 1.19 (95% CI 1.06–1.35)]. We found no evidence (p = 0.91) that the tag SNP rs4641 is associated with type 2 diabetes. However, a meta-analysis of all available rs4641 genotype data in a total of 15,591 participants produced borderline evidence of association [p = 0.054, OR 1.05 (95% CI 1.00–1.11)]. SNP rs6669212, in the 3′ untranslated region of LMNA, exhibited suggestive associations with WHR (p = 0.013), fasting serum levels of total cholesterol (p = 0.023) and triacylglycerol (p = 0.015). We emphasise that these quantitative trait associations are not corrected for multiple testing. Conclusions/interpretation The available data do not support a major effect of common LMNA variation on type 2 diabetes susceptibility in northern Europeans. Further large-scale studies are required to conclusively establish the extent to which LMNA variants have an impact on quantitative metabolic traits. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

Aims/hypothesis  New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants and gestational diabetes mellitus (GDM). Methods  The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A−CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls. Results  Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34–1.79, p = 4.17 × 10⁻⁹) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29–1.72, p = 1.05 × 10⁻⁷) in the CDKN2A−CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09–1.49, p = 0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01–1.38, p = 0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07–1.43, p = 0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03–2.43, p = 0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A–CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM. Conclusions/interpretation  Some of the type 2 diabetes-associated genetic variants that were discovered in the recent GWA studies are also associated with GDM in Koreans. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Y. M. Cho and T. H. Kim contributed equally to this study.     

Gastroduodenal Crohn's Disease Is Associated With <Emphasis Type="Italic">NOD2/CARD15</Emphasis>Gene Polymorphisms,Particularly <Emphasis Type="Italic">L1007P</Emphasis>Homozygosity

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15gene polymorphisms. The aim of this study was to assess the association between NOD2polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702Wand the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007Phomozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6–7.3) and to be homozygous for L1007P(11% vs. 1%; OR 5.2; 95% CI 2.5–9.4). G908Rheterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1–2.9) and smoking habits (OR 2.4; 95% CI 1.2–3.8), whereas L1007Phomozygosity was associated with GDCD (OR 5.8; 95% CI 2.6–10.8). L1007Pvariation was associated with younger age at diagnosis as well. There was no specific association between R702Whomo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15gene variants, particularly L1007Phomozygosity. There is evidence of specific variant-phenotype associations. G908Rheterozygosity is associated with ileal involvement and smoking, whereas L1007Phomozygosity is strongly associated with GDCD and younger age at diagnosis.     

Polymorphisms in <Emphasis Type="Italic">AHI1</Emphasis> are not associated with type 2 diabetes or related phenotypes in Danes: non-replication of a genome-wide association result

Aims/hypothesis A genome-wide association study recently identified an association between common variants, rs1535435 and rs9494266, in the AHI1 gene and type 2 diabetes. The aim of the present study was to investigate the putative association between these polymorphisms and type 2 diabetes or type 2 diabetes-related metabolic traits in Danish individuals. Methods The previously associated polymorphisms were genotyped in the population-based Inter99 cohort (n = 6162), the Danish ADDITION study (n = 8428), a population-based sample of young healthy participants (n = 377) and in additional type 2 diabetes (n = 2107) and glucose-tolerant participants (n = 483) using Taqman allelic discrimination. The case–control study involved 4,104 type 2 diabetic patients and 5,050 glucose-tolerant control participants. Type 2 diabetes-related traits were investigated in 17,521 individuals. Results rs1535435 and rs9494266 were not associated with type 2 diabetes. Odds ratios (OR) were OR_add 1.0 (95% C.I. 0.9–1.2; p _add = 0.7) and OR_add 1.1 (0.9–1.2; p _add = 0.4), respectively, a finding supported by meta-analyses: OR_add 1.0 (0.9–1.1; p _add = 0.6) and OR_add 1.0 (0.9–1.1; p _add = 0.6), respectively. Neither rs1535435 nor rs9494266 were consistently associated with any of the tested type 2 diabetes-related metabolic traits. Conclusions/interpretation Data from large samples of Danish individuals do not support a role for AHI1 rs1535435 nor rs9494266 as major type 2 diabetes variants. This study highlights the importance of independent and well-powered replication studies of the recent genome-wide association scans before a locus is robustly validated as being associated with type 2 diabetes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

The independent association of renal dysfunction and arrhythmias in critically ill patients

STUDY OBJECTIVES: The purpose of this study was to quantify the impact of baseline renal dysfunction on incidence and occurrence of cardiac arrhythmias in the coronary ICU. BACKGROUND: Renal dysfunction is an established predictor of all-cause mortality in the ICU setting. We set out to evaluate the independent contributory effect of renal dysfunction to arrhythmias and mortality in this population. DESIGN AND SETTING: We analyzed a prospective coronary care unit registry of 12,648 admissions by 9,557 patients over 8 years at a single, tertiary center. An admission serum creatinine level was available for 9,544 patients. Those patients not receiving long-term dialysis were classified into quartiles of corrected creatinine clearance with cutpoints of 46.2 mL/min/72 kg (group 1), 63.1 mL/min/72 kg, and 81.5 mL/min/72 kg. Dialysis patients (n = 527) were considered as a fifth comparison group (group 5). MEASUREMENTS AND RESULTS: Baseline characteristics including older age, African-American race, diabetes, hypertension, history of previous coronary disease, and heart failure were incrementally more common with increasing renal dysfunction strata. There were graded, independent increased risks for accelerated idioventricular rhythm (relative risk [RR], 2.43; 95% confidence interval [CI], 1.40 to 4.20; p = 0.002), sustained ventricular tachycardia (RR, 2.07; 95% CI, 1.02 to 4.22; p = 0.04), ventricular fibrillation (RR, 2.42; 95% CI, 1.13 to 5.15; p = 0.02), and complete heart block (RR, 3.64; 95% CI, 1.77 to 7.48; p = 0.0004, group 5 vs group 1). CONCLUSIONS: We conclude that baseline renal function is a powerful, independent predictor of cardiac arrhythmias in the coronary ICU population.     

Paraoxonase (PON)1 192R Allele Carriage is Associated with Reduced Risk of Inflammatory Bowel Disease

The paraoxonase (PON) genes family maps to chromosome 7q21-q22, within a loci that also showed evidence of susceptibility genes for both Crohn’s disease (CD) and ulcerative colitis (UC). In this case-control study we investigated the possible relationship between PON1 and PON2 polymorphisms and the risk of inflammatory bowel disease (IBD). PON1 192Q/R, PON1 55L/M, and PON2 311S/C polymorphisms were investigated by RFLP analysis in DNA samples from 224 patients with CD, 58 patients with UC, and 311 healthy controls. The PON1 192R allele was significantly less common among IBD Ashkenazi patients (allelic OR = 0.61, P = 0.004, 95% CI = 0.44–0.85). In agreement with the individual SNP analysis, Ashkenazi IBD patients had a higher frequency of haplotype PON1 192Q/PON1 55L/PON2 311S (26.3% vs 17.3%; P=0.003) and a lower frequency of haplotype PON1 192R/PON1 55L/PON2 311S (18.9% vs 27.7%; P=0.008). Our results suggest that in this Ashkenazi Jewish population, carriage of PON1 R192 allele may confer protection against the development of IBD.     

Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations

AIMS/HYPOTHESIS: Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. METHODS: Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. RESULTS: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p=0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p=4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p=4.9 x 10(-11)). CONCLUSIONS/INTERPRETATION: In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.     

Variations in the <Emphasis Type="Italic">HHEX</Emphasis> gene are associated with increased risk of type 2 diabetes in the Japanese population

Aims/hypothesis Recently, several groups have carried out whole-genome association studies in European and European-origin populations and found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population. Methods Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 ± 9.5 years (mean±SD), BMI 24.3 ± 3.9 kg/m²) and 864 Japanese control individuals (386 men and 478 women; age 69.5 ± 6.8 years, BMI 23.8 ± 3.7 kg/m²). Results The SNPs rs5015480 [odds ratio (OR) = 1.46 (95% CI 1.20–1.77), p = 2.0 × 10⁻⁴], rs7923837 [OR = 1.40 (95% CI 1.17–1.68), p = 2.0 × 10⁻⁴] and rs1111875 [OR = 1.30 (95% CI 1.11–1.52), p = 0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR = 1.22 (95% CI 1.03–1.46), p = 0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively). Conclusions/interpretation HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. M. Horikoshi and K. Hara contributed equally to this study.     

Association study of genetic polymorphisms of SLC2A10 gene and type 2 diabetes in the Taiwanese population

Aims/hypothesis The gene encoding solute carrier family 2, facilitated glucose transporter, member 10 (SLC2A10, previously known as glucose transporter 10 [GLUT10]) is a promising candidate gene for type 2 diabetes since it is highly expressed in liver and pancreas and is located on human chromosome region 20q12–q13.1, a region previously shown to harbour type 2 diabetes susceptibility genes. We investigated whether the SLC2A10 gene could be a type 2 diabetes susceptibility gene in the Taiwanese population.Subjects and methods Sequencing of SLC2A10 gene from 48 diabetic subjects detected short tandem repeat polymorphisms in the promoter region, but did not detect any other sequence variants or new single-nucleotide polymorphisms (SNPs) other than those already in the SNPper database () (30 June 2005).Results Using these genetic polymorphisms, we divided the SLC2A10 gene into four distinct linkage disequilibrium blocks and performed a case-control association study in a group of type 2 diabetes subjects (n=375) and normoglycaemic individuals (n=377). The HapD (A-G-T-C) haplotype in block 3, a rare haplotype, which consisted of four SNPs (rs3092412, rs2235491, rs2425904 and rs1059217), was modestly associated with type 2 diabetes with a haplotype score of −2.95567 (p=0.012 with the haplotype-specific test).Conclusions/interpretation Our results suggest that SLC2A10 genetic variations do not appear to be major determinants for type 2 diabetes susceptibility in the Taiwanese population.W. H. Lin and L. M. Chuang contributed equally to this work.     

Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes

Aims/hypothesis Raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with a poor cardiac outcome in non-diabetic populations. Elevated NT-proBNP predicts excess morbidity and mortality in diabetic patients with an elevated urinary albumin excretion rate. This study investigated the prognostic value of NT-proBNP in a cohort of type 2 diabetic patients. Subjects, materials and methods In a prospective observational follow-up study, 315 type 2 diabetic patients with normoalbuminuria (n=188), microalbuminuria (n=80) and macroalbuminuria (n=47) at baseline were followed for a median (range) of 15.5 (0.2–17.0) years. Plasma NT-proBNP concentrations were determined by immunoassay at baseline. Endpoints were overall and cardiovascular mortality. Results Of the patients, 162 died (51%), 119 of them (74%) due to cardiovascular causes. All-cause mortality was increased in patients with NT-proBNP in the second and third tertiles (hazard ratios [95% CI] compared with the first tertile, 1.70 [1.08–2.67] and 5.19 [3.43–7.88], p<0.001). These associations persisted after adjustment for urinary albumin excretion rate, glomerular filtration rate and conventional cardiovascular risk factors (covariate adjusted hazard ratios 1.46 [0.91–2.33] and 2.54 [1.56–4.14], p<0.001). This increased mortality was attributable to more cardiovascular deaths in the second and third NT-proBNP tertile (unadjusted hazard ratios 1.63 [0.96–2.77] and 4.88 [3.01–7.91], p<0.001; covariate adjusted 1.37 [0.79–2.37] and 2.26 [1.27–4.02], p=0.01). When patients with normo-, micro- and macroalbuminuria were analysed separately, NT-proBNP levels above the median (62 ng/l) were consistently associated with increased overall and cardiovascular mortality in all three groups (p<0.001). Conclusions/interpretation In patients with type 2 diabetes, elevated circulating NT-proBNP is a strong predictor of the excess overall and cardiovascular mortality, this predictor status being independent of urinary albumin excretion rate and conventional cardiovascular risk factors.     

Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

Aims/hypothesis Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes. Materials and methods We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 −866G→A) and calpain 10 (CAPN10 SNP43 and SNP44). Results The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02−1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05−1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7, 9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women. Conclusions/interpretation The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women. Electronic supplementary material Supplementary material is available for this article at and accessible for authorised users