Systematic Search for Single Nucleotide Polymorphisms in the Resistin Gene

Osawa, Haruhiko; Onuma, Hiroshi; Murakami, Akiko; Ochi, Masayuki; Nishimiya, Tatsuya; Kato, Koichi; Shimizu, Ikki; Fujii, Yasuhisa; Ohashi, Jun; Makino, Hideichi

doi:10.2337/diabetes.51.3.863

Cited by 82 publications

(60 citation statements)

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“…Several genetic association studies in humans had contradictory results, which can be divided into three categories: (i) an association with obesity but not with diabetes [12,13]; (ii) an association with insulin sensitivity but not with obesity or diabetes [14,15]; and (iii) no association with obesity or with diabetes [16,17,18]. Interestingly, variations in the promoter region of the resistin gene were associated with obesity or insulin resistance [12,15].…”

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Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans

et al. 2004

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Aims/hypothesis. Resistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations. Methods. We examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotypebased promoter activity assays and the gel electrophoretic mobility shift assay. Results. The −420G and the −537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (−537A and −420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the −420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects. Conclusions/interpretation. Polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. [Diabetologia (2004) . Moreover, obese mice given an antiresistin antibody had increased insulin-stimulated glucose uptake, whereas the treatment of normal mice with recombinant resistin impaired insulin action [4]. Resistin therefore could link obesity with insulin resistance and diabetes in mouse models. However, subsequent studies in rodent models have produced disparate findings on the role of resistin in obesity and insulin resistance [5,6,7].In humans, the expression of resistin in adipocytes is much lower than that seen in rodents and does not differ between normal, insulin-resistant or Type 2 diabetic patients [8,9,10]. Little is known about the relationship between circulating resistin concentrations Resistin belongs to a novel family of cystein-rich C-terminal domain proteins called resistin-like molecules, which are identical to those found in inflammatory

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confidence: 99%

Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans

et al. 2004

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“…Resistin expression was low and not significantly different among human fat cells from unaffected, insulin-resistant, and type 2 diabetic patients (21), and mRNA levels in human adipocytes were not correlated with BMI (22). No significant associations have been found between resistin gene variants and type 2 diabetes (23,24). Although we have shown that variation in the resistin gene is unlikely to be responsible for the association and linkage with PCOS that we find in this region, these findings do not eliminate the possible importance of resistin in the etiology of PCOS, especially in view of the insulin sensitivity defects.…”

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confidence: 94%

Variation in Resistin Gene Promoter Not Associated With Polycystic Ovary Syndrome

Urbanek

Silander

et al. 2003

Diabetes

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Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility and affects ϳ4 -7% of reproductive age women in the U.S. It is characterized by hyperandrogenemia and chronic anovulation and is associated with insulin resistance, obesity, and increased risk for type 2 diabetes. In a screen of candidate genes, a region on chromosome 19p13.3 was identified that shows significant evidence for both linkage and association with PCOS. A promising candidate gene for PCOS, resistin, maps to exactly this region. Resistin is a protein hormone thought to modulate glucose tolerance and insulin action. We tested for association between a single nucleotide polymorphism in the promoter region of the resistin gene and three phenotypes: PCOS, obesity, and insulin resistance. We did not find evidence for association with any of the phenotypes. It is therefore unlikely that variation in the resistin gene accounts for the strong association that we observe between chromosome 19p13.3 and PCOS. Instead, this association is most likely due to a gene or genetic element in this region that has not been identified. Diabetes 52: 214 -217, 2003

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“…PCR direct sequencing was performed as described previously with the following modifications (13,14). Genomic DNA was extracted from leukocytes using a DNA Isolation Kit for Mammalian Blood (Boehringer Mannheim, Indianapolis, IN).…”

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confidence: 99%

Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene

et al. 2003

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1FOXC2, a forkhead/winged helix transcription factor, represents a promising candidate gene for type 2 diabetes since transgenic mice that specifically overexpress this gene in adipocytes are lean and insulin sensitive. To determine whether there are single nucleotide polymorphisms (SNPs) in this gene that are associated with type 2 diabetes, sequences of the coding and ϳ1 kb of 5 flanking regions in 24 Japanese type 2 diabetic subjects were initially analyzed using PCR direct sequencing, and the regions containing the identified polymorphisms were then examined. In 200 control subjects, three frequent SNPs were found (g. ؊512C>T [32.3%] and ؊350G>T [13.0%] in the 5 flanking region and ؉1548C>T [10.0%] in the 3 flanking region). Linkage disequilibria were found between all three pairs of these SNPs. Of the eight possible haplotypes defined by these SNPs, only four were found. When the frequencies of these SNPs and the four common haplotypes between 195 type 2 diabetic and 200 control subjects were compared, no association was evident. The ؉898C>T (Pro300Ser), ؉907C>A (Leu303Met), 1167_1169del-CCA (389delHis), and ؉1251C>A (Ala417Ala) identified in the coding region were rare, although ؉907C>A could be higher in type 2 diabetic subjects (1.5%) than in control subjects (0.3%). Thus, the SNPs identified in the FOXC2 gene are unlikely to have major effects on susceptibility to Japanese type 2 diabetes. Diabetes 52: 562-567, 2003

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Systematic Search for Single Nucleotide Polymorphisms in the Resistin Gene

Cited by 82 publications

References 12 publications

Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans

Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans

Variation in Resistin Gene Promoter Not Associated With Polycystic Ovary Syndrome

Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene

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