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

Aldi T. Kraja, Heather A. Lawson, Donna K. Arnett, Ingrid B. Borecki, Ulrich Broeckel, Lisa De Las Fuentes, Steven Hunt, Michael A. Province, James Cheverud, D. C. Rao

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8 Citations (Scopus)

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 ∼137 kbps 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.

Original languageEnglish
Pages (from-to)1129-1141
Number of pages13
JournalMetabolism: Clinical and Experimental
Volume61
Issue number8
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

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Keywords

  • blood pressure
  • BMI
  • body mass index
  • BP
  • DBP
  • diastolic blood pressure
  • fasting insulin, GLUC, fasting glucose
  • fasting triglycerides
  • genome-wide association scans.
  • GWAS
  • HDLC
  • high density lipoprotein cholesterol
  • INS
  • LDLC
  • LOD
  • logarithm of base 10 of odds for linkage evidence
  • low density lipoprotein cholesterol
  • metabolic syndrome
  • MetS
  • PBF
  • percent body fat
  • QTL
  • quantitative trait locus
  • SBP
  • systolic blood pressure
  • T2D
  • TG
  • type 2 diabetes mellitus
  • waist circumference
  • waist-to-hip ratio
  • WC
  • WHR

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Kraja, A. T., Lawson, H. A., Arnett, D. K., Borecki, I. B., Broeckel, U., De Las Fuentes, L., Hunt, S., Province, M. A., Cheverud, J., & Rao, D. C. (2012). Obesity-insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice. Metabolism: Clinical and Experimental, 61(8), 1129-1141. https://doi.org/10.1016/j.metabol.2012.01.008