Dual Effects of a RETN Single Nucleotide Polymorphism (SNP) at-420 on Plasma Resistin: Genotype and DNA Methylation

作者：Onuma Hiroshi; Tabara Yasuharu; Kawamura Ryoichi; Ohashi Jun; Nishida Wataru; Takata Yasunori; Ochi Masaaki; Nishimiya Tatsuya; Ohyagi Yasumasa; Kawamoto Ryuichi; Kohara Katsuhiko; Miki Tetsuro; Osawa Haruhiko^*

来源：Journal of Clinical Endocrinology & Metabolism, 2017, 102(3): 884-892.

DOI：10.1210/jc.2016-2417

Context: We previously reported that single nucleotide polymorphism (SNP)-420 C>G (rs1862513) in the promoter region of RETN was associated with type 2 diabetes. Plasma resistin was tightly correlated with SNP-420 genotypes. SNP-420 is a CpG-SNP affecting the sequence of cytosine-phosphate-guanine dinucleotides.
Objective: To examine whether methylation at SNP-420 affects plasma resistin, we analyzed plasma resistin and methylation at RETN SNP-420.
Design and Methods: Genomic DNA was extracted from peripheral white blood cells in 2078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after DNA bisulfite conversion.
Results: Methylation at SNP-420 was highest in the C/C genotype (36.9 +/- 5.7%), followed by C/G (21.4 +/- 3.5%) and G/G (2.9 +/- 1.4%; P, 0.001). When assessed in each genotype, methylation at SNP-420was inverselyassociatedwithplasmaresistin in the C/C (beta = -0.134, P, 0.001) or C/G(beta = -0.227, P<0.001) genotype. In THP-1 humanmonocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC, decreased the methylation at SNP-420 and increased RETN messenger RNA. SNP+ 1263 (rs3745369), located in the 3' untranslated region of RETN, was also associated with methylation at SNP-420. In addition, highly sensitive C-reactive protein was inversely associated with methylation at SNP-420 in the C/C genotype, whereas body mass index was positively associated.
Conclusions: Plasma resistin was inversely associated with the extent of methylation at SNP-420 mainly dependent on the SNP-420 genotype. The association can also be explained partially independent of SNP-420 genotypes. SNP-420 could have dual, genetic and epigenetic effects on plasma resistin.

• 出版日期2017-3