title: Dense genotyping of immune-related loci identifies variants associated with clearance of HPV among HIV-positive women in the HIV epidemiology research study (HERS).
abstract: Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10(-6)). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Staci L
authors.initials: SL
authors.lastname: Sudenga
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Wiener
authors.affiliation: Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: King
authors.affiliation: Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Rompalo
authors.affiliation: Department of Obstetrics and Gynecology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Cu-Uvin
authors.affiliation: Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Klein
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Keerti V
authors.initials: KV
authors.lastname: Shah
authors.affiliation: School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sobel
authors.affiliation: Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Jamieson
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Sadeep
authors.initials: S
authors.lastname: Shrestha
mesh_terms: D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D004279:DNA, Viral