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Melanocortin-4 Receptor Gene Variant I103 Is Negatively Associated with Obesity
- Source :
- Am. J. Hum. Genet. 74, 572-581 (2004)
- Publication Year :
- 2004
- Publisher :
- Elsevier BV, 2004.
-
Abstract
- Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P = .017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N = 2,334 and N = 661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P = .03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.
- Subjects :
- medicine.medical_specialty
Linkage disequilibrium
Medizin
Biology
medicine.disease_cause
Polymorphism, Single Nucleotide
Internal medicine
Report
Genetic variation
medicine
Genetics
SNP
Missense mutation
Animals
Humans
Genetics(clinical)
Obesity
Allele
Genetics (clinical)
Mutation
Haplotype
Genetic Variation
Melanocortin 4 receptor
Endocrinology
COS Cells
Receptor, Melanocortin, Type 4
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 74
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....d8da497599750dd98d582f50768ea461
- Full Text :
- https://doi.org/10.1086/382490