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.     

A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population

Aims/hypothesis  Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population. Methods  We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r ² ≥ 0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls. Results  Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p = 0.0009, empirical p = 0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p = 0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele. Conclusions/interpretation  In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. An erratum to this article can be found at     

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.     

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.     

Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk

Aims/hypothesis  Variation in fasting plasma glucose (FPG) within the normal range is a known risk factor for the development of type 2 diabetes. Several reports have shown that genetic variation in the genes for glucokinase (GCK), glucokinase regulatory protein (GCKR), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2) and melatonin receptor type 1B (MTNR1B) is associated with FPG. In this study we examined whether these loci also contribute to type 2 diabetes susceptibility. Methods  A random selection from the Dutch New Hoorn Study was used for replication of the association with FGP (2,361 non-diabetic participants). For the genetic association study we extended the study sample with 2,628 participants with type 2 diabetes. Risk allele counting was used to calculate a four-gene risk allele score for each individual. Results  Variants of the GCK, G6PC2 and MTNR1B genes but not GCKR were associated with FPG (all, p ≤ 0.001; GCKR, p = 0.23). Combining these four genes in a risk allele score resulted in an increase of 0.05 mmol/l (0.04–0.07) per additional risk allele (p = 2 × 10⁻¹³). Furthermore, participants with less than three or more than five risk alleles showed significantly different type 2 diabetes susceptibility compared with the most common group with four risk alleles (OR 0.77 [0.65–0.93], p = 0.005 and OR 2.05 [1.50–2.80], p = 4 × 10⁻⁶ respectively). The age at diagnosis was also significantly associated with the number of risk alleles (p = 0.009). Conclusions  A combined risk allele score for single-nucleotide polymorphisms in four known FPG loci is significantly associated with FPG and HbA_1c in a Dutch population-based sample of non-diabetic participants. Carriers of low or high numbers of risk alleles show significantly different risks for type 2 diabetes compared with the reference group. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study)

Aims/hypothesis Recent genome-wide association studies performed in selected patients and control participants have provided strong support for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study). Methods We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants (the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes, measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs. Results We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06–1.37, p = 0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04–1.25, p = 0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09–1.33, p = 3.9 × 10⁻⁴). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99–1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p = 8.4 × 10⁻⁴). Conclusions/interpretation Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population

Aims/hypothesis  The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations. Methods  The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes. Results  The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p _(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77–0.96, p _[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p _[add] = 0.0169–5.3 × 10⁻⁶), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p _[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p _[add] = 5.8 × 10⁻⁵) in the combined analysis. Conclusions/interpretation  Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Q. Qi and Y. Wu contributed equally to this study.     

胰岛素受体底物-2基因多态性与2型糖尿病的相关性研究

目的 研究北京地区汉族人群中胰岛素受体底物-2（IRS-2）基因密码子1057g/a多态性与2型糖尿病及其中间表型的相关性。方法 选取北京地区的中国汉族患者110例，对照组80例。用聚合酶链反应-限制性内切酶片段长度多态性（PCR-RFLP）的方法检测IRS-2基因密码了1057g/a多态性。结果 （1）IRS-2基因密码子1057g/a多态性的a等位基因频率在糖尿病组和对照组中分别为26.4%和36.3%。（2）糖尿病组aa基因型频率明显低于对照组，分别为5.5%和18.7%(P=0.016),Logistic相关分析表明：aa基因型为2型糖尿病的保护性因素，OR值为0.28(95%CI=0.09-0.91,P=0.03)。（3）不同基因型组间血压、血脂，胰岛素抵抗指数及胰岛β细胞功能指数等均差异无显著性。结论 中国北方地区汉族人群中IRS-2基因密码子1057g/a多态性的aa基因型在2型糖尿病中明显减少。但2型糖尿病各种中间表型自欺欺人持征在不同基因型间均无明显差异。上述结果有待于进一步扩大样本量来加以确认。     

Association of serine racemase gene variants with type 2 diabetes in the Chinese Han population

A genome‐wide association study in the Chinese Han population has identified several novel genetic variants of the serine racemase (SRR) gene in type 2 diabetes. Our purpose was to systematically evaluate the contribution of SRR variants in the Chinese Han population. rs391300 and rs4523957 in SRR were genotyped respectively in the two independent populations. A meta‐analysis was used to estimate the effects of SRR in 21,305 Chinese Han individuals. Associations between single‐nucleotide polymorphisms and diabetes‐related phenotypes were analyzed among 2,615 newly diagnosed type 2 diabetes patients and 5,029 controls. Neither rs391300 nor rs4523957 were associated with type 2 diabetes in populations. Furthermore, meta‐analysis did not confirm an association between type 2 diabetes and SRR. In the controls, rs391300‐A and rs4523957‐G were associated with higher 30‐min plasma glucose in an oral glucose tolerance test. The present study did not confirm that SRR was associated with type 2 diabetes.     

Genetic variants in potassium channels are associated with type 2 diabetes in a Mongolian population

Background: Recent genome‐wide association studies (GWAS) have identified more than 40 common sequence variants associated with type 2 diabetes (T2D). However, the results are not always the same in populations with differing genetic backgrounds. In the present study, we evaluated a hypothesis that a North Asian population living in a geographic area with unusually harsh environmental conditions would develop unique genetic risks. Methods: A population‐based association study was performed with 21 single‐nucleotide polymorphisms (SNPs) in nine genes selected according to the results of GWAS conducted in other populations. The study participants included 393 full‐heritage Mongolian individuals (177 diagnosed with T2D and 216 matched controls). Genotyping was performed by TaqMan methodology. Results: The strongest association was detected with SNPs located within the potassium channel‐coding genes KCNQ1 (highest odds ratio [OR] = 1.92; P = 3.4 × 10^?5) and ABCC8 (OR = 1.79; P = 5 × 10^?4). Genetic variants identified as strongly influencing the risk of T2D in other populations (e.g. KCNJ11 or TCF7L2) did not show significant association in Mongolia. Conclusions: The strongest T2D risk‐associated SNPs in Mongolians are located within two of three tested potassium channel‐coding genes. Accumulated variations in these genes may be related to the exposure to harsh environmental conditions.     

脂联素基因单倍型与汉族人群2型糖尿病的相关性研究

目的探讨脂联素基因多态性及其单倍型与2型糖尿病（T2DM）的相关性。方法入选T2DM患者202例,糖尿病家族史阴性的非糖尿病个体（NDM）143例。采用聚合酶链反应限制性内切酶片段长度多态性（PCR—RFLP）方法对脂联素基因SNP-11391、SNP-11377、SNP-4522、SNP＋45和SNP＋331位点进行基因分型,并构建单倍型。评估以上5个多态性位点及构建的单倍型与T2DM的相关性。结果T2DM组和NDM组脂联素基因SNP-11391、SNP—11377、SNP～4522、SNP＋45和SNP＋331基因型和等位基因频率差异无统计学意义。T2DM组和NDM组SNP—11377C—SNP-4522T单倍型频率差异有统计学意义（P〈0．05）。结论脂联素基因SNP-11377C—SNP-4522T单倍型与T2DM相关,且可能增加患T2DM风险（OR=1．60,95％CI：1．09～2．35）。     

中国汉族人群2型糖尿病与脂联素基因SNP-11377位点相关性的Meta分析

目的评价脂联素基因SNP-11377位点与T2DM的相关性。方法采用Meta分析评估SNP-11377位点与T2DM的相关性。异质性检验后采用M-H固定效应模型合并比值比(OR)值,并进行发表偏倚检验。结果 (1)共纳入10篇文献,其中病例组2831例、对照组3035例。(2)异质性检验显示,脂联素基因SNP-11377在各研究间是同质(I2=11.2%,P>0.05),各研究之间不存在异质性。(3)M-H固定效应模型进行数据合并,结果显示合并OR为1.09(95%CI为1.00～1.18,P=0.05)。(4)Begg和Egger偏倚分析均显示无明显发表偏倚。结论脂联素基因SNP-11377G等位基因可能与中国汉族人群T2DM的发病风险相关。     

Type 1 innate lymphoid cells are associated with type 2 diabetes

AimType 1 innate lymphoid cells (ILC1s) play a major role in regulating systemic inflammatory diseases. However, the relationship between ILC1s and type 2 diabetes (T2D) remains unclear. Thus, the present study investigated the relationship between ILC1s and glucose homoeostasis in humans.MethodsA total of 37 newly diagnosed T2D patients and 32 subjects with normal glucose tolerance (NGT), matched for age and body mass index (BMI), were enrolled in the study. Flow cytometric analysis of ILC1s derived from peripheral blood mononuclear cells (PBMCs) and omental adipose tissue was performed.ResultsT2D patients displayed greater numbers and frequencies of circulating and adipose tissue ILC1s (P < 0.05) compared with NGT subjects, and the two types of ILC1s correlated positively with each other. Circulating ILC1s were positively associated with glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG), homoeostasis model assessment for insulin resistance (HOMA-IR), adipose tissue insulin resistance index (Adipo-IR) and serum free fatty acids (FFAs). A logistic regression model revealed that patients with higher ILC1 levels exhibited a 13.481-fold greater risk of developing T2D.ConclusionThis study is the first to provide evidence that ILC1 abnormalities are involved in the development of diabetes. The data also suggest a potential role of ILC1s as therapeutic indicators in the treatment of T2D.     

Gender-dependent associations of CDKN2A/2B, KCNJ11, POLI, SLC30A8, and TCF7L2 variants with type 2 diabetes in (North African) Tunisian Arabs

We investigated the impact of gender on T2DM association with confirmed susceptibility loci. CDKN2A/2B rs10811661, KCNJ11 rs5219, and TCF7L2 rs7903146 were associated with T2DM in females, while POLI rs488846 was associated with T2DM among males; the association of SLC30A8 rs13266634 and TCF7L2 rs4506565, rs12243326, and rs12255372 with T2DM was gender-independent.     

脂联素基因多态性与2型糖尿病的相关性

脂联素是新近发现由脂肪组织特异性分泌的蛋白质,由人类脂联素基因(APM-1/ACDC/ADIPOQ)编码.目前许多研究表明脂联素基因多态性与2型糖尿病和胰岛素抵抗相关,且受遗传背景和环境因素影响,不同群体研究结果之间存在差异.同时,脂联素基因多态性与2型糖尿病的治疗和干预也存在相关性.     

Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes

Background

Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D.

Methods

Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean ± SD = 57 ± 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors.

Results

During the mean follow-up period of 8.5 ± 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08–1.65); P = 6.7 × 10⁻³ under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01–1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65–1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12–1.39); P = 4.8 × 10⁻⁵). The adjusted cancer risk was 2.41 (95% C.I. 1.23–4.69) for patients with four risk alleles comparing to patients without risk allele.

Conclusions

T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes.

Impact

Our findings provide novel insights into the pathogenesis of cancer in diabetes.