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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.

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