Variants in the ghrelin gene are associated with metabolic syndrome in the old order amish

Context: Mature ghrelin has been shown to stimulate eating and to participate in the regulation of insulin signaling and glucose homeostasis. Its gene, GHRL, is located on chromosome 3 in a region where we have shown linkage to eating behavior, percentage body fat, and total and low-density lipoprotein cholesterol levels in subjects of the Amish Family Diabetes Study. Objective: Our objective was to determine whether mutations in GHRL might influence eating behavior and risk for metabolic syndrome, obesity, diabetes, and related traits. Design: We genotyped 856 Amish samples for three missense polymorphisms in GHRL, Arg51Gln, Leu72Met ( rs696217), and Gln90Leu ( rs4684677) and performed association analyses with eating behavior traits and metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines. Subjects: Our subjects were adult participants in the Amish Family Diabetes Study. Results: The allele frequencies of these variants were 0.03, 0.04, and 0.03, respectively. The prevalence of metabolic syndrome was lower among those carrying the 51Gln allele ( 3.8 vs. 15.8%; age- and sex-adjusted odds ratio = 0.22; P = 0.031). Hunger scores tended to be lower among 51Gln allele carriers but did not reach statistical significance ( P = 0.07). The Leu72Met variant was also associated with increased prevalence of metabolic syndrome ( 23.2 vs. 13.4%; age- and sex-adjusted odds ratio = 2.57; P = 0.02) as well as higher fasting glucose, lower high-density lipoprotein, and higher triglyceride levels ( P = 0.02, P = 0.007, and P = 0.04, respectively). The two variants were not in linkage disequilibrium with each other, suggesting independent effects. We conclude that mutations in GHRL may confer risk for the metabolic syndrome.