Genetic risk factors in inflammatory abdominal aortic aneurysms: Polymorphic residue 70 in the HLA-DR B1 gene as a key genetic element

• Published in: Journal of vascular surgery Vol. 25; no. 2; pp. 356 - 364
• Main Authors: Rasmussen, Todd E, Hallett, John W., Mathieu Metzger, Renate L., Richardson, Darcy M., Harmsen, William S., Goronzy, Jorg J., Weyand, Cornelia M.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-02-1997; Elsevier
• Subjects: Aged; Alleles; Amino Acid Sequence; Aortic Aneurysm, Abdominal - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the aorta; Female; Giant Cell Arteritis - genetics; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Humans; Inflammation; Male; Medical sciences; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors; Human; Genetic inheritance; Major histocompatibility system; HLA-DR-System; Aneurysm; Cardiovascular disease; Inflammation; Arterial disease; Vascular disease; Abdominal aorta; Risk factor; Aortic disease; Polymorphism
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/S0741-5214(97)70358-6

Purpose: Evidence of a genetic predisposition to the development of inflammatory abdominal aortic aneurysms (AAAs) exists as a positive family history in 17% of patients. Familial clustering and other similarities between inflammatory AAAs and giant cell arteritis (GCA), which possesses a genetic risk determinant mapped to the HLA-DR molecule, suggest a role of genetic risk factors in inflammatory AAAs. The purpose of this study was to explore whether patients with inflammatory AAAs express disease-relevant genes associated with the HLA-DR region on the short arm of chromosome 6.
Methods: Thirty-seven patients with histomorphologic 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: Distribution of HLA-DR B1 alleles was nonrandom in patients with inflammatory AAAs versus control subjects. The HLA-DR B1 alleles B1*15 and B1*0404 were enriched in patients with inflammatory AAAs compared with control subjects (47% versus 27%, and 14% versus 3%; p < 0.05, respectively). Analysis of functionally relevant amino acid polymorphisms encoded by the HLA-DR B1 gene showed relevance at amino acid position 70. HLA-DR B1 alleles overrepresented in patients with inflammatory AAAs express a glutamine substitution at position 70, whereas alleles disfavored 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 risk determinant can be mapped to the HLA-DR B1 locus in patients with inflammatory AAAs. This association suggests a critical contribution of antigen binding in the pathogenesis of this disease. (J Vasc Surg 1997;25:356-64.)