Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS

J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):279-84. doi: 10.1097/QAI.0b013e318204982b.


Background: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance.

Methods: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections.

Results: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻⁶), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹⁵, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹⁰, OR = 2.9) and NOTCH4 (9.08 × 10⁻⁰⁷, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻⁰⁶, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant.

Conclusions: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / genetics*
  • Adult
  • Alleles*
  • Disease Progression
  • Europe
  • Female
  • GTPase-Activating Proteins / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • HIV Long-Term Survivors
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • United States


  • ARHGAP44 protein, human
  • GTPase-Activating Proteins