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Diabetologia. 2000 Mar;43(3):373-6.

Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes.

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  • 1Department of Medicine, Kurume University School of Medicine, Japan.

Abstract

AIMS/HYPOTHESIS:

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).

CONCLUSION/INTERPRETATION:

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.

PMID:
10768099
[PubMed - indexed for MEDLINE]
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