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MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation

To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensi...

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Autores principales: Bian, Li, Traurig, Michael, Hanson, Robert L., Marinelarena, Alejandra, Kobes, Sayuko, Muller, Yunhua L., Malhotra, Alka, Huang, Ke, Perez, Jessica, Gale, Alex, Knowler, William C., Bogardus, Clifton, Baier, Leslie J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792696/
https://www.ncbi.nlm.nih.gov/pubmed/23825110
http://dx.doi.org/10.1093/hmg/ddt291
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author Bian, Li
Traurig, Michael
Hanson, Robert L.
Marinelarena, Alejandra
Kobes, Sayuko
Muller, Yunhua L.
Malhotra, Alka
Huang, Ke
Perez, Jessica
Gale, Alex
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
author_facet Bian, Li
Traurig, Michael
Hanson, Robert L.
Marinelarena, Alejandra
Kobes, Sayuko
Muller, Yunhua L.
Malhotra, Alka
Huang, Ke
Perez, Jessica
Gale, Alex
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
author_sort Bian, Li
collection PubMed
description To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(−7) and 8.1 × 10(−7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(−2)–10(−5)), and the combined P-values across both American Indians and Caucasian were P = 10(−4)–10(−9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.
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spelling pubmed-37926962013-10-18 MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation Bian, Li Traurig, Michael Hanson, Robert L. Marinelarena, Alejandra Kobes, Sayuko Muller, Yunhua L. Malhotra, Alka Huang, Ke Perez, Jessica Gale, Alex Knowler, William C. Bogardus, Clifton Baier, Leslie J. Hum Mol Genet Association Studies Articles To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(−7) and 8.1 × 10(−7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(−2)–10(−5)), and the combined P-values across both American Indians and Caucasian were P = 10(−4)–10(−9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation. Oxford University Press 2013-11-01 2013-07-03 /pmc/articles/PMC3792696/ /pubmed/23825110 http://dx.doi.org/10.1093/hmg/ddt291 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Association Studies Articles
Bian, Li
Traurig, Michael
Hanson, Robert L.
Marinelarena, Alejandra
Kobes, Sayuko
Muller, Yunhua L.
Malhotra, Alka
Huang, Ke
Perez, Jessica
Gale, Alex
Knowler, William C.
Bogardus, Clifton
Baier, Leslie J.
MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title_full MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title_fullStr MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title_full_unstemmed MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title_short MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation
title_sort map2k3 is associated with body mass index in american indians and caucasians and may mediate hypothalamic inflammation
topic Association Studies Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792696/
https://www.ncbi.nlm.nih.gov/pubmed/23825110
http://dx.doi.org/10.1093/hmg/ddt291
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