Variants in the LEPR Gene Are Nominally Associated With Higher BMI and Lower 24-h Energy Expenditure in Pima Indians

Authors

  • Michael T. Traurig,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Jessica M. Perez,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Lijun Ma,

    1. Department of Internal Medicine-Endocrinology, Wake Forest University School of Medicine, Medical Center Blvd Winston-Salem, Winston-Salem, North Carolina, USA
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  • Li Bian,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Sayuko Kobes,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Robert L. Hanson,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • William C. Knowler,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Jonathan A. Krakoff,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Clifton Bogardus,

    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
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  • Leslie J. Baier

    Corresponding author
    1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health Phoenix, Phoenix, Arizona, USA
      (lbaier@phx.niddk.nih.gov)
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(lbaier@phx.niddk.nih.gov)

Abstract

Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n = 80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n = 2,842) and several common variants including rs2025804 were nominally associated with BMI (P = 0.05–0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n = 2,969) and three of the variants showed nominal replication (P = 0.03–0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P = 0.0003–0.0001). A subset of these individuals (n = 403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24-h energy expenditure (24hEE) as assessed in a human respiratory chamber (P = 0.0007 adjusted for age, sex, fat mass, fat-free mass, activity, and family membership). We conclude that common noncoding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans.

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