Association of genetic variants in Sirt1 and Nrf2 gene with metabolic syndrome risk in a Chinese Han population


 Metabolic syndrome (MetS) is a complex of interrelated risk factors including central adiposity, raised blood pressure, hyperglycemia, elevated triglyceride levels and low high-density lipoprotein. Association studies have reported several genetic variants in Sirt1 gene and Nrf2 gene (Sirt1 rs7895833 A>G, Sirt1 rs2273773 C>T and Nrf2 rs6721961 C>A ) with contributions to T2DM susceptibility as well as some glycemic and metabolic traits. However, little is known about contributions of these three single nucleotide polymorphisms (SNPs) to above phenotypes in Chinese. Our study recruited 141 individuals with MetS and 549 individuals without MetS to investigate association between three SNPs of Sirt1, Nrf2 gene and MetS risk in a Chinese Han population using PCR-CTPP method. The result showed that the AA genotype of Sirt1 rs7895833was 2.41 times higher in MetS group than those of AG genotype（P=0.038）and 1.94 times higher than those of GG genotype（P=0.016）. he serum level of low-density lipoprotein cholesterol and HOMA-IR were significantly higher (P<0.05) in AA genotype of Sirt1 rs7895833 compared with AG and GG genotype in general population. And the serum level of total cholesterol in AA genotype was lower (P=0.033) than other two genotypes. However, the genotype frequency of Sirt1 rs2273773 and Nrf2 rs6721961 in MetS group were not significantly different from that in the control subjects, and those two genetic variants were not correlated with metabolic traits. These results underscore the contributions of SNPs of Sirt1 rs7895833 to MetS susceptibility in Chinese as well as glycemic and metabolic traits.

times higher than those of GG genotype(P=0.016). he serum level of low-density 23 lipoprotein cholesterol and HOMA-IR were significantly higher (P<0.05) in AA 24 genotype of Sirt1 rs7895833 compared with AG and GG genotype in general population. 25 And the serum level of total cholesterol in AA genotype was lower (P=0.033) than other 26 two genotypes. However, the genotype frequency of Sirt1 rs2273773 and Nrf2 27 rs6721961 in MetS group were not significantly different from that in the control 28 subjects, and those two genetic variants were not correlated with metabolic traits. These 29 results underscore the contributions of SNPs of Sirt1 rs7895833 to MetS susceptibility 30 in Chinese as well as glycemic and metabolic traits.  Our study aimed to investigate the relationship between Sirt1 rs7895833 A>G in the 75 promoter region, Sirt1 rs2273773 C>T in exon 5 silent mutation and Nrf2 rs6721961 76 subjects were excluded according to: 1) impaired liver or renal function, 2) malignant 88 tumors, 3) cardiovascular or peripheral vascular disease, 4) acute infectious disease or 89 chronic inflammatory disease, 5) pregnancy, 6) thyroid disease and with glucocorticoid 90 treatment, 7) incomplete clinical data.

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Results of association between each SNP and MetS risk are shown in Table 3  Based on the previous studies, the A allele carriers in rs7895833 tend to be obese, and 235 thereby at a high risk for MetS, which was consistent with the present study. Thus, it is 236 conceivable to see that subjects carrying the rs7895833 AG and AA genotypes had 237 higher levels of LDL-C and HOMA-IR than those carrying the GG genotype. The most 238 puzzling aspect of findings in this study is that the rs7895833 showed a negative 239 correlation with TC. It is possible that other factors disturbed the correlation between 240 the rs7895833 and TC level, such as lipid-lowering drugs, sample selection and skewed distribution of data. Furthermore, the SNP of rs7895833 is located in the promoter. In 242 addition, its base sequence is TTGACT, which has been proved to be a W-box-like 243 element of promoter [23]. Therefore, it is likely that these polymorphisms affect the 244 activity of Sirt1 gene through regulating promoter activity and thereby Sirt1 expression.

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Sirt1 deacetylates PGC-1α to promote its activity and interacts with PPAR-γ to repress 246 its transcription [6,7,24,25]. Thus, gene polymorphism of Sirt1 might affect the 247 activities of PGC-1α and PPAR-γ, and consequently it might be related to risk factors 248 of MetS. This study showed the findings so they could be, suggesting the rs7895833A 249 genotypes to be a possible biomarker of increased MetS susceptibility.

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Van den Berg SW et al. [26] reported that the CT genotype of Sirt1 rs2273773 had a 251 higher BMI than TT genotype. In another study, the frequencies of TT genotypes and 252 alleles for rs2273773 were significantly higher in patients with CVD compared to 253 control group [27]. Shimoyama et al. [19] also observed that the Nrf2 rs6721961 254 polymorphism has been associated with blood pressure in Japanese subjects. Wang et 255 al. [12] investigated Nrf2 gene polymorphism (rs6721961) in a Chinese population and 256 observed that individuals with the AA genotype had a significantly higher risk of 257 developing T2DM, relative to those with the CC genotype. However, there was no 258 significant difference in genotype and allele distributions between groups in the present 259 study. We speculated that our non-significant finding was majorly due to environmental 260 factor and the limited sample size.

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There are some limitations in the current study. The gene expressions and activities 262 were not determined. The studied sample size was relatively small. Based on a retrospective design, bias such as information bias and selection bias could not be rule 264 out. Despite these limitations, this is the first epidemiological study that associates the 265 SNPs of Sirt1 and Nrf2 genes to MetS.