Toll 样受体 4 Asp299Gly 多态性在 HIV 感染患者心血管疾病发展中的作用。

Role of toll-like receptor 4 Asp299Gly polymorphism in the development of cardiovascular diseases in HIV-infected patients.

机构信息

Laboratory of Immunovirology, Biomedicine Institute of Seville, Virgen del Rocío University Hospital, IBIS/CSIC/SAS/University of Seville.

Molecular Immunobiology Laboratory, General Universitary Hospital Gregorio Marañon, Health Research Institute Gregorio Marañon, Spanish HIV HGM BioBank, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid.

出版信息

AIDS. 2018 May 15;32(8):1035-1041. doi: 10.1097/QAD.0000000000001797.

DOI:10.1097/QAD.0000000000001797

PMID:29547441

Abstract

OBJECTIVE

Cardiovascular diseases (CVDs) are one of the main causes of morbimortality in HIV-infected patients on suppressive antiretroviral therapy. The objective of this work was to evaluate the role of single nucleotide polymorphisms (SNPs) in lipopolysaccharide (LPS) Toll-like receptor 4 (TLR4) and CVDs occurrence in HIV-infected patients. Additionally, the functional consequences of carrying these SNPs were analyzed.

METHODS

The association of TLR4 SNPs, Asp299Gly/Thr399Ile with CVDs occurrence was analyzed using multivariate logistic regression models. Clinical, immunological, and traditional cardiovascular risk factors were used as covariates. The monocyte phenotype and response were assessed by multiparametric flow cytometry comparing carriers with noncarriers of this SNP.

RESULTS

Asp299Gly SNP, assayed in 253 HIV-infected patients, was independently associated with the occurrence of CVDs after adjusting for CD4+ T-cell nadir, HCV-coinfection, bacterial pneumonia, diabetes mellitus, and traditional cardiovascular risk factors [odds ratio (confidence interval 95%) = 3.672 (1.061-12.712), P = 0.04). Carriers of Asp299Gly SNP showed higher percentage of patrolling and intermediate monocytes producing a proinflammatory combination of cytokines compared with noncarriers (P = 0.037 and P = 0.046, respectively). Intermediate monocyte subset levels correlated with soluble interleukin-6 levels only in carriers (r = 0.89; P = 0.01).

CONCLUSION

TLR4 Asp299Gly polymorphism is independently associated with the occurrence of CVDs in HIV-infected patients. The proinflammatory profile associated to this variant could be involved in the development of atherosclerotic pathologies.

摘要

目的

心血管疾病（CVDs）是接受抑制性抗逆转录病毒疗法的 HIV 感染者发病率和死亡率的主要原因之一。本研究旨在评估脂多糖（LPS）Toll 样受体 4（TLR4）单核苷酸多态性（SNPs）在 HIV 感染者 CVDs 发生中的作用，并分析携带这些 SNPs 的功能后果。

方法

采用多变量逻辑回归模型分析 TLR4 SNPs（Asp299Gly/Thr399Ile）与 CVDs 发生的相关性。将临床、免疫和传统心血管危险因素作为协变量。通过比较携带和不携带该 SNP 的单核细胞表型和反应，采用多参数流式细胞术评估单核细胞表型和反应。

结果

在 253 名 HIV 感染者中检测到 Asp299Gly SNP，经调整 CD4+T 细胞最低值、HCV 合并感染、细菌性肺炎、糖尿病和传统心血管危险因素后，该 SNP 与 CVDs 的发生独立相关[比值比（置信区间 95%）=3.672（1.061-12.712），P=0.04]。与非携带者相比，携带 Asp299Gly SNP 的患者中巡逻和中间单核细胞的比例更高，且产生促炎细胞因子的组合也更高（P=0.037 和 P=0.046）。中间单核细胞亚群水平仅与携带者的可溶性白细胞介素-6 水平相关（r=0.89；P=0.01）。