Variants in host viral replication cycle genes are associated with heterosexual HIV-1 acquisition in Africans.
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.
*Department of Anthropology, University of Michigan, Ann Arbor, MI; Departments of †Global Health; ‡Epidemiology; §Medicine, University of Washington, Seattle, WA; ‖Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa; ¶Department of Medicine, University of Manitoba, Winnipeg, Canada; #Department of Obstetrics and Gynaecology, University of Nairobi, Nairobi, Kenya; Departments of **Pediatrics; ††Genome Sciences; ‡‡Laboratory Medicine, University of Washington, Seattle, WA; and §§Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Abigail W
AW
Bigham
Romel D
RD
Mackelprang
Connie
C
Celum
Guy
G
De Bruyn
Kristin
K
Beima-Sofie
Grace
G
John-Stewart
Allan
A
Ronald
Nelly R
NR
Mugo
Kati
K
Buckingham
Michael J
MJ
Bamshad
James I
JI
Mullins
M J
MJ
McElrath
Jairam R
JR
Lingappa
D000328:Adult; D044383:Black People; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000453:epidemiology* / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load; D014779:Virus Replication; D055815:Young Adult
D012367:RNA, Viral