Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions

• Authors: Xuelin Li, University of Alabama Birmingham; Matthew A. Price, International AIDS Vaccine Initiative; Dongning He, University of Alabama Birmingham; Anatoli Kamali, MRC/UVRI Uganda Virus Research Unit on AIDS; Etienne Karita, Projet San Francisco; Shabir Lakhi, Emory University; Eduard J. Sanders, Kenya Medical Research Institute (KEMRI); Omu Anzala, Kenya AIDS Vaccine Initiative (KAVI); Pauli N. Amornkul, International AIDS Vaccine Initiative; Susan Allen, Emory University; Eric Hunter, Emory University; Richard A. Kaslow, International AIDS Vaccine Initiative; Jill Gilmour, Chelsea & Westminster Hospital; Jianming Tang, University of Alabama Birmingham
• Journal Title: Human Genetics
• Volume: Volume 133, Number 9
• Publisher: Springer International Publishing AG | 2014-09-01, Pages 1187-1197
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1007/s00439-014-1465-x
• Subjects: Health Sciences, Epidemiology; Health Sciences, Public Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; GENETICS & HEREDITY; IMMUNODEFICIENCY-VIRUS TYPE-1; HLA CLASS-I; T-CELL RESPONSES; EXTENDED HUMAN MHC; MISSING HERITABILITY; DISEASE PROGRESSION; HEREDITARY HEMOCHROMATOSIS; HETEROSEXUAL TRANSMISSION; QUANTITATIVE TRAITS; LEUKOCYTE ANTIGENS

Abstract

Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of “missing heritability” in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.