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

Li X, Price MA, He D, Kamali A, Karita E, Lakhi S, Sanders EJ, Anzala O, Amornkul PN, Allen S, Hunter E, Kaslow RA, Gilmour J, Tang J. "Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions." Hum. Genet.. 2014;133(9):1187-97.


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.



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