Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians

OBJECTIVE: To investigate whether the neuropeptide Y receptor 5 gene (NPY5R ) is associated with obesity in humans. DESIGN: The NPY5R gene was screened for polymorphisms by direct sequencing in two groups of Pima Indians, selected for extremes of body mass index (BM I). Genotype frequencies were analyzed for association with BMI extreme. SUBJECTS: Full-heritage Pima Indians, non-diabetic and not first degree rel atives. Obese group: 19 M/24 F, BMI = 49 +/- 7 kg/m(2) (mean +/- s.d.) age = 24 +/- 2 y, lean group: 16 M/16 F, BMI = 23 +/- 2 kg/m(2), age = 27 +/- 3 y. MEASUREMENTS: Initially, the entire gene (proximal promoter, exon 1A, codin g sequence, 5' and 3' UTRs) was sequenced in a subset of 20 individuals. No variants were found in the coding sequence, however three novel single nuc leotide polymorphisms were detected in the non-coding regions: (1) a C-->T transition located within the promoter 28 bp upstream of the exon 1A transc ription start site; (2) a T-->C transition 94 bp downstream of the stop cod on; and (3) a G-->A transition 432 bp downstream of the stop codon. The pol ymorphisms were then screened in all 75 subjects. RESULTS: The polymorphisms had mean heterozygosities of 0.34-0.50 and were in strong linkage disequilibrium (P < 0.001). Genotype frequencies differed significantly in lean and obese Pimas for P2 (P = 0.04) and for a triple h aplotype (P = 0.02, Bonferroni corrected). CONCLUSION: Considering the importance of this gene in regulation of body w eight, the association of these polymorphisms with extremes of BMI in Pima Indians indicates that NPY5R, or a locus nearby, may contribute to suscepti bility to obesity in this population.