Mutations in the preproghrelin/ghrelin gene associated with obesity in humans

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/-3.4 kg/m(2 )) and in 96 non-obese female controls (mean BMI 23.0 +/-1.4 kg/m(2)) of th e Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg5 1Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p<0.05). The self-reported weight a t 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respe ctively, among obese Gin allele carriers versus obese non-carriers. In addi tion, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detec ted in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozy gotes) subjects. This mutation outside the coding region of the mature ghre lin product tended to be associated with lower age of self-reported onset o f obesity (15.6<plus/minus>7.9 vs. 20.5 +/- 10.5 years; p=0.09). In additio n to these two mutations in coding regions, a G274A base change in a non-co ding region between exons one and two was found only in two obese individua ls. The Arg51 Gln amino acid substitution may alter the cleavage site of en doproteases and the length of the mature ghrelin product. The functional si gnificance of the Leu72Met mutation and a G274A base change remains to be d etermined. In conclusion, the data provide evidence that a low frequency se quence variation in the ghrelin gene could play a role in the etiology of o besity.