Mohamed Mahmoud K, Atef Azza A, Moemen Leqaa A, Abdel Azeem Amira A, Mohalhal Islam A, Taha Alshaimaa M
Biochemistry Unit, Research Institute of Ophthalmology, Giza, Egypt.
Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
J Genet Eng Biotechnol. 2022 Aug 15;20(1):122. doi: 10.1186/s43141-022-00401-9.
Genetic factors are implicated in the progression of DR-a global cause of blindness. Hence, the current work investigated the association of HIF-1α rs11549465 and VEGF rs3025039 genetic variants with the different stages of retinopathy among T2DM Egyptian patients. The crosslinks of these variants were explored with angiogenesis (VEGF), inflammation (AGEP and VCAM-1), and anti-inflammation (CTRP3) markers. Two hundred eighty-eight subjects were recruited in this study: 72 served as controls and 216 were having T2DM and were divided into diabetics without retinopathy (DWR), diabetics with non-proliferative retinopathy (NPDR), and diabetics with proliferative retinopathy (PDR). The genetic variants were analyzed using PCR-RFLP and their associations with NPDR and PDR were statistically tested. The circulating levels of AGEP, VCAM-1, HIF-1α, VEGF, and CTRP3 were assayed followed by analyzing their associations statistically with the studied variants.
Only HIF-1α rs11549465 genetic variant (recessive model) was significantly associated with the development of NPDR among T2DM patients (p < 0.025) with a significant correlation with the circulating HIF-1α level (p < 0.0001). However, this variant was not associated with PDR progression. Neither HIF-1α rs11549465 nor VEGF rs3025039 genetic variants were associated with the PDR progression. The circulating AGEP, VCAM-1, HIF-1α, and VEGF were significantly elevated (p < 0.0001) while the CTRP3 was significantly decreased (p < 0.0001) in NPDR and PDR groups. The HIF-1α rs11549465 CT and/or TT genotype carriers were significantly associated with AGEP and VCAM-1 levels in the NPDR group, while it showed a significant association with the CTRP3 level in the PDR group. The VEGF rs3025039 TT genotype carriers showed only a significant association with the CTRP3 level in the PDR group.
The significant association of HIF-1α rs11549465 other than VEGF rs3025039 with the initiation of NPDR in T2DM Egyptian patients might protect them from progression to the proliferative stage via elevating circulating HIF-1α. However, this protective role was not enough to prevent the development of NPDR because of enhancing angiogenesis and inflammation together with suppressing anti-inflammation. The non-significant association of HIF-1α rs11549465 with PDR among T2DM patients could not make this variant a risk factor for PDR progression.
遗传因素与糖尿病视网膜病变（DR）的进展有关，DR是全球失明的一个原因。因此，当前研究调查了缺氧诱导因子-1α（HIF-1α）基因rs11549465和血管内皮生长因子（VEGF）基因rs3025039的遗传变异与埃及2型糖尿病患者视网膜病变不同阶段的关联。探讨了这些变异与血管生成（VEGF）、炎症（晚期糖基化终末产物（AGEP）和血管细胞黏附分子-1（VCAM-1））以及抗炎（C1q/TNF相关蛋白3（CTRP3））标志物之间的交联。本研究招募了288名受试者：72名作为对照，216名患有2型糖尿病，分为无视网膜病变的糖尿病患者（DWR）、非增殖性糖尿病视网膜病变（NPDR）患者和增殖性糖尿病视网膜病变（PDR）患者。使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析遗传变异，并对其与NPDR和PDR的关联进行统计学检验。检测AGEP、VCAM-1、HIF-1α、VEGF和CTRP3的循环水平，然后分析它们与研究变异的统计学关联。
仅HIF-1α基因rs11549465遗传变异（隐性模型）与2型糖尿病患者中NPDR的发生显著相关（p < 0.025），且与循环HIF-1α水平显著相关（p < 0.0001）。然而，该变异与PDR进展无关。HIF-1α基因rs11549465和VEGF基因rs3025039的遗传变异均与PDR进展无关。NPDR和PDR组中，循环AGEP、VCAM-1、HIF-1α和VEGF显著升高（p < 0.0001），而CTRP3显著降低（p < 0.0001）。NPDR组中，HIF-1α基因rs11549465的CT和/或TT基因型携带者与AGEP和VCAM-1水平显著相关，而在PDR组中与CTRP3水平显著相关。VEGF基因rs3025039的TT基因型携带者仅在PDR组中与CTRP3水平显著相关。
在埃及2型糖尿病患者中，HIF-1α基因rs11549465而非VEGF基因rs3025039与NPDR的起始显著相关，可能通过升高循环HIF-1α保护患者免于进展到增殖期。然而，由于促进血管生成和炎症以及抑制抗炎作用，这种保护作用不足以预防NPDR的发生。2型糖尿病患者中HIF-1α基因rs11549465与PDR无显著关联，这使得该变异不是PDR进展的危险因素。
