Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
PLoS One. 2010 Mar 16;5(3):e9718. doi: 10.1371/journal.pone.0009718.
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 -420 (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 = 4.94x10(-324); G at SNP-420, r(2) = 0.2616, P = 1.71x10(-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 -358, 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 -420 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 -358 may not exist, suggesting that SNP-358 could explain this ethnic difference.
胰岛素抵抗是 2 型糖尿病的特征。抵抗素是脂肪细胞分泌的一种蛋白，它在小鼠中引起胰岛素抵抗。我们之前的研究报道，人类抵抗素基因（RETN）-420 （rs1862513）处的单核苷酸多态性（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。日本人的血浆抵抗素水平最高，其次是 C/G 基因型和 C/C 基因型。在这项研究中，我们对 2019 名居住在社区的日本受试者的血浆抵抗素和 RETN 区域中的 SNP 进行了横断面分析。血浆抵抗素与 SNP-638（rs34861192）、SNP-537（rs34124816）、SNP-420、SNP-358（rs3219175）、SNP+299（rs3745367）和 SNP+1263（rs3745369）相关（所有情况下 P<10(-13)）。SNP-638、SNP-420、SNP-358 和 SNP+157 位于同一连锁不平衡（LD）块中。SNP-358 和 SNP-638 几乎完全处于 LD（r(2) = 0.98），并且与 SNP-420 紧密相关（r(2) = 0.50 和 0.51）。SNP-358 或 SNP-638 或 SNP-420 与血浆抵抗素之间的相关性似乎很强（高血浆抵抗素的风险等位基因；SNP-358 的 A，r(2) = 0.5224，P = 4.94x10(-324)；SNP-420 的 G，r(2) = 0.2616，P = 1.71x10(-133)）。在由 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（0.0011），这表明-358 位的 A 通常在-420 位为 G。这种 G-A 单倍型导致最高的血浆抵抗素（与 C-G 相比，每个等位基因相差 8.24ng/ml，P<0.0001）。在 THP-1 细胞中，具有 G-A 单倍型的 RETN 启动子显示出最高的活性。核蛋白特异性识别 SNP-358 处的一个碱基差异，但不识别 SNP-638 处的差异。因此，-358 位的 A 是-420 位的 G 赋予普通日本人群中最高血浆抵抗素所必需的。在白种人中，SNP-420 与血浆抵抗素之间的关联并不强，并且可能不存在-358 位的 A，这表明 SNP-358 可以解释这种种族差异。
