Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients

Jeanette J. McCarthy, Joanne Meyer, David J. Moliterno, L. Kristin Newby, William J. Rogers, Eric J. Topol

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Major genetic determinants of the metabolic syndrome - a clustering of abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure and high fasting glucose - remain elusive. We surveyed 207 single-nucleotide polymorphisms in 110 candidate genes among coronary artery disease patients, a population enriched for metabolic abnormalities. The number of abnormalities (0-5) was determined in the 214 male and 91 female patients, and the association with each polymorphism evaluated by means of ordinal regression analysis. Polymorphisms in eight genes, including LDLR, GBE1, IL1R1, TGFB1, IL6, COL5A2, SELE and LIPC, were associated with metabolic syndrome in the whole population (P values ranged from 0.047 to 0.008). Variants in seven additional genes showed significant gene by gender interaction. Among these, separate analyses in men and women revealed a strong association with a silent polymorphism in the low-density lipoprotein receptor-related protein gene, LRPAP1, among females (P=0.0003), but not males (P=0.292). Other genes associated only in females included THBS1, ACAT2, ITGB3, F2 and SELF (P values ranging from 0.032 to 0.002). Only one gene (PRCP) was significantly associated in men alone (P=0.039). Our results propose several new candidate genes for the metabolic syndrome and suggest that the genetic basis of this syndrome may be strongly modified by gender.

Original languageEnglish
Pages (from-to)87-98
Number of pages12
JournalHuman Genetics
Issue number1
StatePublished - Dec 2003

Bibliographical note

Funding Information:
This work has been reported on behalf of the GeneQuest multicenter study, which involves the following investigators and coordinators: Eric J. Topol (chairperson) (Cleveland Clinic Foundation); David J. Moliterno, Ruth Cannata, Patricia Welsh, Monique Rosenthal (Cleveland Clinic Foundation, Cleveland, Ohio); Spencer B. King, III, William Anderson, Joe Jean Borowski, Kris Anderberg (Emory University Hospital, Atlanta, Georgia); David R. Holmes Jr, Charanjit Rihal, Sharon McIntire-Langworthy (Mayo Clinic, Rochester, Minnesota); William Rogers, Ann Snider (University of Alabama Medical Center, Birmingham, Alabama); L. Kristin Newby, Laura Drew (Duke University Medical Center, Durham, North Carolina); Dean Kereiakes, Eli Roth, Louise Wohlford (The Lindner Center for Clinical Cardiovascular Research, Cincinnati, Ohio); Anthony De Franco, Teresa Schrader (LeBauer Cardiovascular Research Foundation, Greensboro, North Carolina); Phillip Gainey, Sandra Arsenault (St. Joseph Hospital, Savannah, Georgia); Paul Casale, Joann Tuzi (Lancaster Heart Foundation, Lancaster, Pennsylvania); Jeffrey Anderson, Juli Jerman, Rob Pearson Ann Allen (Latter Day Saints Hospital, Salt Lake City, Utah); Sherwyn Schwartz, Sue Beasie (Diabetes and Glandular Associates, San Antonio, Texas); Frank Aguirre, Sandra Aubuchon, Kristin Weisbrod (St Louis University Hospital, St. Louis, Missouri); Jeffrey Carney, Muriel Harris (The Heart Group, Saginaw, Michigan); Jim Bengtson, Mary Adolphson (Michigan Heart and Vascular Institute, Ypsilanti, Michigan); John Rudoff, Sue Williams (Oregon Cardiology Clinic, PC, Portland, Oregon); Jeanette McCarthy, Laura Carleu (Millennium Pharmaceuticals, Cambridge, Massachusetts)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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