title: Homozygosity for the 168His variant of the minor histocompatibility antigen HA-1 is associated with reduced risk of primary Sjögren's syndrome.
abstract: The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the minor histocompatibility antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjögren's syndrome ("Sjögren-epitope"). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjögren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjögren's syndrome patients than in controls (p<0.003). In contrast, the frequencies of all ABCA7 allelic variants and additional HA-1 polymorphisms were similar in patients and controls. In cohorts of patients with systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis, no significant differences in the frequencies of ABCA7 and HA-1 allelic variants were observed relative to controls. Our results suggest that the HA-1 168His variant is associated with reduced susceptibility to primary Sjögren's syndrome.
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, D-93042 Regensburg, Germany.
authors.forename: Mariann
authors.initials: M
authors.lastname: Harangi
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Kaminski
authors.forename: Martin
authors.initials: M
authors.lastname: Fleck
authors.forename: Evelyn
authors.initials: E
authors.lastname: Orsó
authors.forename: Margit
authors.initials: M
authors.lastname: Zeher
authors.forename: Emese
authors.initials: E
authors.lastname: Kiss
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szekanecz
authors.forename: Erika
authors.initials: E
authors.lastname: Zilahi
authors.forename: Jörg
authors.initials: J
authors.lastname: Marienhagen
authors.forename: Charalampos
authors.initials: C
authors.lastname: Aslanidis
authors.forename: György
authors.initials: G
authors.lastname: Paragh
authors.forename: Anne Isine
authors.initials: AI
authors.lastname: Bolstad
authors.forename: Roland
authors.initials: R
authors.lastname: Jonsson
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D015331:Cohort Studies; D005060:Europe; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D005810:Multigene Family; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology; D009842:Oligopeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012859:Sjogren's Syndrome / Q000235:genetics* / Q000276:immunology*
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; C110615:HA-1 antigen; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides