title: DRB1-TNF-alpha-TNF-beta haplotype is strongly associated with severe aortoiliac occlusive disease, a clinical form of atherosclerosis.
abstract: Severe aortoiliac occlusive disease (AOD) is a clinical manifestation of peripheral arteriosclerosis. Atherosclerosis has been associated with some human leukocyte antigen (HLA)-DRB1 alleles, stressing its relationship with autoimmune or inflammatory disorders. Additionally, in rheumatoid arthritis patients, the DRB1*0404 allele is specifically associated with endothelial dysfunction. Our objective was to assess the role of class II HLA alleles in the susceptibility to AOD; a combined study of the nearby tumor necrosis factor (TNF) locus was also performed. We included 104 AOD patients and 504 healthy controls from Madrid. DRB1 typing and DRB1*04 subtyping was done by polymerase chain reaction amplification followed by hybridization with specific oligonucleotides. TNF-alpha and TNF-beta microsatellites were studied by polymerase chain reaction and capillary electrophoresis. None of the markers was associated with AOD, although a trend was observed for DRB1*0404 (OR = 2.18; p = 0.05). However, among DRB1*0404 individuals, the TNFa11-b4 pair was present more frequently in patients than in controls (OR = 16.0; p = 0.007). The combined appearance of TNFa11-b4 and DRB1*0404 was much more frequent in patients than in controls (OR = 5.92; p = 0.0013), a result enhanced by haplotypic estimates (OR = 10.0; p = 0.00017). Our results show that the HLA region modulates the predisposition to AOD. More specifically, they suggest that an extended haplotype encompassing DRB1*0404 and TNFa11-b4 carries a genetic factor conferring susceptibility to AOD.
authors.affiliation: Department of Immunology Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mas
authors.forename: E
authors.initials: E
authors.lastname: Blanco
authors.forename: G
authors.initials: G
authors.lastname: Moñux
authors.forename: E
authors.initials: E
authors.lastname: Urcelay
authors.forename: F J
authors.initials: FJ
authors.lastname: Serrano
authors.forename: E G
authors.initials: EG
authors.lastname: de la Concha
authors.forename: A
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000483:Alleles; D001157:Arterial Occlusive Diseases / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D016001:Confidence Intervals; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C488436:HLA DRB1*04:04 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha