Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes.
OBJECTIVE
Polymorphisms in the upstream region of the 5-HT2C receptor gene could play a part in the development of obesity.


METHODS
We screened the upstream region from 27 men by the single strand conformational polymorphism analysis and PCR-direct sequencing and then genotyped 466 non-obese (body mass index < 28 kg/m2) and 123 obese (> or = 28 kg/m2) men including 138 patients with Type II (non-insulin-dependent) diabetes mellitus.


RESULTS
Three loci of single nucleotide substitution (G-->A at -995, C-->T at -759, G-->C at -697) and a (GT)n dinucleotide repeat polymorphism at -1,027 were identified. The frequency of -995/-759 and -697 variants was higher in non-obese subjects and that of -995/-759 variants in non-diabetic subjects. In the dinucleotide repeat locus, five alleles were detected including Z containing 17 repeats. The Z - 6 allele was more common in non-obese subjects and the Z + 2 allele in obese subjects. Haplotype 3 (Z - 6, -995A, -759T, -697C) was associated with leanness (p = 0.02) and the absence of diabetes (p = 0.033) and haplotype 9 (Z + 2, -995G, -759C, -697G) with obesity (p = 0.007). Haplotype 2 (Z - 6, -995G, -759C, -697C) tended to be more common in non-obese subjects. A luciferase reporter assay showed that haplotype 2 and haplotype 3 had 1.44- or 2.58-fold higher promoter activities than the most common haplotype 6 (Z, -995G, -759C, -697G).


CONCLUSIONS
The haplotypes containing the nucleotide substitutions could be associated with higher transcription levels of the gene and thereby with resistance to obesity and Type II diabetes. Promoter polymorphisms of the 5-HT2C receptor gene may play an important part in genetic predisposition to the disorders.
Yuan
X
X
Department of Medicine, Kurume University School of Medicine, Japan.
Yamada
K
K
Ishiyama-Shigemoto
S
S
Koyama
W
W
Nonaka
K
K
D000328:Adult; D000483:Alleles; D001483:Base Sequence / Q000235:genetics; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D018900:Dinucleotide Repeats / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000235:genetics*; D012016:Reference Values; D014158:Transcription, Genetic / Q000235:genetics
D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin