A at Single Nucleotide Polymorphism-358 Is Required for G at-420 to Confer the Highest Plasma Resistin in the General Japanese Population
A at Single Nucleotide Polymorphism-358 Is Required for G at-420 to Confer the Highest Plasma Resistin in the General Japanese Population
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DOI：
10.1371/journal.pone.0009718
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发表时间：
2010-03-16
期刊：
影响因子：
3.7
通讯作者：
Osawa, Haruhiko
中科院分区：
文献类型：
--
作者：
Onum, Hiroshi;Tabara, Yasuharu;Osawa, Haruhiko
胰岛素抵抗是2型糖尿病的一个特征。抵抗素，由脂肪细胞分泌，导致小鼠胰岛素抵抗。我们以前报道过，人类RETN基因2420（rs 1862513）单核苷酸多态性（SNP）的G/G基因型通过增强其启动子活性增加了2型糖尿病的易感性。日本受试者中G/G基因型的血浆肌酐水平最高，其次是C/G和C/C。在这项研究中，我们对2,019名居住在社区的日本受试者的RETN区域的血浆SNPs和SNPs进行了横断面分析。血浆Gln与SNP-638（rs34861192）、SNP-537（rs34124816）、SNP-420、SNP-358（rs3219175）、SNP+299（rs3745367）和SNP+1263（rs3745369）相关（P，所有病例均为10（-13））。SNP-638、SNP-420、SNP-358和SNP+157处于同一连锁不平衡区。SNP-358和SNP-638与完全LD接近（r（2）= 0.98），与SNP-420密切相关（r（2）分别为0.50和0.51）。SNP-358（或SNP-638）或SNP-420与血浆β-内酰胺酶之间的相关性似乎很强（高血浆β-内酰胺酶的危险等位基因; SNP-358处的A，r（2）= 0.5224，P = 4.94610 2324; SNP-420处的G，r（2）= 0.2616，P = 1.71610（-133））。在SNP-420和SNP-358确定的单倍型中，C-G、G-A和G-G的估计频率分别为0.6700、0.2005和0.1284，C-A很少见（0.0011），这表明在2358处具有A的受试者通常在-420处具有G。该G-A单倍型赋予最高的血浆Gln（与C-G相比，8.24ng/ml差异/等位基因，P < 0.0001）。在THP-1细胞中，具有G-A单倍型的RETN启动子表现出最高的活性。核蛋白特异性识别SNP-358处的一个碱基差异，但不识别SNP-638处的一个碱基差异。因此，在一般日本人群中，需要-358的A和2420的G才能产生最高的血浆肌酐。在高加索人中，SNP-420和血浆中的Gln之间的关联并不强，2358处的A可能不存在，这表明SNP-358可以解释这种种族差异。
Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at 2420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P, 10(-13) in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r(2) = 0.98), and were tightly correlated with SNP-420 (r(2) = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r(2) = 0.5224, P = 4.94610 2324; G at SNP-420, r(2) = 0.2616, P = 1.71610(-133)). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at 2358, generally had G at -420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P < 0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at 2420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at 2358 may not exist, suggesting that SNP-358 could explain this ethnic difference.