GENETIC RISK-FACTORS IN INFLAMMATORY ABDOMINAL AORTIC-ANEURYSMS - POLYMORPHIC RESIDUE-70 IN THE HLA-DR-B1 GENE AS A KEY GENETIC ELEMENT

Purpose: Evidence of a genetic predisposition to the development of in flammatory abdominal aortic aneurysms (AAAs) exists as a positive fami ly history in 17% of patients. Familial clustering and other similarit ies between inflammatory AAAs and giant cell arteritis (GCA), which po ssesses a genetic risk determinant mapped to the HLA-DR molecule, sugg est a role of genetic risk factors in inflammatory AAAs. The purpose o f this study was to explore whether patients with inflammatory AAAs ex press disease-relevant genes associated with the HLA-DR region on the short arm of chromosome 6. Methods: Thirty-seven patients with histomo rphologic findings of inflammatory AAA at operation were genotyped for the polymorphism of the HLA-DR B1 and HLA-DQ B1 alleles and compared to ethnically matched, healthy control subjects (n = 90). Results: Dis tribution of HLA-DR B1 alleles was nonrandom in patients with inflamma tory AAAs versus control subjects, The HLA-DR B1 alleles B115 and B1* 0404 were enriched in patients with inflammatory AAAs compared with. c ontrol subjects (47% versus 27%, and 14% versus 3%; p < 0.05, respecti vely). Analysis of functionally relevant amino acid polymorphisms enco ded by the HLA-DR B1 gene showed relevance at amino acid position 70. HLA-DR B1 alleles overrepresented in patients with inflammatory AAAs e xpress a glutamine substitution at position 70, whereas alleles disfav ored in the patient cohort express a negatively charged aspartic acid. Distribution of HLA-DQ B1 alleles were indistinguishable in patients and control subjects. Conclusion: These data indicate that a genetic r isk determinant can be mapped to the HLA-DR B1 locus in patients with inflammatory AAAs. This association suggests a critical contribution o f antigen binding in the pathogenesis of this disease.