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

• Published in: The journal of clinical endocrinology and metabolism Vol. 102; no. 3; pp. 884 - 892
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.03.2017; Copyright Oxford University Press; Oxford University Press
• Subjects: 3' Untranslated regions; Aged; Asians - genetics; Azacytidine; Bisulfite; Body mass; Body Mass Index; C-reactive protein; C-Reactive Protein - metabolism; Cell Line; CpG Islands; Cytosine; Deoxyribonucleic acid; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; DNA; DNA Methylation; Epigenesis, Genetic - genetics; Female; Gene polymorphism; Genotype; Genotype & phenotype; Genotypes; Guanine; Humans; Japan; Leukocytes; Male; Middle Aged; Monocytes; mRNA; Plasma; Polymorphism; Polymorphism, Single Nucleotide; Resistin - blood; Resistin - genetics; RNA, Messenger - metabolism; Single-nucleotide polymorphism; Japan
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2016-2417

Context:We previously reported that SNP (single nucleotide polymorphism) -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 CpG 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 2,078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after the bisulfite conversion of DNA.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-420 was inversely associated with plasma resistin in C/C (β= -0.134, P< 0.001) or C/G (β=-0.227, P<0.001) genotype. In THP-1 human monocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC decreased the methylation at SNP-420, and increased RETN mRNA. SNP+1263 (rs3745369), located in the 3’ untranslated region of RETN, was also associated with methylation at SNP-420. In addition, hs-CRP (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.