Obesity-insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice

Abstract

Identifying metabolic syndrome (MetS) genes is important for novel drug development and health care. This study extends the findings on human chromosome 3p26-25 for an identified obesity-insulin factor QTL, with an LOD score above 3. A focused association analysis comprising up to 9578 African American and Caucasian subjects from the HyperGEN Network (908 African Americans and 1025 whites), the Family Heart Study (3035 whites in time 1 and 1943 in time 2), and the Framingham Heart Study (1317 in Offspring and 1320 in Generation 3) was performed. The homologous mouse region was explored in an F(16) generation of an advanced intercross between the LG/J and SM/J inbred strains, in an experiment where 1002 animals were fed low-fat (247 males; 254 females) or high-fat (253 males; 248 females) diets. Association results in humans indicate pleiotropic effects for SNPs within or surrounding CNTN4 on obesity, lipids and blood pressure traits and for SNPs near IL5RA, TRNT1, CRBN, and LRRN1 on central obesity and blood pressure. Linkage analyses of this region in LG/J×SM/J mice identify a highly significant pleiotropic QTL peak for insulin and glucose levels, as well as response to glucose challenge. The mouse results show that insulin and glucose levels interact with high and low fat diets and differential gene expression was identified for Crbn and Arl8b. In humans, ARL8B resides ~137kbps away from BHLHE40, expression of which shows up-regulation in response to insulin treatment. This focused human genetic analysis, incorporating mouse research evidenced that 3p26-25 has important genetic contributions to MetS components. Several of the candidate genes have functions in the brain. Their interaction with MetS and the brain warrants further investigation.

Fig. 1

A. Linkage results on chromosome 3 of the HyperGEN study. B. Linkage results on chromosome 6 of generation 16 of LG/J × SM/J mouse syntenic with humans. C. Association test results from 3 human studies (HyperGEN, Framingham Heart Study and Family Heart Study) in the region 3p26-25 (for more details on Fig. 1C, see Supplemental Figures 1 and 2, and Supplemental Table 2).

Fig. 2

Linkage, association, and gene expression results in human samples and mouse. This schematic summarizes results from Supplemental Tables 2, 3a–c, and 4a–f.

Fig. 2

Linkage, association, and gene expression results in human samples and mouse. This schematic summarizes results from Supplemental Tables 2, 3a–c, and 4a–f.

Fig. 2

Linkage, association, and gene expression results in human samples and mouse. This schematic summarizes results from Supplemental Tables 2, 3a–c, and 4a–f.