GENES, ASSOCIATED WITH LEFT VENTRICULAR MASS, BODY SIZE, AND BLOOD PRESSURE IN YOUNG WOMEN

Left ventricular hypertrophy is an independent risk factor for cardiovascular disease morbidity and mortality in adults. Left ventricular (LV) mass varies substantially among individuals, and several studies suggest that genetic factors make a significant contribution to the observed variability in LV mass. However, to date, the specific polymorphisms that may be associated with LV mass have not been conclusively determined. The current study seeks to examine multiple candidate genes for their association with LV mass in 574 African American and Caucasian young women. Data on body composition was collected, blood pressure readings were performed, and echocardiograms were performed to assess left ventricular mass and geometry. The subjects were genotyped by PCR at multiple loci using previously reported polymorphisms for specific candidate genes related to obesity and blood pressure. The use of path anaylsis permits the simultaneous testing of both the direct effects of genes on the determination of LV mass and the indirect effects of genes through obesity and hypertension. Epidemiologic relationships of the phenotypic variables fat mass, lean mass, blood pressure and LV mass are consistent with previous studies. Polymorphisms of angiotensinogen, aldosterone synthase, leptin and its receptor, POMC and TNF-α are associated with fat mass in the path analytic model. The path analytic model also identifies relationships between ACE, aldosterone synthase, leptin and neuropeptide Y, with blood pressure. The path analytic model identifies direct associations between the ACE and TNF-α polymorphisms and left ventricular mass. Over half of the observed genetic contribution to LV mass consists of indirect relationships involving body size and blood pressure. Genotypes for these polymorphisms are associated with from 1-2 to 25 % differences in the outcome measures. These relationships differ from the associations observed by univariate analyses or multivariate regression models, stressing the importance of assessing polygenic traits in the context of their relationships with other polygenic traits. The present study takes into account the polygenic nature of the heritability of LV mass, blood pressure and body size, and the relationships among the phenotypic variables, and suggests that indirect genetic associations are important to the genetic determination of LV mass. ACKNOWLEDGEMENTS The staff of the Cincinnati center of National Growth and Health Study, who originally recruited subjects and collected subject data and blood samples for genotyping, provided invaluable contributions to this study, especially Janet Dietz and Phil Khoury, M.S. All genotyping was performed in the laboratory of Anil Menon, Ph.D, with his assistance and the invaluable help of laboratory personnel, especially Yan Ru Su, M.D., Shodimu-Emmanuel Olufemi, Ph.D. and Susan Ingraham. Assistance with statistical analyses was generously provided by Paul Succop, Ph.D. Special thanks are due my committee: Bob Colbert, M.D., Ph.D.; Sandra Degen, Ph.D.; Anil Menon, Ph.D.; Ward Rice M.D., Ph.D.; and Paul Succop, Ph.D. An extra special thanks to my advisor and committee chair, Stephen Daniels, M.D., Ph.D. Finally, this work could not have been completed without the assistance of my friend and fellow student, Laura Young, and the loving support of my husband, Doug, and all my family and friends. Thank you all.