The -1535 Promoter Variant of The Visfatin Gene Is Associated with Serum Triglyceride and HDL-cholesterol Levels in Japanese Subjects

Abstract

Abstract. Visfatin is a novel adipocytokine that is expressed by the visceral fat cells. We investigated the role of genetic variation in the visfatin gene in the pathophysiology of type 2 diabetes and clinical variables in Japanese subjects. The 11 exons, and the promoter region of the visfatin gene were screened for single nucleotide polymorphisms (SNPs) by PCRdirect sequencing. We found SNPs in the promoter region (SNP -1535T>C), exon 2 (SNP + 131C>G, Thr44Arg), and exon 7 (SNP + 903G>A). The allele and genotype frequencies of these SNPs showed no significant differences between 200-448 diabetic and 200-333 control subjects. However, the -1535T/T genotype was associated with lower serum triglyceride levels (T/T vs. T/C + C/C (p = 0.015) and T/T vs. C/C (p = 0.043)) and higher HDL-cholesterol levels (T/T vs. C/C, p = 0.0496) in the nondiabetic subjects. Reporter gene assay of 3T3-L1 adipocytes revealed that the promoter activity of -1535T and -1535C was similar, suggesting that the observed association may reflect linkage disequilibrium between -1535T>C and causative variations of the visfatin gene. ADIPOCYTES secrete a variety of proteins known as adipocytokines, which have various important roles in metabolism [1,2]. Visfatin is a novel adipocytokine strongly expressed by the visceral fat cells of both humans and mice [3]. Visfatin is identical to pre-B cell colony-enhancing factor (PBEF) which has been identified as a growth factor for early stage B cells [4]. Visfatin has an insulin-like effect on cultured cells. It stimulates glucose uptake by adipocytes, myocytes and osteoblasts [3,5], and inhibits glucose release from liver cells [3]. In addition, administration of visfatin to mice has been shown to decrease the plasma glucose level [3], and mice that are heterozygous (+/-) for visfatin have higher plasma glucose levels than wild-type mice [3]. Furthermore, clinical studies have shown that plasma visfatin levels are about two-fold higher in type 2 diabetic patients than in nondiabetic controls [6,7]. These findings suggest a role of visfatin in glucose metabolism and in the pathogenesis of type 2 diabetes. It has been reported that variations of the genes for other adipocytokines (e.g. adiponectin) can influence the risk of type 2 diabetes [8][9][10][11][12][13], but the relation between visfatin gene polymorphism and type 2 diabetes remains unknown. The visfatin/PBEF gene consists of 11 exons and 10 introns spanning 34.7-kb and is located on chromosome 7q22.2 [14]. In the present study, we systematically investigated polymorphisms of the coding region and promoter region of this gene in Japanese subjects and then performed association studies in type 2 diabetic and non-diabetic subjects. We also examined the

In-vitro function of upstream visfatin polymorphisms that are associated with adverse cardiometabolic parameters in obese children

“…2). Our finding is similar to that reported by Tokunaga et al who also found no difference in transcriptional activity between variant 1.6kbp visfatin promoter containing c.-1537C > T SNP and wild-type 1.6kbp promoter [11]. However, this differs from the reports by Wang et al and Ye et al who showed that c.-1537C > T SNP was associated with lower transcriptional activity [9, 10].…”

“…Among the reported upstream SNPs, the c.-1537C > T SNP (rs61330082) has been shown to cause a reduction in the transcriptional activity of luciferase reporter assay [9, 10]. However, another study by Tokunaga et al found no difference in reporter gene expression between C and T allele of c.-1537C > T SNP [11]. Our group has previously reported perfect linkage disequilibrium between rs61330082 and another SNP, c.-3187C > T (rs11977021) which was found to be significantly associated with total plasma cholesterol and LDL-cholesterol levels in French-Canadian subjects [5].…”

The visfatin (PBEF1) G-948T gene polymorphism is associated with increased high-density lipoprotein cholesterol in obese subjects

“…Several recent reports have shown a positive association between visfatin and HDL cholesterol in various populations [11][12][13][14][15]. These findings are likely a reflection of differences in insulin sensitivity between the subjects resulting in the typical dyslipidemia of insulin resistance and the metabolic syndrome, that is, increased triglyceride levels and decreased HDL cholesterol.…”

Visfatin Polymorphism May Increase Tendency to Diabetic Nephropathy

“…2 The visfatin/PBEF gene is located on chromosome 7q22.2 and consists of 11 exons and 10 introns, spanning 34·7kb of genomic DNA. 3 Visfatin is an adipocytokine and a new marker of inflammation and endothelial damage. 1,[4][5][6][7] It was suggested to have a role in insulin resistance, dyslipidemia, obesity atherothrombotic disease, pathogenesis of rheumatoid arthritis and infection-induced pre-term birth.…”