Genome-wide Scan for Serum Ghrelin Detects Linkage on Chromosome 1p36 in Hispanic Children: Results From the Viva La Familia Study

0031-3998/07/6204-0445 PEDIATRIC RESEARCH Copyright © 2007 International Pediatric Research Foundation, Inc. Vol. 62, No. 4, 2007 Printed in U.S.A. Genome-wide Scan for Serum Ghrelin Detects Linkage on Chromosome 1p36 in Hispanic Children: Results From the Viva La Familia Study V. SAROJA VORUGANTI, HARALD H.H. GÖRING, VINCENT P. DIEGO, GUOWEN CAI, NITESH R. MEHTA, KARIN HAACK, SHELLEY A. COLE, NANCY F. BUTTE, AND ANTHONY G. COMUZZIE Department of Genetics [V.S.V., H.H.H.G., V.P.D., K.H., S.A.C., A.G.C.], Southwest Foundation for Biomedical Research, San Antonio, Texas 78227; Department of Pediatrics [G.C., N.R.M., N.F.B.], USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030 metabolic pathways) can also result in obesity in both children and adults (3). A key player in the regulation of energy homeostasis is the central nervous system (CNS), which controls food intake with the help of information received from distinct metabolic, hormonal, and neural signals (4). Ghrelin, a gastrointestinal hormone, is one such signal that is secreted by X/A-like cells in the fundus portion of the stomach and acts through its receptors situated on neurons in the arcuate nucleus of the hypothalamus (5). Circulating levels of ghrelin are at their highest before a meal and drop to their lowest after a meal (6), making it a possible signal for a low-energy state (7). Several human and animal studies have shown circulating ghrelin to be inversely related to body weight, BMI, waist circumference, serum insulin, and insulin resistance (8,9). Similar results have been reported in studies conducted with children (10,11). However, few studies have shown the genetic influence on circulating ghrelin, particularly in children. A small number of studies have identified genetic variants in the ghrelin gene in children. The effects of these variants on energy balance or weight regulation are, however, not yet clear as these studies have produced contradictory results (12,13). Therefore, this study was conducted to estimate the genetic influence on serum ghrelin and to investigate the genetic correlations between ghrelin and other obesity-related phenotypes in Hispanic children. ABSTRACT: This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n ⫽ 1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducted according to standard procedures. Mean age, body mass index (BMI), and serum ghrelin were 11 ⫾ 0.13 y, 25 ⫾ 0.24 kg/m2 and 38 ⫾ 0.5 ng/mL, respectively. Significant heritabilities (p ⬍ 0.001) were obtained for BMI, weight, fat mass, percent fat, waist circumference, waist-to-height ratio, and ghrelin. Bivariate analyses of ghrelin with adiposity traits showed significant negative genetic correlations (p ⬍ 0.0001) with weight, BMI, fat mass, percent fat, waist circumference, and waist-to-height ratio. A genome-wide scan for ghrelin detected significant linkage on chromosome 1p36.2 between STR markers D1S2697 and D1S199 (LOD ⫽ 3.2). The same region on chromosome 1 was the site of linkage for insulin (LOD ⫽ 3.3), insulinlike growth factor binding protein 1 (IGFBP1) (LOD ⫽ 3.4), homeostatic model assessment method (HOMA) (LOD ⫽ 2.9), and C-peptide (LOD ⫽ 2.0). Several family-based studies have reported linkages for obesity-related phenotypes in the region of 1p36. These results indicate the importance of this region in relation to adiposity in children from the VFS. (Pediatr Res 62: 445–450, 2007) O besity among children and adolescents is of great concern because accompanying adverse health consequences usually persist into adulthood. In the United States (US), there has been steady increase in past 20 y in the number of children who are overweight. The proportion of children in age group 6 –18 y who are overweight increased from 6% in 1976 –1980 to 16% in 1999 –2002 (1). These data reflect changing patterns in diet and lifestyle. A decrease in physical activity and shift in diet toward high-fat foods among children may be some of the contributing factors to obesity (2). In addition, disruption in energy balance (energy intake and expenditure or relevant METHODS Study design. Data for this study were obtained from children participating in the VFS (14). Participants (n ⫽ 1030) in this study were taken from 319 Hispanic families residing in and around Houston, TX. The VFS was designed to characterize and identify genes influencing variation in obesityrelated phenotypes in Hispanic children. To participate in this study, a proband was required to be overweight (⬎95 percentile for BMI and ⬎85 percentile for fat mass) and between ages 4 and 19 y. In addition, only those families who had three or more children in the age group 4 –19 y were recruited. Information regarding pedigree structure, sociodemographics, and anthropometrics was obtained. All participants underwent physical examination, and blood samples were taken after a 12-h overnight fast. Serum was extracted and stored in aliquots at ⫺80°C for clinical chemistries and endo- Received January 11, 2007; accepted May 19, 2007. Correspondence: V. Saroja Voruganti, Ph.D., Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549; e-mail: This project was funded with federal funds from the NIH R01. DK59264, USDA/ARS under Cooperative Agreement 58-6250-51000-037 and MH59490 from NIH. This investigation was conducted in a facility constructed with support from Research Facilities. Improvement Program Grant Number 1 C06 RR13556-01 from the National Center for Research. Resources supported by the NIH. Abbreviations: HOMA, homeostatic model assessment method; IGFBP1, insulinlike growth factor binding protein 1; IGFBP3, insulin-like growth factor binding protein 3; QTL, quantitative trait locus 445 446 VORUGANTI ET AL. crine assays. Genotyping was conducted with DNA derived from lymphocytes. Informed consent was obtained from all participants in this study, which was approved by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals and for the Southwest Foundation for Biomedical Research. Phenotyping. Anthropometric measurements included height, weight, waist circumference, and BMI. Weight for the children was measured twice by a trained nurse using a Healthometer electronic scale (Bridgeview, IL). Standing height was measured twice to the nearest 0.1 cm using a SECA wall-mounted stadiometer (Holtain Limited, Crymych, UK). The waist circumference was measured twice, in millimeters, midway between the inferior border of the rib cage and the superior border of the iliac crest. The hip circumference was also measured twice, in millimeters, at the level of the trochanter. The average of the two measurements for eac (...truncated)