Abstract: HLA and Susceptibility to Juvenile Idiopathic Arthritis: A Study of Affected Sibpairs in an Isolated Finnish Population

HLA and Susceptibility to Juvenile Idiopathic Arthritis: A Study of Affected Sibpairs in an Isolated Finnish Population

HANNA SÄILÄ, JANNE PITKÄNIEMI, JAAKKO TUOMILEHTO, ANNELI SAVOLAINEN, NOORA ALAKULPPI, EVA TUOMILEHTO-WOLF, MARJATTA LEIRISALO-REPO, and KIMMO AHO

ABSTRACT.

Objective. To determine the effects of class I (A, B, and C) and II (DRB1 and DQB1) HLA loci alleles and DRB1-DQB1 haplotypes on genetic susceptibility to juvenile idiopathic arthritis (JIA) in families with 2 or more affected siblings.

Methods. A total of 83 affected siblings belonging to 38 families and corresponding to 50 affected sibpairs, their parents, and 45 healthy sibs were typed for HLA in A, C, B, DRB1, and DQB1 loci. Two study designs were used to explore linkage and association: a case-population control design and a family design using the linkage method: identical-by-descent (IBD) allele-sharing and the association analysis methods. Associations in family data were analyzed using the independent transmission disequilibrium test (TDT) for linkage in the presence of association. This was supplemented by the family-based association test (FBAT) to look for association in the presence of linkage, and is robust for population stratification and phenotype-based selection of data.

Results. Significantly increased HLA allele frequencies among the affected siblings compared to Finnish bone marrow donors were observed for HLA alleles Cw4 (odds ratio, OR, 1.7), B27 (1.8), B35 (1.7), and DR8 (3.7). The observed ratio of sharing 0, 1, and 2 HLA haplotypes (A, C, B, DRB1, and DQB1) among affected sibpairs (ASP) was 10:23:17, significantly different from expected (p < 0.001), using a formula that takes into account disease prevalence and the sibling recurrence risk. In the univariate association analysis, both independent TDT and FBAT found significantly increased transmission of the DRB1*0801 and DQB1*0402 alleles and Cw*0401. Independent positive allele effects of Cw*0401, DRB1*0801, and DQB1*0402 as well as negative effects of Cw*0701 and DQB1*0302 were shown by the family-based association analysis of the joint allele main effects. Multi-allelic test for association of each locus confirmed significant associations of the DRB1 and DQB1 loci in the risk of JIA. We found DRB1*0801/DQB1*0402 haplotype to be strongly associated (p < 0.001) with JIA, supporting findings of the haplotype associations-based ASP design.

Conclusion. Both linkage analysis of the affected sibpairs and association analysis of nuclear families with JIA provided overwhelming evidence of the major contribution of HLA to genetic susceptibility to JIA. The association analysis of HLA-A, C, B, DRB1, and DQB1 alleles by both TDT and FBAT tests confirmed in the Finnish population that the most significant associations prevailed for DRB1*0801, DQB1*0402, as expected from previous observations, and supported the independent role of Cw*0401. (J Rheumatol 2004;31:2281-5)

Key Indexing Terms:

JUVENILE IDIOPATHIC ARTHRITIS
SIBLINGS
HLA
GENETICS

From the Rheumatism Foundation Hospital, Heinola; Diabetes and Genetic Epidemiology Unit, National Public Health Institute and Department of Public Health, University of Helsinki, Helsinki; University Central Hospital, Department of Medicine, Division of Rheumatology, Helsinki; and the National Public Health Institute, Helsinki, Finland.

Supported in part by National Institutes of Health grant AR44422, Academy of Finland grant 46558, Päivikki and Sakari Sohlberg Foundation, and by a grant from Helsinki University Central Hospital Research Funds.

H. Säilä, MD, Pediatric Rheumatology Fellow, Rheumatism Foundation Hospital; J. Pitkäniemi, MSc (Biometry), Diabetes and Genetic Epidemiology Unit, Department of Epidemiology; J. Tuomilehto, MD, MPolSc, Professor, Diabetes and Genetic Epidemiology Unit, National Public Health Institute and Department of Public Health, University of Helsinki; A. Savolainen, MD, Chief Specialist in Pediatric Rheumatology, Rheumatism Foundation Hospital; N. Alakulppi, MSc, Diabetes and Genetic Epidemiology Unit, National Public Health Institute, currently at the Finnish Red Cross Blood Transfusion Service; E. Tuomilehto-Wolf, MD, FRCPath, Senior Researcher, Diabetes and Genetic Epidemiology Unit, National Public Health Institute; M. Leirisalo-Repo, MD, Professor, Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital; K. Aho, MD, Professor, National Public Health Institute.

Address reprint requests to Dr. H. Säilä, Rheumatism Foundation Hospital, Fin-18120, Heinola, Finland. E-mail: Hanna.Saila@reuma.fi

Submitted December 1, 2003; revision accepted April 7, 2004.