GWAS研究SNP位点与中国人群HIV-1感染者疾病进程和疗效相关性研究
摘要
[目的]全球已进行了多个艾滋病全基因组关联分析(GWAS),发现了许多与艾滋病疾病进程相关的新位点,目前尚无在亚洲人群开展的对已发现GWAS位点的研究报道。本研究将探讨GWAS研究位点在中国人群与疾病进程的关系,并探讨部分与疾病进程有关的经典位点在中国人群与疾病进程和HAART疗效的相关关系
[方法]研究对象共纳入HIV感染者1098例,来自四个随访队列；以CD4细胞下降率为疾病进程观察指标,以至病毒有效抑制时间(VL<400/mL)和至病毒完全抑制时间(VL<50/mL)为疗效观察指标；共选择GWAS研究结果及部分经典位点共18个；从全血中提取DNA,以MassARRAY分型平台进行基因分型；使用秩和检验和卡方检验分析不同基因型的效应。对发现的与疾病进程相关的阳性位点,在长期不进展人群中进行验证。
[结果]对基因分型结果进行检出率和哈迪-温伯格平衡检验,最终共14个位点纳入研究。疾病进程研究样本共376例,结果发现GWAS研究位点rs9264942、 rs13199524和rs12198173与中国人群HIV感染者CD4细胞计数下降的速率有显著相关关系,在中国HIV感染者典型进展人群与长期不进展人群中分布有显著性差异。rs2395029位点在中国HIV感染者典型进展人群与长期不进展人群中分布有显著性差异。与疾病进程有关的经典位点未发现与CD4细胞下降率有相关关系；疗效研究样本共531例,发现治疗基线时病毒载量是治疗至病毒有效／完全抑制时间的独立影响因素。在校正了基线时病毒载量影响后,未发现与疗效有关的经典位点在中国人群与治疗至病毒有效／完全抑制时间有统计学相关关系。
[结论]研究首次在中国人群验证了GWAS结果的主要位点,证明在控制HIV病毒复制和疾病进程上,6号染色体MHC区对于中国人群均起中心作用。治疗基线时病毒载量是治疗至病毒有效／完全抑制时间的独立影响因素,提示对于基线病毒载量较高的患者,应使用更强效的HAART治疗方案,以预防耐药的发生。
[Objective]There has been several AIDS Genome-wide association studies which discovered many variants related to disease progression. To our knowledge, they have not been replicated in Asian population. We attempted to confirm these finding in Chinese population and studied the association between the classic AIDS restricted variants and disease progression as well as virological suppression after HAART therapy.
[Methods]We recruited1098HIV infected subjects from4study cohort. We define Rate of CD4decline as phenotype of the disease progression study and time to virological control (VL<400/mL)/suppression (VL<50/mL) as phenotype of treatment response study.18SNPs of GWAS study and classic variants were selected. Kruskal Wallis Test and Pearson Chi-Square test were used. Significant variants in the first phase were replicated in a LTNP cohort.
[Results]3SNPs were excluded which failed in Hardy-Weinberg test. In the disease progression study (n=376), rs9264942, rs13199524and rs12198173from GWAS showed statistically significant association with the rate of CD4decline, which were confirmed in the LTNP cohort. rs2395029from CHAVI study showed significant different frequency between reference population and LTNP cohort. None of the classic AIDS restricted variants showed statistically significant association with the rate of CD4decline. In treatment response study, baseline VL is an independent influence factor of time to virological control/suppression. After correcting the influence of baseline VL, None of the classic AIDS restricted variants showed statistically significant association with time to virological control/suppression in Chinese population.
[Conclusions] Our study for the first time replicated the major variants from GWAS in Chinese population which shows the central role of MHC region in Chromosome6in the control of HIV viral replication and disease progress. Baseline VL, as an independent influence factor of time to virological control/suppression, implies more potent HAART regime in case of resistance in high baseline VL patients.
[方法]研究对象共纳入HIV感染者1098例,来自四个随访队列；以CD4细胞下降率为疾病进程观察指标,以至病毒有效抑制时间(VL<400/mL)和至病毒完全抑制时间(VL<50/mL)为疗效观察指标；共选择GWAS研究结果及部分经典位点共18个；从全血中提取DNA,以MassARRAY分型平台进行基因分型；使用秩和检验和卡方检验分析不同基因型的效应。对发现的与疾病进程相关的阳性位点,在长期不进展人群中进行验证。
[结果]对基因分型结果进行检出率和哈迪-温伯格平衡检验,最终共14个位点纳入研究。疾病进程研究样本共376例,结果发现GWAS研究位点rs9264942、 rs13199524和rs12198173与中国人群HIV感染者CD4细胞计数下降的速率有显著相关关系,在中国HIV感染者典型进展人群与长期不进展人群中分布有显著性差异。rs2395029位点在中国HIV感染者典型进展人群与长期不进展人群中分布有显著性差异。与疾病进程有关的经典位点未发现与CD4细胞下降率有相关关系；疗效研究样本共531例,发现治疗基线时病毒载量是治疗至病毒有效／完全抑制时间的独立影响因素。在校正了基线时病毒载量影响后,未发现与疗效有关的经典位点在中国人群与治疗至病毒有效／完全抑制时间有统计学相关关系。
[结论]研究首次在中国人群验证了GWAS结果的主要位点,证明在控制HIV病毒复制和疾病进程上,6号染色体MHC区对于中国人群均起中心作用。治疗基线时病毒载量是治疗至病毒有效／完全抑制时间的独立影响因素,提示对于基线病毒载量较高的患者,应使用更强效的HAART治疗方案,以预防耐药的发生。
[Objective]There has been several AIDS Genome-wide association studies which discovered many variants related to disease progression. To our knowledge, they have not been replicated in Asian population. We attempted to confirm these finding in Chinese population and studied the association between the classic AIDS restricted variants and disease progression as well as virological suppression after HAART therapy.
[Methods]We recruited1098HIV infected subjects from4study cohort. We define Rate of CD4decline as phenotype of the disease progression study and time to virological control (VL<400/mL)/suppression (VL<50/mL) as phenotype of treatment response study.18SNPs of GWAS study and classic variants were selected. Kruskal Wallis Test and Pearson Chi-Square test were used. Significant variants in the first phase were replicated in a LTNP cohort.
[Results]3SNPs were excluded which failed in Hardy-Weinberg test. In the disease progression study (n=376), rs9264942, rs13199524and rs12198173from GWAS showed statistically significant association with the rate of CD4decline, which were confirmed in the LTNP cohort. rs2395029from CHAVI study showed significant different frequency between reference population and LTNP cohort. None of the classic AIDS restricted variants showed statistically significant association with the rate of CD4decline. In treatment response study, baseline VL is an independent influence factor of time to virological control/suppression. After correcting the influence of baseline VL, None of the classic AIDS restricted variants showed statistically significant association with time to virological control/suppression in Chinese population.
[Conclusions] Our study for the first time replicated the major variants from GWAS in Chinese population which shows the central role of MHC region in Chromosome6in the control of HIV viral replication and disease progress. Baseline VL, as an independent influence factor of time to virological control/suppression, implies more potent HAART regime in case of resistance in high baseline VL patients.
引文
[1]Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study[J]. Science, 1996,273(5283):1856-1862.
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[2]O'Brien SJ, Nelson GW. Human genes that limit AIDS[J]. Nat Genet,2004,36(6): 565-574.
[3]An P, Winkler CA. Host genes associated with HIV/AIDS:advances in gene discovery[J]. Trends Genet,2010,26(3):119-131.
[4]Kim S, Misra A. SNP genotyping:technologies and biomedical applications[J]. Annu Rev Biomed Eng,2007,9:289-320.
[5]Gabriel S, Ziaugra L, Tabbaa D. SNP genotyping using the Sequenom MassARRAY iPLEX platform[J]. Curr Protoc Hum Genet,2009,Chapter 2:Unit 2 12.
[6]Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1[J]. Science,2007,317(5840):944-947.
[7]Dalmasso C, Carpentier W, Meyer L, et al. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection:the ANRS Genome Wide Association 01 study[J]. PLoS One,2008,3(12):e3907.
[8]Bleiber G, May M, Martinez R, et al. Use of a combined ex vivo/in vivo population approach for screening of human genes involved in the human immunodeficiency virus type 1 life cycle for variants influencing disease progression[J]. J Virol,2005,79(20): 12674-12680.
[9]van Manen D, Kootstra NA, Boeser-Nunnink B, et al. Association of HLA-C and HCP5 gene regions with the clinical course of HIV-1 infection[J]. AIDS,2009,23(1): 19-28.
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