Modi William S, Lautenberger James, An Ping, Scott Kevin, Goedert James J, Kirk Gregory D, Buchbinder Susan, Phair John, Donfield Sharyne, O'Brien Stephen J, Winkler Cheryl
SAIC-Frederick, Inc., Basic Research Program, Frederick, MD 21702-1201, USA.
Am J Hum Genet. 2006 Jul;79(1):120-8. doi: 10.1086/505331. Epub 2006 May 30.
CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.
CCL3（巨噬细胞炎性蛋白-1α）、CCL4（巨噬细胞炎性蛋白-1β）和CCL18（树突状细胞趋化因子1/肺和激活调节趋化因子/巨噬细胞来源的趋化因子-1）是由巨噬细胞、自然杀伤细胞、成纤维细胞、肥大细胞、CD4(+) T细胞和CD8(+) T细胞产生的强效趋化因子。CCL3和CCL4是原发性人类免疫缺陷病毒1型（HIV-1）共受体CCR5的天然配体，也已知可激活并增强自然杀伤细胞的细胞毒性。对参加美国五个获得性免疫缺陷综合征（AIDS）自然史队列研究的3000多名参与者的基因组DNA进行基因分型，检测17号染色体q12区域47kb区间内包含CCL3、CCL4和CCL18基因的21个单核苷酸多态性（SNP）。所有21个SNP在非裔美国人（AA）中均具有多态性，而在欧裔美国人（EA）中，21个中有7个次要等位基因频率<0.01。在一个包含17个SNP的37kb区间内观察到显著的连锁不平衡，在两个种族群体中，许多成对的D'值均超过0.70，尤其是在EA中。在AA和EA中分别观察到4个和3个单倍型模块。各模块之间相关性很强，模块内常见单倍型的多样性有限。报告了两个显著关联，重复了一项早期研究。首先，在注射吸毒者的AIDS与静脉注射经历队列的AA成员中，与HIV-1感染的血清转化者相比，在高暴露、持续未感染HIV-1的个体中，CCL3中覆盖2231bp的3个相关SNP的频率显著升高（P = 0.02 - 0.03）。其次，在多中心AIDS队列研究队列的EA中，跨越36kb并包含所有三个基因的7个高度相关SNP与疾病进展更快显著相关（P = 0.01 - 0.02）。这些结果重申了趋化因子基因变异在HIV-1/AIDS发病机制中的重要性，并强调局部连锁不平衡使得确定因果突变变得困难。
