Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Postgraduate Program in Gastroenterology and Hepatology Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Int J Immunogenet. 2024 Feb;51(1):20-31. doi: 10.1111/iji.12646. Epub 2023 Nov 20.
This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [p = .012 (OR 3.0; 95%CI 3.0-333.3) and p = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.
本研究通过比较系统性红斑狼疮（SLE）患者和与之匹配的对照组的 CCR5 启动子区域多态性，研究 CCR5 启动子区域多态性对系统性红斑狼疮发病的影响。共对 382 例 SLE 患者（289 例欧洲裔和 93 例非洲裔）和 375 名对照者（243 例欧洲裔和 132 例非洲裔）进行了 CCR2-64I G > A（rs1799864）、CCR5-59353 C > T（rs1799988）、CCR5-59356 C > T（rs41469351）、CCR5-59402 A > G（rs1800023）和 CCR5-59653 C > T（rs1800024）多态性的基因分型，方法为聚合酶链反应-限制性片段长度多态性和直接测序。研究中还包括 CCR5Δ32 分析的先前数据，以推断 CCR5 单倍型，并作为二元逻辑回归中的一个可能的混杂因素。与对照组相比，欧洲裔患者表现出更高的 CCR5 野生型基因型频率（相反，Δ32 等位基因频率降低）和 HHG2 单倍型频率降低，这两个因素均显著影响疾病风险[P =.003（OR 3.5，95%CI 1.6-7.5）和 2.0%与 7.2%（残余 P = 2.9E-5），分别]。此外，非洲裔患者与对照组之间的 HHA/HHB、HHC 和 HHG2 单倍型频率存在差异[10%比 20.5%（残余 P =.003），29.4%比 17.4%（残余 P =.003）和 3.9%比 0.8%（残余 P =.023），分别]。考虑到疾病的临床表现，CCR5Δ32 的存在被证实为非洲裔患者发生 IV 型肾炎的易感因素，当所有患者进行比较时也是如此[P =.012（OR 3.0；95%CI 3.0-333.3）和 P =.0006（OR 6.8；95%CI 1.9-24.8），分别]。总之，本研究表明 CCR5 启动子多态性是 SLE 的重要疾病修饰因子。现有数据进一步证实了 CCR5Δ32 多态性是欧洲裔患者发病的保护性因素，是非洲裔患者发生 IV 型肾炎的易感因素。此外，我们还描述了非洲裔患者中 HHA/HHB 单倍型频率降低和 HHC 和 HHG*2 单倍型频率增加，这可能改变特定细胞亚群中 CCR5 蛋白的表达。
