Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis

• Published in: Rheumatology (Oxford, England) Vol. 51; no. 1; pp. 52 - 59
• Main Authors: Beretta, Lorenzo, Rueda, Blanca, Marchini, Maurizio, Santaniello, Alessandro, Simeón, Carmen P., Fonollosa, Vicente, Caronni, Monica, Rios-Fernandez, Raquel, Carreira, Patricia, Rodriguez-Rodriguez, Luis, Moreno, Antonia, López-Nevot, Miguel A., Escalera, Ana, González-Escribano, Maria F., Martin, Javier, Scorza, Raffaella
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2012
• Subjects: Autoantibodies - analysis; Basic Science; Biological and medical sciences; Case-Control Studies; Diseases of the osteoarticular system; Genetic Predisposition to Disease; Histocompatibility Testing - methods; HLA-D Antigens - genetics; HLA-DQ alpha-Chains - genetics; HLA-DQ beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Italy - epidemiology; Medical sciences; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - epidemiology; Scleroderma, Systemic - genetics; Scleroderma, Systemic - immunology; Spain - epidemiology; Italy; Spain; epidemiology; systemic sclerosis; genetics; HLA; Human; Immunopathology; Connective tissue disease; HLA-System; Skin disease; Italian; Rheumatology; Autoimmune disease; Epidemiology; Antigen; Systemic disease; Genetics; Scleroderma
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/ker335

Objective. To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry. Methods. Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted. Results. In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI95) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI95 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI95 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI95 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI95 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI95 0.384, 0.651; P < 0.001). Conclusions. We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc.