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Li DX, Yin LP, Song YQ, Shao NN, Zhu H, He CS, Sun JJ. KCNQ1 rs2237895 gene polymorphism increases susceptibility to type 2 diabetes mellitus in Asian populations. World J Diabetes 2024; 15:552-564. [PMID: 38591089 PMCID: PMC10999049 DOI: 10.4239/wjd.v15.i3.552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/13/2023] [Accepted: 02/02/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND The association of single nucleotide polymorphism of KCNQ1 gene rs2237895 with type 2 diabetes mellitus (T2DM) is currently controversial. It is unknown whether this association can be gene realized across different populations. AIM To determine the association of KCNQ1 rs2237895 with T2DM and provide reliable evidence for genetic susceptibility to T2DM. METHODS We searched PubMed, Embase, Web of Science, Cochrane Library, Medline, Baidu Academic, China National Knowledge Infrastructure, China Biomedical Liter-ature Database, and Wanfang to investigate the association between KCNQ1 gene rs2237895 and the risk of T2DM up to January 12, 2022. Review Manager 5.4 was used to analyze the association of the KCNQ1 gene rs2237895 polymorphism with T2DM and to evaluate the publication bias of the selected literature. RESULTS Twelve case-control studies (including 11273 cases and 11654 controls) met our inclusion criteria. In the full population, allelic model [odds ratio (OR): 1.19; 95% confidence interval (95%CI): 1.09-1.29; P < 0.0001], recessive model (OR: 1.20; 95%CI: 1.11-1.29; P < 0.0001), dominant model (OR: 1.27. 95%CI: 1.14-1.42; P < 0.0001), and codominant model (OR: 1.36; 95%CI: 1.15-1.60; P = 0.0003) (OR: 1.22; 95%CI: 1.10-1.36; P = 0.0002) indicated that the KCNQ1 gene rs2237895 polymorphism was significantly correlated with susceptibility to T2DM. In stratified analysis, this association was confirmed in Asian populations: allelic model (OR: 1.25; 95%CI: 1.13-1.37; P < 0.0001), recessive model (OR: 1.29; 95%CI: 1.11-1.49; P = 0.0007), dominant model (OR: 1.35; 95%CI: 1.20-1.52; P < 0.0001), codominant model (OR: 1.49; 95%CI: 1.22-1.81; P < 0.0001) (OR: 1.26; 95%CI: 1.16-1.36; P < 0.0001). In non-Asian populations, this association was not significant: Allelic model (OR: 1.06, 95%CI: 0.98-1.14; P = 0.12), recessive model (OR: 1.04; 95%CI: 0.75-1.42; P = 0.83), dominant model (OR: 1.06; 95%CI: 0.98-1.15; P = 0.15), codominant model (OR: 1.08; 95%CI: 0.82-1.42; P = 0.60. OR: 1.15; 95%CI: 0.95-1.39; P = 0.14). CONCLUSION KCNQ1 gene rs2237895 was significantly associated with susceptibility to T2DM in an Asian population. Carriers of the C allele had a higher risk of T2DM. This association was not significant in non-Asian populations.
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Affiliation(s)
- Dong-Xu Li
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Li-Ping Yin
- School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Yu-Qi Song
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Nan-Nan Shao
- School of Clinical Medicine, Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Huan Zhu
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Chen-Sen He
- School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jiang-Jie Sun
- School of Health Care Management, Anhui Medical University, Hefei 230032, Anhui Province, China
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Dai XP, Huang Q, Yin JY, Guo Y, Gong ZC, Lei MX, Jiang TJ, Zhou HH, Liu ZQ. KCNQ1 gene polymorphisms are associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetic patients. Clin Exp Pharmacol Physiol 2013; 39:462-8. [PMID: 22414228 DOI: 10.1111/j.1440-1681.2012.05701.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment. The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA-IR values (P < 0.01) than those with the A allele. Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes. In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.
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Affiliation(s)
- Xing-Ping Dai
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
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Wu C, Gong Y, Yuan J, Gong H, Zou Y, Ge J. Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies. Cardiovasc Diabetol 2012; 11:68. [PMID: 22697793 PMCID: PMC3481354 DOI: 10.1186/1475-2840-11-68] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 05/28/2012] [Indexed: 01/10/2023] Open
Abstract
Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI)-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA), which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.
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Affiliation(s)
- Chaoneng Wu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Tanaka D, Nagashima K, Sasaki M, Yamada C, Funakoshi S, Akitomo K, Takenaka K, Harada K, Koizumi A, Inagaki N. GCKR mutations in Japanese families with clustered type 2 diabetes. Mol Genet Metab 2011; 102:453-60. [PMID: 21236713 DOI: 10.1016/j.ymgme.2010.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 12/15/2010] [Indexed: 12/01/2022]
Abstract
OBJECTIVE The aim was to investigate the genetic background of familial clustering of type 2 diabetes. SUBJECTS AND METHODS We recruited Japanese families with a 3-generation history of diabetes. Genome-wide linkage analysis was performed assuming an autosomal dominant model. Genes in the linkage region were computationally prioritized using Endeavour. We sequenced the candidate genes, and the frequencies of detected nucleotide changes were then examined in normoglycemic controls. RESULTS To exclude known genetic factors, we sequenced 6 maturity onset diabetes of the young (MODY) genes in 10 familial cases. Because we detected a MODY3 mutation HNF1A R583G in one case, we excluded this case from further investigation. Linkage analysis revealed a significant linkage region on 2p25-22 (LOD score=3.47) for 4 families. The 23.6-Mb linkage region contained 106 genes. Those genes were scored by computational prioritization. Eleven genes, i.e., top 10% of 106 genes, were selected and considered primary candidates. Considering their functions, we eliminated 3 well characterized genes and finally sequenced 8 genes. GCKR ranked highly in the computational prioritization. Mutations (minor allele frequency less than 1%) in exons and the promoter of GCKR were found in index cases of the families (3 of 18 alleles) more frequently than in controls (0 of 36 alleles, P=0.033). In one pedigree with 9 affected members, the mutation GCKR g.6859C>G was concordant with affection status. No mutation in other 7 genes that ranked highly in the prioritization was concordant with affection status in families. CONCLUSIONS We propose that GCKR is a susceptibility gene in Japanese families with clustered diabetes. The family based approach seems to be complementary with a large population study.
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Affiliation(s)
- Daisuke Tanaka
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Chen Z, Yin Q, Ma G, Qian Q. KCNQ1 gene polymorphisms are associated with lipid parameters in a Chinese Han population. Cardiovasc Diabetol 2010; 9:35. [PMID: 20701788 PMCID: PMC2925337 DOI: 10.1186/1475-2840-9-35] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Accepted: 08/11/2010] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Four single nucleotide polymorphisms (SNPs) (rs2237892, rs2237895, rs2237897, and rs2283228) in KCNQ1 are reported to be associated with type 2 diabetes mellitus (T2DM), possibly caused by a reduction in insulin secretion and higher fasting glucose, but the results are inconsistent. We investigated whether these 4 genetic markers are associated with serum lipid metabolism in a middle-aged Chinese Han population. METHODS We enrolled 398 consecutive patients, including 180 with premature coronary artery disease (CAD) (male < 55 years, female < 65 years) and 218 controls without documented CAD. All subjects were genotyped for 4 SNPs by using the ligase detection reaction method. Fasting blood sugar (FBS) and plasma concentrations of total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1(apo A1), and apolipoprotein B (apo B) were determined by standard biochemical methods. Main anthropometric and metabolic characteristics are analyzed among 3 genotypes at rs2283228, rs2237895, rs2237897, or rs2237892 in KCNQ1. RESULTS The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, and TT were present in rs2237897 and rs2237892. The minor genotypes CC at rs2283228 and TT at rs2237892 were associated with higher levels of TG (P = 0.007 and 0.026, respectively). Furthermore, subjects with the CC genotype at rs2283228 had lower levels of HDL-C and apo A1 than in the other 2 genotype groups (P = 0.052 and 0.055, respectively). No other associations were detected between these 4 SNPs and FBS or other lipid parameters. CONCLUSIONS Our data suggest that rs2283228 and rs2237892 in KCNQ1 are associated with lipid metabolism in a middle-aged Chinese Han population.
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Affiliation(s)
- Zhong Chen
- Department of Cardiology, the Affiliated ZhongDa Hospital and Institute of Cardiovascular Disease of Southeast University, Nanjing 210009, PR China.
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Chen Z, Zhang X, Ma G, Qian Q, Yao Y. Association study of four variants in KCNQ1 with type 2 diabetes mellitus and premature coronary artery disease in a Chinese population. Mol Biol Rep 2009; 37:207-12. [PMID: 19575309 DOI: 10.1007/s11033-009-9597-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 06/22/2009] [Indexed: 12/20/2022]
Affiliation(s)
- Zhong Chen
- Department of Cardiology, The Affiliated ZhongDa Hospital of Southeast University, Nanjing, People's Republic of China.
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Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, Ohnaka K, Ikegami H, Sugiyama T, Katsuya T, Miyagishi M, Nakashima N, Nawata H, Nakamura J, Kono S, Takayanagi R, Kato N. Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 2009; 58:1690-9. [PMID: 19401414 PMCID: PMC2699880 DOI: 10.2337/db08-1494] [Citation(s) in RCA: 194] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population. RESEARCH DESIGN AND METHODS In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 x 10(-5) for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. RESULTS Four loci-1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 x 10(-5)) and three previously reported-were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10(-19)). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. CONCLUSIONS The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.
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Affiliation(s)
- Fumihiko Takeuchi
- Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan
- Wellcome Trust Sanger Institute, Cambridge, U.K
| | - Masakuni Serizawa
- Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan
| | - Ken Yamamoto
- Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Tomomi Fujisawa
- Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Eitaro Nakashima
- Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Metabolism and Endocrine Internal Medicine, Chubu Rosai Hospital, Nagoya, Japan
| | - Keizo Ohnaka
- Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Ikegami
- Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka, Japan
| | - Takao Sugiyama
- Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Tomohiro Katsuya
- Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Makoto Miyagishi
- Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan
| | - Naoki Nakashima
- Department of Medical Informatics, Kyushu University Hospital, Fukuoka, Japan
| | - Hajime Nawata
- Fukuoka Prefectural University, Fukuoka, Tokyo, Japan
| | - Jiro Nakamura
- Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suminori Kono
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norihiro Kato
- Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan
- Corresponding author: Norihiro Kato,
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Liu Y, Zhou DZ, Zhang D, Chen Z, Zhao T, Zhang Z, Ning M, Hu X, Yang YF, Zhang ZF, Yu L, He L, Xu H. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China. Diabetologia 2009; 52:1315-21. [PMID: 19448982 PMCID: PMC2688614 DOI: 10.1007/s00125-009-1375-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Accepted: 04/03/2009] [Indexed: 11/30/2022]
Abstract
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 x 10(-4)); rs2237895 (OR 1.20, 95% CI 1.09-1.32, p = 1.9 x 10(-4)); and rs2237897 (OR 1.24, 95% CI 1.13-1.36, p = 3.9 x 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 x 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.
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Affiliation(s)
- Y. Liu
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - D. Z. Zhou
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - D. Zhang
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Z. Chen
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - T. Zhao
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Z. Zhang
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - M Ning
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - X. Hu
- Ruijin Hospital, Luwan Branch, Shanghai, People’s Republic of China
| | - Y. F. Yang
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Z. F. Zhang
- Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA USA
| | - L. Yu
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - L. He
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
| | - H. Xu
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, 200031 People’s Republic of China
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
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Lillioja S, Wilton A. Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies. Diabetologia 2009; 52:1061-74. [PMID: 19296077 DOI: 10.1007/s00125-009-1324-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 02/13/2009] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. METHODS We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. RESULTS Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. CONCLUSIONS/INTERPRETATION Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.
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Affiliation(s)
- S Lillioja
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
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Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, Hirota Y, Mori H, Jonsson A, Sato Y, Yamagata K, Hinokio Y, Wang HY, Tanahashi T, Nakamura N, Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H, Kashiwagi A, Takeda J, Maeda E, Shin HD, Cho YM, Park KS, Lee HK, Ng MCY, Ma RCW, So WY, Chan JCN, Lyssenko V, Tuomi T, Nilsson P, Groop L, Kamatani N, Sekine A, Nakamura Y, Yamamoto K, Yoshida T, Tokunaga K, Itakura M, Makino H, Nanjo K, Kadowaki T, Kasuga M. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 2009; 40:1092-7. [PMID: 18711367 DOI: 10.1038/ng.207] [Citation(s) in RCA: 552] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Accepted: 06/06/2008] [Indexed: 11/09/2022]
Abstract
We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
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Affiliation(s)
- Kazuki Yasuda
- Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan
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Yamaguchi Y, Moritani M, Tanahashi T, Osabe D, Nomura K, Fujita Y, Keshavarz P, Kunika K, Nakamura N, Yoshikawa T, Ichiishi E, Shiota H, Yasui N, Inoue H, Itakura M. Lack of association of genetic variation in chromosome region 15q14-22.1 with type 2 diabetes in a Japanese population. BMC MEDICAL GENETICS 2008; 9:22. [PMID: 18366806 PMCID: PMC2324080 DOI: 10.1186/1471-2350-9-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Accepted: 03/27/2008] [Indexed: 11/15/2022]
Abstract
Background Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test. Methods A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed. Results SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07–1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing. Conclusion The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations.
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Affiliation(s)
- Yuka Yamaguchi
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.
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12
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Affiliation(s)
- Hiromasa Yoshie
- Division of Periodontology, Department of Oral Biological Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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13
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Elbers CC, Onland-Moret NC, Franke L, Niehoff AG, van der Schouw YT, Wijmenga C. A strategy to search for common obesity and type 2 diabetes genes. Trends Endocrinol Metab 2007; 18:19-26. [PMID: 17126559 DOI: 10.1016/j.tem.2006.11.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2006] [Revised: 11/01/2006] [Accepted: 11/14/2006] [Indexed: 12/24/2022]
Abstract
Worldwide, the incidence of type 2 diabetes is rising rapidly, mainly because of the increase in the incidence of obesity, which is an important risk factor for this condition. Both obesity and type 2 diabetes are complex genetic traits but they also share some nongenetic risk factors. Hence, it is tempting to speculate that the susceptibility to type 2 diabetes and obesity might also partly be due to shared genes. By comparing all of the published genome scans for type 2 diabetes and obesity, five overlapping chromosomal regions for both diseases (encompassing 612 candidate genes) have been identified. By analysing these five susceptibility loci for type 2 diabetes and obesity, using six freely available bioinformatics tools for disease gene identification, 27 functional candidate genes have been pinpointed that are involved in eating behaviour, metabolism and inflammation. These genes might reveal a molecular link between the two disorders.
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Affiliation(s)
- Clara C Elbers
- Complex Genetics Section, Department of Biomedical Genetics, University Medical Centre Utrecht, PO Box 85060, 3508 AB Utrecht, the Netherlands
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14
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Kunika K, Tanahashi T, Kudo E, Mizusawa N, Ichiishi E, Nakamura N, Yoshikawa T, Yamaoka T, Yasumo H, Tsugawa K, Moritani M, Inoue H, Itakura M. Effect of +36T>C in intron 1 on the glutamine: fructose-6-phosphate amidotransferase 1 gene and its contribution to type 2 diabetes in different populations. J Hum Genet 2006; 51:1100-1109. [PMID: 17024311 DOI: 10.1007/s10038-006-0072-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Accepted: 09/04/2006] [Indexed: 10/24/2022]
Abstract
Glutamine: fructose-6-phosphate amidotransferase 1 (GFPT1) acts as a rate-limiting enzyme in the hexosamine biosynthetic pathway, which is an alternative branch of glucose metabolism. To evaluate GFPT1 as a susceptibility gene to type 2 diabetes, we surveyed the polymorphisms related with the gene function of GFPT1 and assessed its contribution to type 2 diabetes with a case-control association study. Screening of the 5'-flanking and all coding regions of GFPT1 revealed eight polymorphisms, one in the 5'-flanking region, one synonymous polymorphism in exon 8, five in introns and one in 3'-UTR, but no mis-sense or non-sense polymorphism. With in silico simulation, a putative promoter region was apparently predicted between 1 kb upstream and 1 kb downstream of the start codon. In this region, +36T>C polymorphism was located on the GC box sequence in intron 1, and its functional effect on promoter activity was confirmed by luciferase reporter assay, introducing a new functional polymorphism of the GFPT1 gene. To examine its association with type 2 diabetes, we analyzed 2,763 Japanese (1,461 controls and 1,302 cases) and 330 Caucasians (190 controls and 140 cases). One possible association of +36T>C was observed in Caucasians, but no association of polymorphisms including +36T>C in intron 1 or haplotypes was observed in Japanese. Although we could not completely rule out a contribution to specific sub-groups or other populations, genetic variation of GFPT1 is unlikely to have a major role in the susceptibility to type 2 diabetes in Japanese.
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Affiliation(s)
- Kiyoshi Kunika
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Toshihito Tanahashi
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Eiji Kudo
- Department of Human Pathology, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Noriko Mizusawa
- Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Eiichiro Ichiishi
- New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai-city, Miyagi, 980-8579, Japan
| | - Naoto Nakamura
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, 465, Kajii-cho, Hirokoji-Kawaramachi, Kamigyo-ku, Kyoto-city, Kyoto, 602-8566, Japan
| | - Toshikazu Yoshikawa
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, 465, Kajii-cho, Hirokoji-Kawaramachi, Kamigyo-ku, Kyoto-city, Kyoto, 602-8566, Japan
| | - Takashi Yamaoka
- Yamaoka Clinic, 3-13-25, Narashinodai, Funabashi-city, Chiba, 274-0063, Japan
| | - Hiroaki Yasumo
- Core Technology Laboratories, Sankyo Co., Limited, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan
| | - Kazue Tsugawa
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Maki Moritani
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Hiroshi Inoue
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan
| | - Mitsuo Itakura
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan.
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15
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Tanahashi T, Osabe D, Nomura K, Shinohara S, Kato H, Ichiishi E, Nakamura N, Yoshikawa T, Takata Y, Miyamoto T, Shiota H, Keshavarz P, Yamaguchi Y, Kunika K, Moritani M, Inoue H, Itakura M. Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese. Hum Genet 2006; 120:527-42. [PMID: 16955255 DOI: 10.1007/s00439-006-0231-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2006] [Accepted: 07/03/2006] [Indexed: 10/24/2022]
Abstract
Several linkage studies have predicted that human chromosome 20q is closely related to type 2 diabetes, but there is no clear evidence that certain variant(s) or gene(s) have strong effects on the disease within this region. To examine disease susceptibility variant in Japanese, verified SNPs from the databases, with a minor allele frequency larger than 0.15, were selected at 10-kb intervals across a 19.31-Mb region (20q11.21-13.13), which contained 291 genes, including hepatocyte nuclear factor 4alpha (HNF4alpha). As a result, a total of 1,147 SNPs were genotyped with TaqMan assay using 1,818 Japanese samples. By searching for HNF4alpha as a representative disease-susceptible gene, no variants of HNF4alpha were strongly associated with disease. To identify other genetic variant related with disease, we designed an extensive two-stage association study (725 first and 1,093 second test samples). Although SNP1146 (rs220076) was selected as a landmark within the 19.31 Mb region, the magnitude of the nominal P value (P = 0.0023) was rather weak. Subsequently, a haplotype-based association study showed that two common haplotypes were weakly associated with disease. All of these tests resulted in non-significance after adjusting for Bonferroni's correction and the false discovery rate to control for the impact of multiple testing. Contrary to the initial expectations, we could not conclude that certain SNPs had a major effect on this promising locus within the framework presented here. As a way to extend our observations, we emphasize the importance of a subsequent association study including replication and/or meta-analysis in multiple populations.
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Affiliation(s)
- Toshihito Tanahashi
- Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Tokushima, Japan
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16
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Tiffin N, Adie E, Turner F, Brunner HG, van Driel MA, Oti M, Lopez-Bigas N, Ouzounis C, Perez-Iratxeta C, Andrade-Navarro MA, Adeyemo A, Patti ME, Semple CAM, Hide W. Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes. Nucleic Acids Res 2006; 34:3067-81. [PMID: 16757574 PMCID: PMC1475747 DOI: 10.1093/nar/gkl381] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases.
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Affiliation(s)
- Nicki Tiffin
- South African National Bioinformatics Institute, University of the Western Cape, Bellville, 7535, South Africa.
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Einarsdottir E, Mayans S, Ruikka K, Escher SA, Lindgren P, Agren A, Eliasson M, Holmberg D. Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden. Diabetes 2006; 55:1879-83. [PMID: 16731857 DOI: 10.2337/db05-1495] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We present data from a genome-wide scan identifying genetic factors conferring susceptibility to type 2 diabetes. The linkage analysis was based on 59 families from northern Sweden, consisting of a total of 129 cases of type 2 diabetes and 19 individuals with impaired glucose tolerance. Model-free linkage analysis revealed a maximum multipoint logarithm of odds score of 3.19 for D2S2987 at 267.7 cM (P=0.00058), suggesting that a gene conferring susceptibility to type 2 diabetes in the northern Swedish population resides in the 2q37 region. These data replicate, in a European population, previously identified linkage of marker loci in this region to type 2 diabetes in Mexican Americans. In contrast, no evidence in support of association to the previously identified single nucleotide polymorphisms in the calpain-10 gene was observed in a case-control cohort derived from the same population.
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Affiliation(s)
- Elisabet Einarsdottir
- Department of Medical Biosciences, Division of Medical and Clinical Genetics, Umeå University, SE-901 87 Umeå, Sweden
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