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

T. E. Rasmussen, Jr Hallett, R. L.M. Metzger, D. M. Richardson, W. S. Harmsen, J. J. Goronzy, C. M. Weyand

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

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 AAA 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.

Original languageEnglish (US)
Pages (from-to)356-364
Number of pages9
JournalJournal of vascular surgery
Volume25
Issue number2
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

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