妊娠糖尿病與IL-10基因多型性之探討

Abstract

妊娠糖尿病(Gestational diabetes mellitus, GDM)是在妊娠時期最常見的代謝疾病，而抗發炎性細胞激素Interleukin-10(IL-10)具有穩定與維持妊娠發育的重要功能，根據先前研究指出在IL-10基因啟動子區域三個位置-592 C>A (rs1800872)、-819 C>T (rs1800871)和-1082 A>G (rs1800896)的單核苷酸多型性(single nucleotide polymorphisms, SNPs)會影響IL-10表現量，但這三個位置的多型性對於妊娠糖尿病發生的影響尚未清楚，我們除了研究常見-592、-819和-1082三個位置外，還探討未被發表過3388 A>C (rs3021094)位置，希望藉由分析這些SNPs變異可以找出對於IL-10表現量影響與妊娠糖尿病發生的相關性。 我們的研究對象依據75公克葡萄糖口服耐性測試(oral glucose tolerance tests, OGTT)分為100位受試者是健康對照組，42位受試者是妊娠糖尿病患者，使用卡方檢定(Chi-square test)或是費雪精確性檢定(Fisher’s exact test)分析基因型與對偶基因頻率，勝算比(Odds ratio, OR)與95%信賴區間(confidence interval, CI)評估妊娠糖尿病發生的風險值；而IL-10 SNPs基因型與IL-10表現量關係，使用ELISA測量母血中IL-10濃度，以無母數Kruskal-Wallis H test或是Mann-Whitney U test統計分析。 研究結果顯示，IL-10 3388 A>C在顯性模式(AA+CA versus CC)下，屬於基因型AA+CA與對偶基因A在妊娠糖尿病所占的比例顯著高於對照組(P < 0.05)，並且具有較高風險發生妊娠糖尿病(OR = 2.88，95% CI [1.03-8.07]；OR = 1.85，95%CI [1.10-3.12])，而比較-592 C>A、-819 C>T和-1082 A>G的基因型與對偶基因頻率在妊娠糖尿病以及對照組間沒有顯著差異(P ≥ 0.05)；IL-10表現量方面，當-592 C>A基因型是CC、-819 C>T基因型是CC與3388 A>C基因型是AA時，IL-10表現量有顯著較高的情形(P < 0.05)，但比較-1082 A>G基因型沒有顯著差異(P ≥ 0.05)。 總而言之，在IL-10 3388 A>C (rs3021094)的位置，對於IL-10表現量與妊娠糖尿病發生都有顯著相關，未來有機會可以考慮納入預測妊娠糖尿病發生的指標之一。

Gestational diabetes mellitus (GDM) is the most common metabolic disease in pregnant women. Interleukin-10 (IL-10) is an important anti-inflammatory cytokines for pregnancy maintenance and development. Previous studies indicated that three IL-10 promoter region single nucleotide polymorphisms (SNPs) at position -592 C>A (rs1800872), -819 C>T (rs1800871), and -1082 A>G (rs1800896) play an important role in IL-10 secretion capacity, but it’s genetic polymorphisms in GDM are unknown. In addition to the three common SNPs -592, -819, and -1082, we also explore a rare to be reported position 3388 A>C (rs3021094). We examined whether these SNPs variant are associated with IL-10 production and GDM susceptibility. Our case-control study included 100 healthy controls and 42 women with GDM grouped according to 75g oral glucose tolerance tests (OGTT). The polymorphisms of genotype and allele frequencies were analyzed by Chi-square test or Fisher’s exact test. Odds ratio (OR) and 95% confidence interval (CI) were used to explain relative risk of GDM. Maternal plasma IL-10 levels were measured by ELISA and associated with the polymorphisms of genotype were analyzed by non-parametric Kruskal-Wallis H test or Mann Whitney U test. In the dominant model (AA+CA versus CC) of IL-10 3388 A>C, AA+CA genotype and A allele frequencies were significantly higher in cases compared with controls (P < 0.05), suggesting significant association with risk of GDM (OR = 2.88, 95% CI [1.03-8.07]; OR = 1.85, 95%CI [1.10-3.12]). No significant difference of -592 C>A, -819 C>T, and -1082 A>G were observed between cases and controls (P > 0.05). CC genotype of -592 C>A, CC genotype of -819 C>T, and AA genotype of 3388 A>C were all significantly higher IL-10 plasma level production compared with other genotypes (P < 0.05), suggesting significant association with IL-10 high-level production. No significant difference of -1082 A>G were observed (P > 0.05). In conclusion, SNP at position IL-10 3388 A>C was significantly associated with the risk of GDM and IL-10 plasma level high production. IL-10 3388 A>C has potential for use as a predictive maker for GDM.