aDepartment of Epidemiology and Biostatistics, University at Albany, State University of New York, Rensselaer, New York bDepartment of Statistics. George Washington University, Washington, DC cDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx dDepartment of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx eDepartment of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York fDepartment of Medicine, Georgetown University Medical Center, Washington, DC gDepartment of Medicine, University of Southern California, Los Angeles, California hDepartment of Medicine, Rush University Medical Center, Chicago, Illinois iDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland jBluestone Center for Clinical Research kDepartment of Oral and Maxillofacial Surgery, New York University, New York, New York lDepartment of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC mDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
AIDS. 2017 Nov 28;31(18):2483-2492. doi: 10.1097/QAD.0000000000001648.
To assess variation in genes that regulate cholesterol metabolism in relation to the natural history of HIV infection.
Cross-sectional and longitudinal analysis of the Women's Interagency HIV Study.
We examined 2050 single nucleotide polymorphisms (SNPs) in 19 genes known to regulate cholesterol metabolism in relation to HIV viral load and CD4 T-cell levels in a multiracial cohort of 1066 antiretroviral therapy-naive women.
Six SNPs were associated with both HIV viral load and CD4 T-cell levels at a false discovery rate of 0.01. Bioinformatics tools did not predict functional activity for five SNPs, located in introns of nuclear receptor corepressor 2, retinoid X receptor alpha (RXRA), and tetratricopeptide repeat domain 39B. Rs17111557 located in the 3' untranslated region of proprotein convertase subtilisin/kexin type 9 (PCSK9) putatively affects binding of hsa-miR-548t-5p and hsa-miR-4796-3p, which could regulate PCSK9 expression levels. Interrogation of rs17111557 revealed stronger associations in the subset of women with HIV/hepatitis C virus (HCV) coinfection (n = 408, 38% of women). Rs17111557 was also associated with low-density lipoprotein cholesterol levels in HIV/HCV coinfected (β: -10.4; 95% confidence interval: -17.9, -2.9; P = 0.007), but not in HIV monoinfected (β:1.2; 95% confidence interval: -6.3, 8.6; P = 0.76) women in adjusted analysis.
PCSK9 polymorphism may affect HIV pathogenesis, particularly in HIV/HCV coinfected women. A likely mechanism for this effect is PCSK9-mediated regulation of cholesterol metabolism. Replication in independent cohorts is needed to clarify the generalizability of the observed associations.
评估与 HIV 感染自然史相关的调节胆固醇代谢的基因变异。
妇女艾滋病研究机构间的横断面和纵向分析。
我们在一个由 1066 名未接受抗逆转录病毒治疗的妇女组成的多种族队列中，研究了与 HIV 病毒载量和 CD4 T 细胞水平相关的 19 个调节胆固醇代谢的基因中的 2050 个单核苷酸多态性（SNP）。
在假发现率为 0.01 时，有 6 个 SNP 与 HIV 病毒载量和 CD4 T 细胞水平均相关。生物信息学工具并未预测位于核受体共抑制因子 2、视黄醇 X 受体α（RXRA）和四肽重复结构域 39B 内含子中的 5 个 SNP 的功能活性。位于前蛋白转化酶枯草杆菌蛋白酶/柯萨奇蛋白酶 9（PCSK9）3'非翻译区的 rs17111557 可能影响 hsa-miR-548t-5p 和 hsa-miR-4796-3p 的结合，从而调节 PCSK9 的表达水平。rs17111557 的检测结果显示，在 HIV/丙型肝炎病毒（HCV）合并感染的亚组妇女（n=408，占妇女的 38%）中，其相关性更强。rs17111557 还与 HIV/HCV 合并感染妇女的低密度脂蛋白胆固醇水平相关（β：-10.4；95%置信区间：-17.9，-2.9；P=0.007），但与 HIV 单感染妇女无关（β：1.2；95%置信区间：-6.3，8.6；P=0.76）。
PCSK9 多态性可能影响 HIV 的发病机制，特别是在 HIV/HCV 合并感染的妇女中。这种影响的一个可能机制是 PCSK9 介导的胆固醇代谢调节。需要在独立的队列中进行复制，以阐明观察到的关联的普遍性。
