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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0000000000000113
Basic and Translational Science

Variants in Host Viral Replication Cycle Genes Are Associated With Heterosexual HIV-1 Acquisition in Africans

Bigham, Abigail W. PhD*; Mackelprang, Romel D. PhD; Celum, Connie MD†,‡,§; Bruyn, Guy De MD; Beima-Sofie, Kristin PhD; John-Stewart, Grace MPH, MD, PhD†,‡,§; Ronald, Allan MD; Mugo, Nelly R. MD, MPH, MMed†,#; Buckingham, Kati BS**; Bamshad, Michael J. MD**,††; Mullins, James I. PhD¶,‡‡; McElrath, M. J. MD, PhD¶,§§; Lingappa, Jairam R. MD, PhD†,§,**

Open Access
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Abstract

Objective: We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort.

Methods: Using a nested case–control study within a cohort of heterosexual HIV-1–serodiscordant couples, we genotyped 475 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) and 18 SNPs previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazard regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set point, and a composite measure of HIV-1 disease progression. Significant thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing.

Results: We evaluated 491 HIV-1–infected and 335 HIV-1–uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and tagSNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio = 0.14, P = 0.03, and odds ratio = 2.11, Pcorr = 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies per milliliter lower plasma HIV-1 RNA set point (P = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2.

Conclusions: Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.

© 2014 by Lippincott Williams & Wilkins

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