2 型糖尿病视网膜病变印度患者九种候选基因多态性的关联分析。
Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy.
机构信息
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.
出版信息
BMC Med Genet. 2010 Nov 10;11:158. doi: 10.1186/1471-2350-11-158.
BACKGROUND
Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM).
METHODS
Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies.
RESULTS
Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied.
CONCLUSIONS
This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM.
背景
糖尿病视网膜病变（DR）通常被定义为一种小血管疾病，主要影响糖尿病（DM）的小内视网膜血管。它是一种多因素疾病，具有很强的遗传成分。本研究旨在调查一组九个候选基因与南亚人群中 2 型糖尿病（T2DM）患者糖尿病视网膜病变发展的关联。
方法
基于文献中报道的与 DR 的关联，选择了七个候选基因（RAGE、PEDF、AKR1B1、EPO、HTRA1、ICAM 和 HFE）。另外选择了两个基因 CFH 和 ARMS2，基于它们在先前报道与 DR 或其他相关疾病相关的生物途径中的作用。对 345 名 DR 和 356 名无视网膜病变的糖尿病患者（DNR）的 14 个单核苷酸多态性（SNP）和一个二核苷酸重复多态性进行了基因分型，这些 SNP 和多态性之前与 DR 或其他相关疾病有关联。在该筛选组中显示出阳性关联的基因在阿瓦林德眼科医院的另外 100 名 DR 和 90 名 DNR 患者的进一步检测中进行了测试。在二次筛查中显示出关联的基因进行了合并分析，合并了之前通过印度 Sankara Nethralaya 医院招募并通过基因分型的 100 名 DR 和 100 名 DNR 患者。使用直接测序、TaqMan SNP 基因分型、RFLP 分析和 SNaPshot PCR 检测等组合评估基因型。使用卡方检验和 Fisher 精确检验分析基因型和等位基因频率。
结果
在所筛选的九个基因座（15 个多态性）中，RAGE 基因中的 SNP rs2070600（G82S）与 DR 显著相关（与 DNR 相比，等位基因 P = 0.016，显性模型 P = 0.012）。SNP rs2070600 进一步在确认队列中与 DR 显著相关（P = 0.035，显性模型 P = 0.032）。将两个队列合并，等位基因 P < 0.003，显性 P = 0.0013。与 Sankara Nethralaya 队列的合并分析显示等位基因 P = 0.0003，显性 P = 0.00011，次要等位基因的比值比为 0.49（0.34 - 0.70）。在 HTRA1 中，rs11200638（G > A）与 DR 呈边缘显著相关（P = 0.055），而 LOC387715 中的 rs10490924 则为 P = 0.07。在所研究的其他 7 个基因中未观察到 SNP 的统计学意义。
结论
本研究在患有 T2DM 的印度人群中仅确认了一个多态性（RAGE 中的 rs2070600）与 DR 显著相关。
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