Implication of Genetic Variants NearNEGR1,SEC16B,TMEM18,ETV5/DGKG,GNPDA2,LIN7C/BDNF,MTCH2,BCDIN3D/FAIM2,SH2B1,FTO,MC4R, andKCTD15with Obesity and Type 2 Diabetes in 7705 Chinese

Ng, Maggie; Tam, Claudia H.T.; So, Wing Yee; Ho, Janice; Chan, Alfred W H; Lee, Heung Man; Wang, Ying; Lam, Vincent K. L.; Chan, Juliana C.N.; Ronald, C.

doi:10.1210/jc.2009-2077

Cited by 121 publications

(88 citation statements)

References 30 publications

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“…We did not detect associations with variants at NEGR1, SH2B1 and KCTD15 that have previously replicated in Han Chinese populations. 11,12,14 These SNPs tended to be those for which we had lower power in our study. Furthermore, the common form of obesity is considered a multi-factorial condition, involving complex interplay of genes and environment and, therefore, population-specific gene-environment interactions 19 may exist, attenuating true genetic signals.…”

Section: Discussionmentioning

confidence: 72%

“…We also detected associations of Z-BMI with SNPs at the GNPDA2, MC4R, SEC16B, TMEM18, ETV5 and the BDNF loci, which is in line with previous replication attempts in East-Asians. [11][12][13][14] Replication of index SNPs at QPCTL/GIPR, MAP2K5/SKOR1 and TNKS/MSRA represents novel findings in Asians. In addition, three SNPs showed significant associations in subgroups, including rs13078807 at the CADM2 (Asian-Indians only); rs1555543 at PTBP2 (Chinese type 2 diabetics only); and rs7138803 at FAIM2 (Chinese children and Chinese type 2 diabetics) loci.…”

Section: Discussionmentioning

confidence: 99%

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Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

et al. 2011

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Objective: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. Methods: We utilised five GWAS (N ¼ 10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. Results: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 Â 10 À7 -7.95 Â 10 À7 ). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 Â 10 À4 -1.44 Â 10 À2 ). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (Pvalue p0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value ¼ 0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. Conclusion: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

et al. 2011

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“…All the cases were unrelated type 2 diabetic patients meeting the 1999 WHO criteria (www.who.int/entity/ diabetes/currentpublications/en); all the controls from Shanghai were defined as having normal glucose tolerance after standard 75 g oral glucose tolerance tests, and those from Hong Kong with fasting plasma glucose less than 6.1 mmol/ l. Detailed information has been described elsewhere [8,9]. Normal weight, overweight and obesity were defined as BMI <25, 25≤ BMI <30 and BMI ≥30 kg/m 2 , respectively.…”

Section: Methodsmentioning

confidence: 99%

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes

Wang¹,

Hu³

et al. 2012

Diabetologia

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Aims/hypothesis There is evidence of overlap between susceptibility loci for type 2 diabetes and obesity. The aim of this study is to explore the association between the established type 2 diabetes locus KCNQ1 and obesity in Han Chinese. Methods We recruited 6,667 and 6,606 diabetic case-control samples from Shanghai and Hong Kong, respectively. Of the samples, 7.5% and 6.3% were excluded because of genotyping failure or data missing in the association analyses of rs2237892 and rs2237895 with obesity/BMI, respectively. Results We found that rs2237892 was associated with lower BMI and lower incidence of overweight/obesity in diabetic patients from Hong Kong (BMI, β0−0.0060 per diabetes risk C allele for log 10 BMI [95% CI −0.0088, −0.0032; However, neither an association with the risk of being overweight or obese nor associations with quantitive traits were detected for rs2237892 or rs2237895 in controls. Conclusion Our findings indicate that KCNQ1 is associated with obesity in Chinese patients with type 2 diabetes.

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“…There was a trend toward an association to BMI but this did not reach statistical significance. 13 In a Japanese adult cohort of 1129 obese and 1736 normal weight controls, the TMEM18-associated SNPs, rs2867125, rs6548238, rs4854344 and rs7561317, were all observed to be associated to obesity. 14 The near-TMEM18 SNP rs7561317 was also tested for association to phenotypes of metabolic disorder in this study, owing to its previous association to type II diabetes.…”

Section: Introductionmentioning

confidence: 97%

Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

et al. 2011

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Genome-wide association studies have shown a strong association of single-nucleotide polymorphisms (SNPs) in the near vicinity of the TMEM18 gene. The effects of the TMEM18-associated variants are more readily observed in children. TMEM18 encodes a 3TM protein, which locates to the nuclear membrane. The functional context of TMEM18 and the effects of its associated variants are as of yet undetermined. To further explore the effects of near-TMEM18 variants, we have genotyped two TMEM18-associated SNPs, rs6548238 and rs4854344, in a cohort of 2352 Greek children (Healthy Growth Study). Included in this study are data on anthropomorphic traits body weight, BMI z-score and waist circumference. Also included are dietary energy and macronutrient intake as measured via 24-h recall interviews. Major alleles of rs6548238 and rs4854344 were significantly associated with an increased risk of obesity (odds ratio¼1.489 (1.161-1.910) and 1.494 (1.165-1.917), respectively), and positively correlated to body weight (P¼0.017, P¼0.010) and waist circumference (P¼0.003, P¼0.003). An association to energy and macronutrient intake was not observed in this cohort. We also correlated food intake and body weight in a food choice model in rats to Tmem18 expression in central regions involved in feeding behavior. We observed a strong positive correlation between TMEM18 expression and body weight in the prefrontal cortex (PFC) (r¼0.5694, P¼0.0003) indicating a potential role for TMEM18 in higher functions related to feeding involving the PFC. Keywords: obesity; TMEM18; FTO INTRODUCTION Genome-wide association (GWA) studies have led to the identification of several loci in the human genome containing genetic variants conferring an increased risk of developing overweight and obesity. 1-2 One such gene to be associated with a higher BMI, the fat mass and obesity-associated gene (FTO) was identified by Frayling et al in 2007. 3 FTO has since been shown to be involved in regulation of feeding behavior via homeostatic hypothalamic pathways, 4-6 and its obesityassociated variants to confer gain-of-function by increasing gene transcription. 7 The most recent meta analyses of GWA studies on obesity, which included genetic information from 249 796 individuals, identified variants at a total of 32 genetic loci affecting the development of BMI. 2 Single-nucleotide polymorphisms (SNPs) in the FTO gene, followed by SNPs in the proximity of TMEM18 and MC4R, have consistently given the strongest associations to obesity in large-scale GWA studies. TMEM18-associated SNPs were first found to be associated with a higher BMI in 2009 by the GIANT consortium, 1 and this was confirmed in the same year by an independent group. 8 Results from child cohorts have shown stronger effects of near-TMEM18 SNPs to obesity, compared with adults. Zhao et al 9 found near-TMEM18 SNPs to confer the strongest effect on pediatric BMI out of 25 studied obesity-associated variants in a cohort of 6078

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Implication of Genetic Variants NearNEGR1,SEC16B,TMEM18,ETV5/DGKG,GNPDA2,LIN7C/BDNF,MTCH2,BCDIN3D/FAIM2,SH2B1,FTO,MC4R, andKCTD15with Obesity and Type 2 Diabetes in 7705 Chinese

Abstract: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Cited by 121 publications

References 30 publications

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes

Association of TMEM18 variants with BMI and waist circumference in children and correlation of mRNA expression in the PFC with body weight in rats

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