title: Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women.
abstract: African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.
authors.affiliation: Division of Gastroenterology and Hepatology, Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sarkar
authors.affiliation: Nursing, University of California San Francisco, San Francisco, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Aouzierat
authors.affiliation: Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bacchetti
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.affiliation: Medicine, CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: French
authors.affiliation: Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Seaberg
authors.affiliation: Division of Cancer Epidemiology and Genetics, Infections and Immunoepidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: O'Brien
authors.affiliation: Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Kuniholm
authors.affiliation: Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Minkoff
authors.affiliation: Division of Infectious Diseases, Georgetown University, Washington D.C., USA.
authors.forename: M
authors.initials: M
authors.lastname: Plankey
authors.affiliation: Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Strickler
authors.affiliation: Division of Gastroenterology and Hepatology, Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Peters
mesh_terms: D001741:Black or African American / Q000235:genetics*; D015331:Cohort Studies; D060085:Coinfection / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000401:mortality* / Q000821:virology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000401:mortality* / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008099:Liver / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human
keywords: death; ethnicity; genetic, interferon-λ; polymorphisms