Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals

Xi, Bo; Takeuchi, Fumihiko; Chandak, Giriraj Ratan; Kato, Norihiro; Pan, Hongwei; Zhou, Donghao; Pan, Haiyan; Mi, Jie

doi:10.1007/s00125-012-2655-5

Cited by 66 publications

(53 citation statements)

References 21 publications

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“…The MC4R gene encodes a downstream receptor in the leptin signaling pathway contributing to the central melanocortinergic system, which plays a vital role in metabolic regulation and energy intake [33] . The MC4R gene was one of the first and most widely studied loci from which genetic variations were associated with human obesity, and recent reports have shown associations between the rs17782313 SNP and obesity in GWAS as well as type 2 diabetes in a meta-analysis [34,35] . Contrary to the findings in our study, the MC4R-rs17782313 variant was not associated with HAZ after adjusting for age, gender, and BMIZ in children of a Chilean family cohort.…”

Section: Discussionmentioning

confidence: 99%

Individual Genetic Variations Related to Satiety and Appetite Control Increase Risk of Obesity in Preschool-Age Children in the STRONG Kids Program

Wang

Donovan

et al. 2013

Hum Hered

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Background/Aims: The burden of the childhood obesity epidemic is well recognized; nevertheless, the genetic markers and gene-environment interactions associated with the development of common obesity are still unknown. In this study, candidate genes associated to satiety and appetite control pathways with obesity-related traits were tested in Caucasian preschoolers from the STRONG Kids project. Methods: Eight genetic variants in genes related to obesity (BDNF, LEPR, FTO, PCSK1, POMC, TUB, LEP, and MC4R) were genotyped in 128 children from the STRONG Kids project (mean age 39.7 months). Data were analyzed for individual associations and to test for genetic predisposition scores (GPSs) with body mass index (BMI) and anthropometric traits (Z-scores, e.g. height-for-age Z-score, HAZ). Covariates included age, sex, and breastfeeding (BF) duration. Results: Obesity and overweight prevalence was 6.3 and 19.5%, respectively, according to age- and sex-specific BMI percentiles. Individual genetic associations of MC4R and LEPR markers with HAZ were strengthened when BF duration was included as a covariate. Our GPSs show that, as the number of risk alleles increased, the risk of higher BMI and HAZ also increased. Overall, the GPSs assembled were able to explain 2-3% of the variability in BMI and HAZ phenotypes. Conclusion: Genetic associations with common obesity-related phenotypes were found in the STRONG Kids project. GPSs assembled for specific candidate genes were associated with BMI and HAZ phenotypes.

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Section: Discussionmentioning

confidence: 99%

Individual Genetic Variations Related to Satiety and Appetite Control Increase Risk of Obesity in Preschool-Age Children in the STRONG Kids Program

Wang

Donovan

et al. 2013

Hum Hered

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“…However, the same variant near MC4R (rs17782313) showed evidence for association with LDL-C and TC in the Chinese Han population [49]. Another study indicated the significant association of rs17782313 polymorphism near the MC4R gene with type 2 diabetes risk, which was independent of BMI [50]. Several missense mutations in different transmembrane domains have been described.…”

Section: Discussionmentioning

confidence: 95%

“…Genome-wide association studies have shown that variants near the MC4R (rs17782313 and rs12970134) are associated with risk of obesity in Europeans. As obesity is associated with an increased risk of type 2 diabetes, many studies have investigated the association between polymorphisms near the MC4R gene and type 2 diabetes risk across different ethnic populations with inconsistent results [24]. To date, MC4R mutations have proven to be of large individual relevance but of small epidemiological relevance [18].…”

Section: Introductionmentioning

confidence: 98%

“…Therefore, further investigation, involving polymorphic variation and their co-relation with the measures of diabetes in the general population, would help elucidate the role of MC4R with regard to public health. Variants in MC4R gene have shown the strongest associations with diabetes and obesity in different populations [11,14,16,[24][25][26][27][28][29]. Because potential associations between type 2 diabetes mellitus and particular single nucleotide polymorphisms are often population dependent, the objectives of this study were to examine polymorphisms of this gene in a Kashmiri population and to assess their contributions to the development of type 2 diabetes in Kashmir.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphic analysis of MC4R gene in ethnic Kashmiri population with type 2 diabetes

Dar

Rasool

Zargar

et al. 2015

Int J Diabetes Dev Ctries

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Activation of MC4R gene has been shown to inhibit appetite and increase basal metabolic rate while deficiency leads to obesity, hyperphagia, severe hyperinsulinemia, increased linear growth and decrease in metabolic activity, facts that drew strong attention as a possible cause of obesity and diabetes. In this study, we aimed to investigate the sequence variations of MC4R gene in a diabetic population of the Kashmir region and work out association of such variations (if any) with the disease phenotype. No such study has ever been taken up in the Jammu and Kashmir State, despite the existence of a significant population of type 2 diabetic patients. A total of 420 samples (200 with type 2 diabetes and 220 controls) were taken. Genomic DNA was extracted from whole blood samples using standard protocols like salting out and proteinase k. The specific fragments of DNA were amplified and hence then purified. Purified amplicons were subjected to heteroduplex assay to screen for SNPs/mutations. Samples which showed heteroduplex bands were sent for sequencing. The genotype and allele frequencies were evaluated using the χ 2 tests or the Fisher exact tests. We here report one novel heterozygous mutation, i.e. C to T at codon 7 in diabetic patients. The results showed significant differences in the 7C/ T genotype (p < 0.001) and allele (p < 0.0001) frequencies between type 2 diabetes mellitus and control subjects. The fasting blood sugar (FBS), postprandial blood sugar (PPBS) and random blood sugar (RBS) levels were higher with CT genotype in type 2 diabetes mellitus patients but difference was not found statistically significant. C to T substituting arginine with cysteine appeared to associate with type 2 diabetes in the Kashmiri population. Insilico predictions show that substitutions likely have an impact on structure and functional properties of protein making it imperative to understand their functional consequences in relation with diabetes and obesity.

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“…Interestingly, two recent meta-analyses indicated that the FTO and MC4R loci were associated with type 2 diabetes independently of BMI. 23,24 In addition, two other GWASs 8,9 have reported the associations between other identified BMI loci and risk of type 2 diabetes. However, for several other loci, the inclusive findings warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Associations of obesity susceptibility loci with hypertension in Chinese children

Zhao

Shen

et al. 2013

Int J Obes

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CONTEXT: Recent genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) that are associated with body mass index (BMI)/obesity. OBJECTIVE: As obesity is an independent risk factor for hypertension, the objective of the study was to investigate the associations of obesity susceptibility loci with blood pressure (BP)/hypertension in a population of Chinese children. DESIGN, SETTING AND PARTICIPANTS: This was a genotype-phenotype association study. Participants included 3077 Chinese children, aged 6-18 years. Based on the Chinese age-and sex-specific BP standards, 619 hypertensive cases and 2458 controls with normal BP were identified. MAIN OUTCOME MEASURES: BP was measured by auscultation using a standard clinical sphygmomanometer. RESULTS: Of the 11 SNPs, only FTO rs9939609 was significantly associated with systolic BP (SBP; P ¼ 0.034) and three SNPs were significantly associated with diastolic BP (DBP; GNPDA2 rs10938397: P ¼ 0.026; FAIM2 rs7138803: P ¼ 0.015; NPC1 rs1805081: P ¼ 0.031) after adjustment for age, sex and hypertension status. In addition, three SNPs were significantly associated with hypertension risk after adjustment for age and sex (FTO rs9939609: odds ratio (OR) ¼ 1.35, 95% confidence interval (CI) 1.12-1.62, P ¼ 0.001; MC4R rs17782313: OR ¼ 1.22, 95% CI 1.06-1.42, P ¼ 0.007; GNPDA2 rs10938397: OR ¼ 1.17, 95% CI 1.02-1.34, P ¼ 0.021). After additional adjustment for BMI, none remained significant. The genetic risk score (GRS), based on three significant SNPs (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397), showed a positive association with SBP (P ¼ 5.17 Â 10 À 4 ) and risk of hypertension (OR ¼ 1.22, 95% CI 1.12-1.33, P ¼ 6.07 Â 10 À 6 ). Further adjustment for BMI abolished the positive associations (SBP: P ¼ 0.220; DBP: P ¼ 0.305; hypertension: P ¼ 0.052). Only FTO rs9939609 and GRS were statistically associated with hypertension risk in the age-and sex-adjusted model after correction for multiple testing. CONCLUSIONS:The present study demonstrated that FTO rs9939609 and combined SNPs were significantly associated with risk of hypertension, which seems to be dependent on BMI.

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Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals

Cited by 66 publications

References 21 publications

Individual Genetic Variations Related to Satiety and Appetite Control Increase Risk of Obesity in Preschool-Age Children in the STRONG Kids Program

Individual Genetic Variations Related to Satiety and Appetite Control Increase Risk of Obesity in Preschool-Age Children in the STRONG Kids Program

Polymorphic analysis of MC4R gene in ethnic Kashmiri population with type 2 diabetes

Associations of obesity susceptibility loci with hypertension in Chinese children

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