Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study

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  • Taylor, Kira C
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
    • Other Affiliation: Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA
  • Carty, Cara L
    • Other Affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Dumitrescu, Logan
    • Other Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
  • Bůžková, Petra
    • Other Affiliation: Department of Biostatistics, University of Washington, Seattle, WA, USA
  • Cole, Shelley A
    • Other Affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
  • Hindorff, Lucia
    • Other Affiliation: Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Schumacher, Fred R
    • Other Affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • Wilkens, Lynne R
    • Other Affiliation: Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
  • Shohet, Ralph V
    • Other Affiliation: Center of Cardiovascular Research, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
  • Quibrera, P Miguel
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Johnson, Karen C
    • Other Affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
  • Henderson, Brian E
    • Other Affiliation: Department of Preventive Medicine, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA
  • Haessler, Jeff
    • Other Affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Franceschini, Nora
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Eaton, Charles B
    • Other Affiliation: Department of Family Medicine and Community Health, Alpert Medical School of Brown University, Providence, RI, USA
  • Duggan, David J
    • Other Affiliation: Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA
  • Cochran, Barbara
    • Other Affiliation: Sponsored Programs, Baylor College of Medicine, Houston, TX, USA
  • Cheng, Iona
    • Other Affiliation: Cancer Research Center, University of Hawaii, Honolulu, HI, USA
  • Carlson, Chris S
    • Other Affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Brown-Gentry, Kristin
    • Other Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
  • Anderson, Garnet
    • Other Affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Ambite, Jose
    • Other Affiliation: Information Sciences Institute, University of Southern California, Los Angeles, CA, USA
  • Haiman, Christopher
    • Other Affiliation: Department of Preventive Medicine, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA
  • Le Marchand, Loïc
    • Other Affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • Kooperberg, Charles
    • Other Affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Crawford, Dana C
    • Other Affiliation: Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
  • Buyske, Steven
    • Other Affiliation: Department of Statistics and Biostatistics, Rutgers University, Piscataway, NJ, USA
  • North, Kari
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology, School of Medicine, Carolina Center for Genome Sciences
  • Fornage, Myriam
    • Other Affiliation: Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA
Abstract
  • Abstract Background High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study. Results A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (phet = 7.4x10-7) and rs3135506 (phet = 4.3x10-4), one SNP in PLTP for HDL levels (rs7679; phet = 9.9x10-4), and one in HMGCR for LDL levels (rs12654264; phet = 3.1x10-5). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses. Conclusions We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
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Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Kira C Taylor et al.; licensee BioMed Central Ltd.
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Journal title
  • BMC Genetics
Journal volume
  • 14
Journal issue
  • 1
Page start
  • 33
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1471-2156
Bibliographic citation
  • BMC Genetics. 2013 May 01;14(1):33
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • May 31, 2013

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file details This file contains Supplementary Tables 1-4 and Supplementary Figure 1 as described in the text. 2019-05-07 Public Download