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author:("selgin, Efe")
1.  Evaluation of Hepatitis C Virus as a Risk Factor for HIV-Associated Neuroretinal Disorder 
Hepatitis C virus (HCV) is a newly identified risk factor for HIV-associated neuroretinal disorder (HIV-NRD). Genetic analysis suggests that alterations in the anti-inflammatory IL-10 signaling pathway increase susceptibility to both HIV-NRD and HCV infection. Inflammation may provide a mechanistic link between HCV and HIV-NRD.
Background. Both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) penetrate the central nervous system. HIV-associated neuroretinal disorder (HIV-NRD), a visual impairment of reduced contrast sensitivity and reading ability, is associated with cytokine dysregulation and genetic polymorphisms in the anti-inflammatory interleukin 10 (IL-10) signaling pathway. We investigated associations between HCV and HIV-NRD and between HCV and single-nucleotide polymorphisms (SNPs) in the IL-10 receptor 1 (IL10R1) gene.
Methods. Logistic and Cox regression analysis were used to analyze risk factors for HIV-NRD in 1576 HIV-positive patients who did not have an ocular opportunistic infection at enrollment. Median follow-up was 4.9 years (interquartile range, 2.4–8.8 years). Four IL10R1 SNPs were examined in a subset of 902 patients.
Results. The group included 290 patients with chronic HCV infection, 74 with prior infection, and 1212 with no HCV markers. There were 244 prevalent cases of HIV-NRD and 263 incident cases (rate = 3.9/100 person-years). In models adjusted for demographics, HIV treatment and status, liver function, and immune status, both the prevalence and incidence of HIV-NRD were significantly higher in patients with chronic HCV infection (odds ratio = 1.54; 95% confidence interval [CI], 1.03–2.31 and hazard ratio = 1.62; 95% CI, 1.13–2.34, respectively), compared to patients with no HCV markers. Chronic HCV was associated with rs2228055 and 2 additional IL-10R1 SNPs expected to reduce IL-10 signaling. HIV-NRD was not significantly associated with these SNPs.
Conclusions. HCV is a possible risk factor for HIV-NRD. Genetic analysis suggests that alterations in the IL-10 signaling pathway may increase susceptibility to HIV-NRD and HCV infection. Inflammation may link HCV and HIV-NRD.
doi:10.1093/cid/cit550
PMCID: PMC3814824  PMID: 24081683
AIDS; hepatitis C virus; HIV-associated neuroretinal disorder; cytomegalovirus retinitis; HIV-1
2.  GWATCH: a web platform for automated gene association discovery analysis 
GigaScience  2014;3:18.
Background
As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations.
Findings
Here we present a dynamic web-based platform – GWATCH – that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis.
Conclusions
GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.
doi:10.1186/2047-217X-3-18
PMCID: PMC4220276  PMID: 25374661
AIDS; HIV; Complex diseases; Genome-wide association studies (GWAS); Whole genome sequencing (WGS)
3.  Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition 
The Journal of Infectious Diseases  2012;205(7):1155-1162.
Background. To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility.
Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10−5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent.
Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10−8.
Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.
doi:10.1093/infdis/jis028
PMCID: PMC3295605  PMID: 22362864
4.  The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove 
PLoS Genetics  2012;8(11):e1003103.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
Author Summary
NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.
doi:10.1371/journal.pgen.1003103
PMCID: PMC3510037  PMID: 23209447
5.  Association of Host Genetic Risk Factors with the Course of Cytomegalovirus Retinitis in Patients Infected with HIV 
American journal of ophthalmology  2011;151(6):999-1006.e4.
Purpose
To evaluate the effects of previously reported host genetics factors that influence cytomegalovirus (CMV) retinitis incidence, progression to AIDS, and efficacy of highly active antiretroviral therapy (HAART) for mortality, retinitis progression, and retinal detachment in patients with CMV retinitis and AIDS in the era of HAART.
Design
Prospective, multicenter, observational study.
Methods
Cox proportional hazards model based genetic association tests examined the influence of IL-10R1_S420L, CCR5Δ32, CCR2-V64I, CCR5 P1, and SDF-3`A polymorphisms among patients with mortality, retinitis progression, and retinal detachment. Participants were 203 European American and 117 African American patients with AIDS and CMV retinitis.
Results
European American patients with the CCR5 +.P1.+ promoter haplotype showed increased risk for mortality (HR=1.83; 95% CI: 1.00–3.40; P=0.05). Although the same haplotype also trended for increased risk for mortality in African American patients, the result was not significant (HR=2.28; 95% CI: 0.93–5.60; P=0.07). However, this haplotype was associated with faster retinitis progression in African Americans (HR=5.22; 95% CI: 1.54–17.71; P=0.007). Increased risk of retinitis progression was also evident for African American patients with the SDF1-3′A variant (HR=3.89; 95% CI: 1.42–10.60; P=0.008). In addition, the SDF1-3′A variant increased the retinal detachment risk in this patient group (HR=3.05; 95% CI: 1.01–9.16; P=0.05).
Conclusion
Besides overall immune health, host genetic factors influence mortality, retinitis progression, and retinal detachment in patients with AIDS and CMV retinitis that are receiving HAART.
doi:10.1016/j.ajo.2010.11.029
PMCID: PMC3103625  PMID: 21396623
6.  Genome-wide Association Study Implicates PARD3B-based AIDS Restriction 
The Journal of Infectious Diseases  2011;203(10):1491-1502.
Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression.
Methods.  European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model).
Results.  Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025).
Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.
doi:10.1093/infdis/jir046
PMCID: PMC3080910  PMID: 21502085
7.  Role of Exonic Variation in Chemokine Receptor Genes on AIDS: CCRL2 F167Y Association with Pneumocystis Pneumonia 
PLoS Genetics  2011;7(10):e1002328.
Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.
Author Summary
Human chemokine receptors are cell surface proteins that may be utilized by HIV-1 for entry into host cells. DNA variation in the HIV-1 major coreceptor CCR5 affects HIV-1 infection and progression. This study comprehensively assesses the role of genetic variation of multiple chemokine receptor genes clustered in the chromosome 3p21 and 3p22 on HIV-1 disease outcomes in HIV-1 natural history cohorts. The multivariate survival analyses identified functional variants that altered disease progression rate in CCRL2, CCR3, and CCR8. CCRL2-F167Y affects the rate to AIDS development through a specific protection against pneumocystis pneumonia (PCP), a common AIDS–defining condition. Our study identified this atypical chemokine receptor CCRL2 as a key factor involved in PCP, possibly through inducing inflammation in the lung.
doi:10.1371/journal.pgen.1002328
PMCID: PMC3203199  PMID: 22046140
8.  Effect of host genetics on CMV retinitis occurrence in patients with AIDS 
The Journal of infectious diseases  2010;202(4):606-613.
Background
Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS and still causes visual morbidity despite the wide spread usage of highly active antiretroviral therapy (HAART). The ubiquitous CMV pathogen contains a human interleukin-10 (IL-10) homolog in its genome and utilizes it to evade host immune reactions through an IL-10 receptor mediated immune-suppression pathway.
Methods
Effects of IL-10R1, IL-10 and previously described AIDS restriction gene variants are investigated on the development of CMV retinitis in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort (n=1284).
Results
In Europen Americans (n=750), a haplotype carrying an amino acid changing variation in the cytoplasmic domain (S420L) of IL-10R1 can be protective (OR = 0.14, CI: 0.02–0.94, P = 0.04) against, whereas another haplotype carrying an amino acid changing variation in the extracellular domain (I224V) of IL-10R1 can be more susceptible (OR = 6.21, CI: 1.22–31.54, P = 0.03) to CMV retinitis. In African Americans (n=534), potential effects of IL-10 variants are observed.
Conclusion
Host genetics may have a role in the occurrence of CMV retinitis in patients infected with HIV.
doi:10.1086/654814
PMCID: PMC2932829  PMID: 20617924
AIDS; CMV retinitis; HIV-1; host genetics; interleukin-10 receptor
9.  Effect of host genetics on incidence of HIV neuroretinal disorder in patients with AIDS 
Approximately 10 to 15% of patients with AIDS but without ocular opportunistic infections will have a presumed neuroretinal disorder (HIV-NRD), manifested by reduced contrast sensitivity and abnormal visual fields. The loss of contrast sensitivity often is sufficient to impair reading speed. To evaluate the effect of host genetics on HIV-NRD, we explored validated AIDS restriction gene variants CCR5Δ32, CCR2-64I, CCR5 P1, SDF-3`A, IL-10-5`A, RANTES -403A, RANTES -28G, RANTES-In1.1C, CX3CR1-249I, CX3CR1-280M, IFNG-179T, MDR1-3435T, and MCP-1364G, each of which has been implicated previously to influence HIV-1 infection, AIDS progression, therapy response, and antiviral drug metabolism, and an IL-10 receptor gene, IL-10R1, in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort. In European Americans (cases=55, controls=290), IL-10-5`A variant and its promoter haplotype (HR=2.09, CI: 1.19–3.67, P = 0.01); in African Americans (cases=54, controls=180) RANTES-In1.1C and the associated haplotype (HR=2.72, CI: 1.48–5.00, P = 0.001), showed increased HIV-NRD susceptibility. While sample sizes are small and P values do not pass a strict Bonferroni correction, our results suggest that, in European Americans, an IL-10-related pathway, and, in African Americans, chemokine receptor ligand polymorphisms in RANTES are risk factors for HIV- NRD development. Clearly, further studies are warrented.
doi:10.1097/QAI.0b013e3181deaf4d
PMCID: PMC2908809  PMID: 20531015
AIDS; HIV-1; host genetics; HIV-neuroretinal disorder
10.  Examination of disease based selection, demographic history and population structure in European Y chromosome haplogroup I 
Journal of human genetics  2010;55(9):613-620.
We attempted to refine the understanding of an association of Y-chromosomal haplogroup I (hg-I) with enhanced AIDS progression that had been previously reported. First, we compared the progression phenotype between hg-I and its phylogenetically closest haplogroup J (hg-J). Then, we took a candidate gene approach resequencing DDX3Y, a crucial autoimmunity gene, in hg-I and other common European Y- chromosome haplogroups looking for functional variants. We extended the genetic analyses to CD24L4 and compared and contrasted the roles of disease based selection, demographic history, and population structure shaping the contemporary genetic landscape of hg-I chromosomes. Our results confirmed and refined the AIDS progression signal to hg-I, though no gene variant was identified that can explain the disease association. Molecular evolutionary and genetic analyses of the examined loci suggested a unique evolutionary history in hg-I, probably shaped by complex interactions of selection, demographic history, and high geographical differentiation leading to the formation of distinct hg-I subhaplogroups that today are associated with HIV/AIDS onset. Clearly, further studies on Y chromosome candidate loci sequencing to discover functional variants and discern the roles of evolutionary factors are warranted.
doi:10.1038/jhg.2010.77
PMCID: PMC2945452  PMID: 20574427
AIDS progression; CD24L4; DDX3Y; population growth; population structure; selection; Y chromosome
11.  Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression 
PLoS ONE  2010;5(9):e12862.
Background
The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.
Methodology/Principal Findings
Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI) on chromosome 6.
Conclusions
Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.
doi:10.1371/journal.pone.0012862
PMCID: PMC2943476  PMID: 20877624
12.  Association of Y chromosome haplogroup I with HIV progression, and HAART outcome 
Human genetics  2009;125(3):281-294.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
doi:10.1007/s00439-008-0620-7
PMCID: PMC2885350  PMID: 19169712
13.  Mitochondrial DNA Haplogroups influence AIDS Progression 
AIDS (London, England)  2008;22(18):2429-2439.
Objective
Mitochondrial function plays a role in both AIDS progression and highly active antiretroviral therapy (HAART) toxicity, therefore we sought to determine whether mitochondrial (mt) DNA variation revealed novel AIDS Restriction Genes (ARGs), particularly as mtDNA single nucleotide polymorphisms (SNPs) are known to influence regulation of oxidative phosphorylation, reactive oxygen species (ROS) production, and apoptosis.
Design
Retrospective cohort study.
Methods
We performed an association study of mtDNA haplogroups among 1833 European American HIV-1 patients from five US cohorts, the Multicenter AIDS Cohort Study (MACS), the San Francisco City Clinic Study (SFCC), Hemophilia Growth and Development Study (HGDS), the Multicenter Hemophilia Cohort Study (MHCS), and the AIDS Linked to Intravenous Experiences (ALIVE) cohort to determine whether the mtDNA haplogroup correlated with AIDS progression rate.
Results
MtDNA haplogroups J and U5a were elevated among HIV-1 infected people who display accelerated progression to AIDS and death. Haplogroups Uk, H3, and IWX appeared to be highly protective against AIDS progression.
Conclusions
The associations found in our study appear to support a functional explanation by which mtDNA variation among haplogroups influencing ATP production, ROS generation, and apoptosis is correlated to AIDS disease progression, however repeating these results in cohorts with different ethnic backgrounds would be informative. These data suggest that mitochondrial genes are important indicators of AIDS disease progression in HIV-1 infected persons.
doi:10.1097/QAD.0b013e32831940bb
PMCID: PMC2699618  PMID: 19005266
Mitochondria; AIDS; HIV-1; apoptosis; disease
14.  141 Gene Discovery and Data Sharing in Genome Wide Association Analyses: lessons form AIDS genetic restriction genes 
As genome wide association studies plus whole genome sequence analyses for complex human disease determinants are expanding, it seems useful to develop strategies to facilitate large data sharing, rapid replication and validation of provocative statistical associations that straddle the threshold for genome wide significance. At this conference, we shall announce GWATCH, (Genome Wide Association Tracks Chromosome Highway) a web based data release platform that can freely display and inspect unabridged genome tracked association data without compromising privacy or Informed Consent constrictions, allowing for rapid discovery and replication opportunities. We illustrate the utility with HIV-AIDS resistance genes screened in combined large multicenter cohort studies GWAS (MACS, HGDS, MHGS, ALLIVE, LSOCA HOMER) developed and studied over the last decades.
doi:10.1097/01.qai.0000446723.52450.65
PMCID: PMC4149668

Results 1-14 (14)