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Association of the Estrogen Receptor- Gene With the Metabolic Syndrome and Its Component Traits in African-American Families

The Insulin Resistance Atherosclerosis Family Study

¹ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
² Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ Department of Health Evaluation Sciences, Penn State College of Medicine, Hershey, Pennsylvania
⁴ Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁵ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
⁷ Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
⁸ Division of Endocrinology, Diabetes and Metabolism, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
⁹ Department of Medicine, University of Virginia, Charlottesville, Virginia
¹⁰ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia

Address correspondence and reprint requests to Michèle M. Sale, PhD, Center for Public Health Genomics, University of Virginia, P.O. Box 800717, Charlottesville, VA 22908. E-mail: msale{at}virginia.edu

Abbreviations: CVD, cardivascular disease; ESR1, estrogen receptor-; FPG, fasting plasma glucose; GEE, generalized estimating equation; PDT, pedigree disequilibrium test; SAT, subcutaneous adipose tissue; SNP, single nucleotide polymorphism; QPDT quantitative PDT; VAT, visceral adipose tissue

OBJECTIVE— We previously detected an association between a region of the estrogen receptor- (ESR1) gene and type 2 diabetes in an African-American case-control study; thus, we investigated this region for associations with the metabolic syndrome and its component traits in African-American families from the Insulin Resistance Atherosclerosis Family Study.

RESEARCH DESIGN AND METHODS— A total of 17 single nucleotide polymorphisms (SNPs) from a contiguous 41-kb intron 1–intron 2 region of the ESR1 gene were genotyped in 548 individuals from 42 African-American pedigrees. Generalized estimating equations were computed using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation.

RESULTS— Significant associations were detected between ESR1 SNPs and the metabolic syndrome (P = 0.005 to P = 0.029), type 2 diabetes (P = 0.001), insulin sensitivity (P = 0.0005 to P = 0.023), fasting insulin (P = 0.022 to P = 0.033), triglycerides (P = 0.021), LDL (P = 0.016 to P = 0.034), cholesterol (P = 0.046), BMI (P = 0.016 to P = 0.035), waist circumference (P = 0.012 to P = 0.023), and subcutaneous adipose tissue area (P = 0.016).

CONCLUSIONS— It appears likely that ESR1 contributes to type 2 diabetes and CVD risk via pleiotropic effects, leading to insulin resistance, a poor lipid profile, and obesity.

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