title: SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.
abstract: The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.
authors.affiliation: Departments of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Aissani
authors.affiliation: Departments of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Boehme
authors.affiliation: Departments of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: H W
authors.initials: HW
authors.lastname: Wiener
authors.affiliation: Departments of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Jacobson
authors.affiliation: 1] Departments of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA [2] Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kaslow
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015658:HIV Infections / Q000150:complications; D006681:HLA-D Antigens / Q000235:genetics*; D006239:Haplotypes; D006566:Herpesviridae Infections / Q000150:complications; D006716:Homosexuality; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000235:genetics*
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens