Quantitative Genetic Analysis of the Metabolic Syndrome in Hispanic Children

0031-3998/05/5806-1243 PEDIATRIC RESEARCH Copyright © 2005 International Pediatric Research Foundation, Inc. Vol. 58, No. 6, 2005 Printed in U.S.A. Quantitative Genetic Analysis of the Metabolic Syndrome in Hispanic Children NANCY F. BUTTE, ANTHONY G. COMUZZIE, SHELLEY A. COLE, NITESH R. MEHTA, GUOWEN CAI, MARIA TEJERO, RAUL BASTARRACHEA, AND E. O’BRIAN SMITH Department of Pediatrics [N.F.B., N.R.M., E.O.S.], USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, Department of Genetics [A.G.C., S.A.C., G.C., M.T., R.B.], Southwest Foundation for Biomedical Research, San Antonio, Texas 78245 ABSTRACT Childhood obesity is associated with a constellation of metabolic derangements including glucose intolerance, hypertension, and dyslipidemia, referred to as metabolic syndrome. The purpose of this study was to investigate genetic and environmental factors contributing to the metabolic syndrome in Hispanic children. Metabolic syndrome, defined as having three or more metabolic risk components, was determined in 1030 Hispanic children, ages 4 –19 y, from 319 families enrolled in the VIVA LA FAMILIA study. Anthropometry, body composition by dual energy x-ray absorptiometry, clinical signs, and serum biochemistries were measured using standard techniques. Risk factor analysis and quantitative genetic analysis were performed. Of the overweight children, 20%, or 28% if abnormal liver function is included in the definition, presented with the metabolic syndrome. Odds ratios for the metabolic syndrome were significantly increased by body mass index z-score and fasting serum insulin; independent effects of sex, age, puberty, and body composition were not seen. Heritabilities ⫾ SE for waist circumference, triglycerides (TG), HDL, systolic blood pressure (SBP), glu- Childhood obesity in the United States has steadily increased in the past two decades according to NHANES, especially among Hispanic children (1,2). The prevalence of overweight, defined as ⱖ95th BMI percentile, was ⬎20% among Mexican-American children. Childhood obesity is associated with several metabolic and endocrine derangements including glucose intolerance, hypertension, and dyslipidemia that predispose to early development of CVD and T2D (3). This constellation of metabolic derangeReceived April 5, 2005; accepted June 8, 2005. Correspondence: N.F. Butte, Ph.D., Children’s Nutrition Research Center, 1100 Bates St., Houston, TX 77030; e-mail: This work is a publication of the U.S. Department of Agriculture (USDA)/Agricultural Research Service (ARS) Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, and Texas Children’s Hospital, Houston, TX. This project was funded with federal funds from the National Institutes of Health (Grant R01 DK59264) and from USDA/ARS under Cooperative Agreement 58-6250-51000-037. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. DOI: 10.1203/01.pdr.0000185272.46705.18 cose, and alanine aminotransferase (ALT) were highly significant. Pleiotropy (a common set of genes affecting two traits) detected between SBP and waist circumference, SBP and glucose, HDL and waist circumference, ALT and waist circumference, and TG and ALT may underlie the clustering of the components of the metabolic syndrome. Significant heritabilities and pleiotropy seen for the components of the metabolic syndrome indicate a strong genetic contribution to the metabolic syndrome in overweight Hispanic children. (Pediatr Res 58: 1243–1248, 2005) Abbreviations ALT, alanine aminotransferase BMI, body mass index CVD, cardiovascular disease FM, fat mass NHANES, National Health and Nutrition Examination Survey SBP, systolic blood pressure T2D, type 2 diabetes TG, triglycerides ments has been defined in adults as the metabolic syndrome. According to the National Cholesterol Education Program (NCEP) Adults Treatment Plan (ATP) III, the metabolic syndrome is defined as having three or more of the following risk factors: abdominal obesity, raised TG, low HDL cholesterol, elevated blood pressure, or glucose intolerance (4). Although abnormal liver function is not conventionally considered among the constellation of risk factors for the metabolic syndrome, it most likely shares common molecular pathway(s) and may contribute independently to the pathophysiology of CVD and T2D and lead to fatty liver disease (5). Abnormal liver function thus may be considered as part of the constellation of metabolic derangements, even in children. In severely obese adults, the metabolic syndrome was strongly correlated with steatosis, fibrosis, and cirrhosis of the liver (5). Although there is no generally accepted clinical definition of the metabolic syndrome in children, its prevalence has been estimated based on the ATP III definition modified for developmental changes in waist circumference, blood pressure, and blood lipids (6 – 8). 1243 1244 BUTTE ET AL. This constellation of metabolic derangements associated with obesity arises as a result of complex interactions between an individual’s genetic predisposition and environmental factors (9,10). The metabolic, physiologic, and genetic mechanisms underlying the clustering of the components of the metabolic syndrome have been studied in adults (11–17) but not in children. Here within, we investigated genetic and environmental factors contributing to the metabolic syndrome in a large cohort of Hispanic children participating in the VIVA LA FAMILIA study that was designed to genetically map childhood obesity in approximately 300 nuclear Hispanic families. Metabolic syndrome was defined as having three or more of the following metabolic risk factors: abdominal obesity, low HDL, hypertriglyceridemia, high blood pressure, and/or impaired fasting glucose. Our family-based study design allowed for the first time quantitative genetic analyses of metabolic syndrome to be conducted in a pediatric population. The specific aims of these analyses were 1) to estimate the percent of children with the metabolic syndrome in this cohort of Hispanic children; 2) to determine the effects of sex, age, and puberty on the metabolic syndrome; 3) to determine the impact of BMI z-score, body composition, and insulin resistance on the components of the metabolic syndrome; 4) to estimate the genetic contribution (heritability) for each component of the metabolic syndrome; and 5) to estimate genetic correlations between components of the metabolic syndrome to test for pleiotropy (shared gene effects) underlying this constellation of risk factors in Hispanic children. METHODS Study Design and Subjects. Genetic and environmental factors affecting the components of the metabolic syndrome were investigated in 1030 children enrolled in the VIVA LA FAMILIA study that was designed to gene (...truncated)