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.


METHODS
The NPY5R gene was screened for polymorphisms by direct sequencing in two groups of Pima Indians, selected for extremes of body mass index (BMI). Genotype frequencies were analyzed for association with BMI extreme.


METHODS
Full-heritage Pima Indians, non-diabetic and not first degree relatives. Obese group: 19 M/24 F, BMI = 49+/-7 kg/m2 (mean+/-s.d.) age = 24+/-2 y, lean group: 16 M/16 F, BMI = 23+/-2 kg/m2, age = 27+/-3 y.


METHODS
Initially, the entire gene (proximal promoter, exon 1A, coding 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 nucleotide polymorphisms were detected in the non-coding regions: (1) a C-->T transition located within the promoter 28 bp upstream of the exon 1A transcription start site; (2) a T-->C transition 94 bp downstream of the stop codon; and (3) a G-->A transition 432 bp downstream of the stop codon. The polymorphisms 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 haplotype (P=0.02, Bonferroni corrected).


CONCLUSIONS
Considering the importance of this gene in regulation of body weight, the association of these polymorphisms with extremes of BMI in Pima Indians indicates that NPY5R, or a locus nearby, may contribute to susceptibility to obesity in this population.
Jenkinson
C P
CP
Clinical Diabetes and Nutrition Section, National Institute of Digestive Diabetes and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA. Cjenkinson@phx.niddk.nih.gov
Cray
K
K
Walder
K
K
Herzog
H
H
Hanson
Ravussin
E
E
D000328:Adult; D015992:Body Mass Index; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D017476:Receptors, Neuropeptide Y / Q000235:genetics*
D017476:Receptors, Neuropeptide Y