Variants in the ghrelin gene are associated with metabolic syndrome in the Old Order Amish.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Steinle
Nanette I
NI
Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA. nsteinle@medicine.umaryland.edu
Pollin
Toni I
TI
O'Connell
Jeffrey R
JR
Mitchell
Braxton D
BD
Shuldiner
Alan R
AR
D000328:Adult; D001120:Arginine; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D054439:Ghrelin; D005973:Glutamine; D006579:Heterozygote; D006801:Humans; D006815:Hunger; D007930:Leucine; D008297:Male; D024821:Metabolic Syndrome / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D008715:Methionine; D008875:Middle Aged; D036361:Peptide Hormones / Q000235:genetics*; D014481:United States
D054439:Ghrelin; D036361:Peptide Hormones; D005973:Glutamine; D001120:Arginine; D008715:Methionine; D007930:Leucine