CCL3L1 Copy Number Variation and Susceptibility to HIV-1 Infection: A Meta-Analysis

Background Although several studies have investigated whether CCL3L1 copy number variation (CNV) influences the risk of HIV-1 infection, there are still no clear conclusions. Therefore, we performed a meta-analysis using two models to generate a more robust estimate of the association between CCL3L1 CNV and susceptibility to HIV-1 infection. Methods We divided the cases and controls into two parts as individuals with CCL3L1 gene copy number (GCN) above the population specific median copy number (PMN) and individuals with CCL3L1 GCN below PMN, respectively. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were given for the main analysis. We also conducted stratified analyses by ethnicity, age group and sample size. Relevant literatures were searched through PubMed and ISI Web of Knowledge up to March 2010. Results In total, 9 studies with 2434 cases and 4029 controls were included. ORs for the main analysis were 1.35 (95% CI, 1.02–1.78, model: GCN ≤ PMN Vs. GCN > PMN) and 1.70 (95% CI, 1.30–2.23, model: GCN < PMN Vs. GCN ≥ PMN), respectively. Either in stratified analysis, statistically significant results can be detected in some subgroups. Conclusions Our analyses indicate that CCL3L1 CNV is associated with susceptibility to HIV-1 infection. A lower copy number is associated with an increased risk of HIV-1 infection, while a higher copy number is associated with reduced risk for acquiring HIV-1.

[1]  Kristen K. Dang,et al.  CCL3L1 and HIV/AIDS susceptibility , 2009, Nature Medicine.

[2]  A. Tobías.  Assessing the influence of a single study in the meta-anyalysis estimate , 1999 .

[3]  Jeremiah D. Degenhardt,et al.  Copy Number Variation of CCL3-like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (Macaca mulatta) , 2009, PLoS genetics.

[4]  F. Pereyra,et al.  CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms , 2007, Nature Immunology.

[5]  R. Kaslow,et al.  Gene copy number: learning to count past two , 2009, Nature Medicine.

[6]  F. Goebel,et al.  Susceptibility to HIV/AIDS: An Individual Characteristic We Can Measure? , 2005, Infection.

[7]  R. Kaslow,et al.  Influence of host genetic variation on susceptibility to HIV type 1 infection. , 2005, The Journal of infectious diseases.

[8]  J. Hirschhorn,et al.  A comprehensive review of genetic association studies , 2002, Genetics in Medicine.

[9]  M. Bamshad,et al.  Reply to: "Experimental aspects of copy number variant assays at CCL3L1". , 2009, Nature medicine.

[10]  John P A Ioannidis,et al.  Commentary: meta-analysis of individual participants' data in genetic epidemiology. , 2002, American journal of epidemiology.

[11]  R. Kaslow,et al.  CCL3L1 and CCL4L1: variable gene copy number in adolescents with and without human immunodeficiency virus type 1 (HIV-1) infection , 2007, Genes and Immunity.

[12]  M. Parmentier,et al.  Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands. , 2006, Seminars in immunology.

[13]  N. Mehra,et al.  Genetic determinants of HIV‐1 infection and progression to AIDS: susceptibility to HIV infection , 2009, Tissue antigens.

[14]  L. Kuhn,et al.  African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine , 2007, AIDS.

[15]  M. Juan,et al.  Copy number variation in chemokine superfamily: the complex scene of CCL3L–CCL4L genes in health and disease , 2010, Clinical and experimental immunology.

[16]  B. Agan,et al.  CCL3L1-CCR5 Genotype Improves the Assessment of AIDS Risk in HIV-1-Infected Individuals , 2008, PloS one.

[17]  W. Haenszel,et al.  Statistical aspects of the analysis of data from retrospective studies of disease. , 1959, Journal of the National Cancer Institute.

[18]  W. G. Cochran.  The combination of estimates from different experiments. , 1954 .

[19]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[20]  C. Mackay.  CCL3L1 dose and HIV-1 susceptibility. , 2005, Trends in molecular medicine.

[21]  Nathaniel Rothman,et al.  Assessing the Probability That a Positive Report is False: An Approach for Molecular Epidemiology Studies , 2004 .

[22]  T. Nakajima,et al.  HIV-1/AIDS susceptibility and copy number variation in CCL3L1, a gene encoding a natural ligand for HIV-1 co-receptor CCR5 , 2009, Cytogenetic and Genome Research.

[23]  D. Clayton,et al.  Experimental aspects of copy number variant assays at CCL3L1 , 2009, Nature Medicine.

[24]  John P A Ioannidis,et al.  Genetic associations: false or true? , 2003, Trends in molecular medicine.

[25]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[26]  B. Rovin,et al.  The Influence of CCL 3 L 1 Gene – Containing Segmental Duplications on HIV-1 / AIDS Susceptibility , 2009 .

[27]  M. Hammer,et al.  Global survey of genetic variation in CCR5, RANTES, and MIP-1α: Impact on the epidemiology of the HIV-1 pandemic , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  John P. Moore,et al.  HIV-1 pathogenesis: the complexities of the CCR5-CCL3L1 complex. , 2007, Cell host & microbe.

[29]  L. Kuhn,et al.  Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission. , 2006, The Journal of general virology.

[30]  M. Bamshad,et al.  Reply to: “CCL3L1 and HIV/AIDS susceptibility” and “Experimental aspects of copy number variant assays at CCL3L1” , 2009, Nature Medicine.

[31]  J. Kaldor,et al.  Analysis of the CCL3-L1 gene for association with HIV-1 susceptibility and disease progression , 2004, AIDS.

[32]  T. Nakajima,et al.  Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia , 2007, Immunogenetics.

[33]  S. Mummidi,et al.  Combinatorial content of CCL3L and CCL4L gene copy numbers influence HIV-AIDS susceptibility in Ukrainian children , 2009, AIDS.

[34]  D. Goldstein,et al.  Genomics meets HIV-1 , 2006, Nature Reviews Microbiology.

[35]  J. Goedert,et al.  Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. , 2006, American journal of human genetics.

[36]  A. Uusküla,et al.  CCL3L1 copy number is a strong genetic determinant of HIV seropositivity in Caucasian intravenous drug users. , 2010, The Journal of infectious diseases.

[37]  J. Phair,et al.  CCL3L1 and HIV/AIDS susceptibility , 2009, Nature Medicine.

[38]  A. Rathore,et al.  Association of CCR5-59029 A/G and CCL3L1 copy number polymorphism with HIV type 1 transmission/progression among HIV type 1-seropositive and repeatedly sexually exposed HIV type 1-seronegative North Indians. , 2009, AIDS research and human retroviruses.

[39]  L. Kuhn,et al.  Host CCL3L1 Gene Copy Number in Relation to HIV-1-Specific CD4+ and CD8+ T-Cell Responses and Viral Load in South African Women , 2008, Journal of acquired immune deficiency syndromes.