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ZNRD1 Zinc Ribbon Domain-Containing 1 RNA polymerase Genome-wide association study (GWAS)

ZNRD1 Zinc Ribbon Domain-Containing 1 RNA polymerase Genome-wide association study (GWAS) #1 gene associated with CD4 + T-cell depletion ( Fellay et al, 2007). Genome-wide gene knock-down One of 250 host proteins required by HIV- 1 (Brass et al, 2008 ).

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ZNRD1 Zinc Ribbon Domain-Containing 1 RNA polymerase Genome-wide association study (GWAS)

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  1. ZNRD1 Zinc Ribbon Domain-Containing 1 RNA polymerase Genome-wide association study (GWAS) #1 gene associated with CD4+ T-cell depletion (Fellay et al, 2007). Genome-wide gene knock-down One of 250 host proteins required by HIV-1 (Brass et al, 2008). Affects host susceptibility to HIV-1 infection? Abstract no. MOPDA0104 Ping An, James J. Goedert, Sharyne Donfield, Susan Buchbinder, Gregory D. Kirk, Roger Detels and Cheryl A. Winkler ZNRD1 gene affects host susceptibility to HIV-1 infection Background Methods • HIV-1 infection susceptibility • SNP frequencies Exposed uninfected vs. HIV-1 infected • HIV-1 natural history cohorts • 1865 European Americans • MACS, SFCC, MHCS, HGDS • 837 African Americans • ALIVE • 13 SNPs, ZNRD1-RNF39-HLA-C

  2. ZNRD1 Haplotypes Haplotype SNP1-12 Frequency in EA Hap1 TTGGGGGATGTA 0.66 Hap2 TTGGCGAATGTA 0.12 Hap3 TTGGGGGAGGTA 0.09 Hap4 GCAAGAGGTTGG 0.06 Hap5 GCAAGGGGTTGG 0.04 Impact on HIV-1 infection Hap2 carrier frequency: HIV - (29%) vs. HIV + (21%) OR for infection = 0.65, P = 0.005 High-risk exposed uninfected (HREU) vs. HIV-1 seroconverters (P = 0.04) In Africa America, OR=0.67, P=0.23 HLA-C rs9264942 (P = 0.40) Hap2 tag SNP rs3132130 (-1850) Cell-specific binding to transcription factors Results ZNRD1haplotype Hap2 on risk of HIV-1 acquisition • The sequence carrying rs3132130 CG SNP differentially • binds to nuclear factors in a gel-shift assay. • (A) Serum response HeLa cells, (B) PMA HeLa cells, C) PHA Jurkat T cells.

  3. HIV-1 disease progression Hap3 1 year faster to CD4 <200 Cox model: RH = 1.39 Tagged by 3’UTR rs8321 Results Conclusions • Kaplan–Meier survival curves of HIV-1 progression from seroconversion to CD4<200, stratified by ZNRD1 rs8321 genotypes in European Americans The first epidemiologic evidence that ZNRD1 mediates host resistance/susceptibility to HIV-1infection Authors declare no conflicts of interest Funded by National Cancer Institute HHSN26120080001E

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