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Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children

Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fif...

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Autores principales: Muller, Yunhua L., Thearle, Marie S., Piaggi, Paolo, Hanson, Robert L., Hoffman, Duncan, Gene, Brittany, Mahkee, Darin, Huang, Ke, Kobes, Sayuko, Votruba, Susanne, Knowler, William C., Bogardus, Clifton, Baier, Leslie J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185108/
https://www.ncbi.nlm.nih.gov/pubmed/25103139
http://dx.doi.org/10.1007/s00439-014-1477-6
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author Muller, Yunhua L.
Thearle, Marie S.
Piaggi, Paolo
Hanson, Robert L.
Hoffman, Duncan
Gene, Brittany
Mahkee, Darin
Huang, Ke
Kobes, Sayuko
Votruba, Susanne
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
author_facet Muller, Yunhua L.
Thearle, Marie S.
Piaggi, Paolo
Hanson, Robert L.
Hoffman, Duncan
Gene, Brittany
Mahkee, Darin
Huang, Ke
Kobes, Sayuko
Votruba, Susanne
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
author_sort Muller, Yunhua L.
collection PubMed
description Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (β = 0.68 kg/m(2) per risk allele, p = 5 × 10(−5); β = 0.58 kg/m(2), p = 0.002, respectively) and BMI z score in childhood (β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (β = 0.89 kg/m(2), p = 5.5 × 10(−7)), and was also associated with childhood BMI z score (β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (β = 0.61 kg/m(2), p = 0.05) and childhood BMI z score (β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (β = 2.2 %, p = 0.002), increased food intake (β = 676 kcal/day, p = 0.007) and decreased energy expenditure (β = −53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-014-1477-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-41851082014-10-08 Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children Muller, Yunhua L. Thearle, Marie S. Piaggi, Paolo Hanson, Robert L. Hoffman, Duncan Gene, Brittany Mahkee, Darin Huang, Ke Kobes, Sayuko Votruba, Susanne Knowler, William C. Bogardus, Clifton Baier, Leslie J. Hum Genet Original Investigation Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (β = 0.68 kg/m(2) per risk allele, p = 5 × 10(−5); β = 0.58 kg/m(2), p = 0.002, respectively) and BMI z score in childhood (β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (β = 0.89 kg/m(2), p = 5.5 × 10(−7)), and was also associated with childhood BMI z score (β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (β = 0.61 kg/m(2), p = 0.05) and childhood BMI z score (β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (β = 2.2 %, p = 0.002), increased food intake (β = 676 kcal/day, p = 0.007) and decreased energy expenditure (β = −53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-014-1477-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2014-08-08 2014 /pmc/articles/PMC4185108/ /pubmed/25103139 http://dx.doi.org/10.1007/s00439-014-1477-6 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Investigation
Muller, Yunhua L.
Thearle, Marie S.
Piaggi, Paolo
Hanson, Robert L.
Hoffman, Duncan
Gene, Brittany
Mahkee, Darin
Huang, Ke
Kobes, Sayuko
Votruba, Susanne
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title_full Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title_fullStr Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title_full_unstemmed Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title_short Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children
title_sort common genetic variation in and near the melanocortin 4 receptor gene (mc4r) is associated with body mass index in american indian adults and children
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185108/
https://www.ncbi.nlm.nih.gov/pubmed/25103139
http://dx.doi.org/10.1007/s00439-014-1477-6
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