Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russian Federation.
Department of General Hygiene, 3 Karl Marx Street, Kursk 305041, Russian Federation.
J Stroke Cerebrovasc Dis. 2024 Jun;33(6):107685. doi: 10.1016/j.jstrokecerebrovasdis.2024.107685. Epub 2024 Mar 24.
Increased plasma gamma-glutamyl transferase (GGT1) has been identified as a robust and independent risk factor for ischemic stroke (IS), but the molecular mechanisms of the enzyme-disease association are unclear. The present study investigated whether polymorphisms in the GGT1 gene contribute to IS susceptibility.
DNA samples obtained from 1288 unrelated individuals (600 IS patients and 688 controls) were genotyped for common single nucleotide polymorphisms of GGT1 using the MassArray-4 platform.
The rs5751909 polymorphism was significantly associated with decreased risk of ischemic stroke regardless sex and age (P ≤ 0.01, dominant genetic model). The haplotype rs4820599A-rs5760489A-rs5751909A showed strong protection against ischemic stroke (OR 0.53, 95 %CI 0.36 - 0.77, P ≤ 0.0001). The protective effect of SNP rs5751909 in the stroke phenotype was successfully replicated in the UK Biobank, SiGN, and ISGC cohorts (P ≤ 0.01). GGT1 polymorphisms showed joint (epistatic) effects on the risk of ischemic stroke, with some known IS-associated GWAS loci (e.g., rs4322086 and rs12646447) investigated in our population. In addition, SNP rs5751909 was found to be strongly associated with a decreased risk of ischemic stroke in non-smokers (OR 0.54 95 %CI 0.39-0.75, P = 0.0002) and non-alcohol abusers (OR 0.43 95 %CI 0.30-0.61, P = 2.0 × 10), whereas no protective effects of this SNP against disease risk were observed in smokers and alcohol abusers (P < 0.05).
We propose mechanisms underlying the observed associations between GGT1 polymorphisms and ischemic stroke risk. This pilot study is the first to demonstrate that GGT1 is a novel susceptibility gene for ischemic stroke and provides additional evidence of the genetic contribution to impaired redox homeostasis underlying disease pathogenesis.
已发现血浆 γ-谷氨酰转移酶（GGT1）升高是缺血性中风（IS）的一个强有力且独立的危险因素，但该酶与疾病关联的分子机制尚不清楚。本研究旨在探讨 GGT1 基因中的多态性是否导致 IS 易感性。
使用 MassArray-4 平台对来自 1288 名无血缘关系个体（600 名 IS 患者和 688 名对照者）的 DNA 样本进行 GGT1 常见单核苷酸多态性的基因分型。
无论性别和年龄，rs5751909 多态性与降低缺血性中风风险显著相关（P ≤ 0.01，显性遗传模型）。rs4820599A-rs5760489A-rs5751909A 单体型对缺血性中风具有很强的保护作用（OR 0.53，95 %CI 0.36-0.77，P ≤ 0.0001）。SNP rs5751909 在中风表型中的保护作用在 UK Biobank、SiGN 和 ISGC 队列中得到了成功复制（P ≤ 0.01）。GGT1 多态性对缺血性中风的风险具有联合（上位性）效应，一些已发现的与 IS 相关的 GWAS 位点（例如 rs4322086 和 rs12646447）在本研究人群中也进行了研究。此外，在非吸烟者（OR 0.54，95 %CI 0.39-0.75，P = 0.0002）和非酗酒者（OR 0.43，95 %CI 0.30-0.61，P = 2.0×10-4）中，SNP rs5751909 与缺血性中风风险降低显著相关，但在吸烟者和酗酒者中未观察到该 SNP 对疾病风险的保护作用（P < 0.05）。
我们提出了观察到的 GGT1 多态性与缺血性中风风险之间关联的潜在机制。本初步研究首次表明 GGT1 是缺血性中风的一个新的易感基因，并为疾病发病机制中氧化还原平衡受损的遗传贡献提供了额外的证据。
