ARTHRITIS & RHEUMATISM Vol. 50, No. 12, December 2004, pp 4022–4027 DOI 10.1002/art.20677 © 2004, American College of Rheumatology Familial Aggregation of Juvenile Idiopathic Arthritis Sampath Prahalad, Elizabeth O’Brien, Alison M. Fraser, Richard A. Kerber, Geraldine P. Mineau, David Pratt, David Donaldson, Michael J. Bamshad, and John Bohnsack Objective. To estimate the degree of familial ag- gregation of juvenile idiopathic arthritis (JIA), deter- mine whether the aggregation of JIA and the aggrega- tion of type 1 diabetes mellitus (type 1 DM) overlap, and identify multiplex JIA pedigrees. Methods. Records of individuals with JIA or type 1 DM were probabilistically linked with records in the Utah Population Database (UPDB), a large computer- ized family history database. For each case of JIA or type 1 DM, 10 matched controls or 5 matched controls, respectively, were selected. All familial relationships among cases of JIA or type 1 DM were established. A familial risk score was calculated for each subject. For various levels of familial exposure to JIA or type 1 DM, one’s risk (odds ratio [OR]) of developing JIA or type 1 DM was established (cases compared with controls). Recurrence risks for JIA were computed for relatives of JIA cases compared with relatives of controls. Extended JIA families were identified from a list of common ancestors. Results. Records of a total of 443 patients were linked with the UPDB. Of these, 381 (86.0%) met criteria for JIA. An increased risk for JIA was observed among relatives of probands with JIA. The prevalence of type 1 DM among JIA cases was higher than the US prevalence of type 1 DM (P < 0.003). The recurrence risk for JIA was significantly elevated among first- degree relatives of cases with JIA (OR 30.4). The overall prevalence of JIA was 28/100,000. Four extended JIA pedigrees were identified. Conclusion. There is familial aggregation of JIA in the Intermountain West region of the US. We have demonstrated that multiplex JIA pedigrees can be iden- tified using a genealogic database. Juvenile idiopathic arthritis (JIA) is a phenotyp- ically heterogeneous group of conditions characterized by the onset of chronic arthritis in childhood (1). JIA includes the different subtypes of juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (2) (i.e., pauciarticular, polyarticular, and systemic), as well as enthesitis-related arthritis, psoriatic arthritis, and other arthritides. The etiology and patho- genesis of JIA are largely unknown, but both genetic and environmental factors are thought to influence disease susceptibility and expression. Identifying the genetic factors underlying JIA has proven difficult for several reasons, including a low prevalence of familial cases and lack of population-based estimates of recurrence risk. A common strategy to improve the odds of identifying genetic variants that influence a complex disease such as JRA is to stratify a disease cohort into phenotypically similar subsets, each of which is assumed to be genetically more homogeneous. We and others are using this approach to identify JRA susceptibility loci. Alternatively, different phenotypes that share some pathophysiologic features appear, in some cases, to be influenced by the same genetic variant(s). For example, a polymorphism in exon 1 of the CTLA4 gene has been associated with autoimmune thyroiditis, type 1 diabetes mellitus (type 1 DM), and celiac disease (3). Therefore, another strategy for finding JIA susceptibility loci is to Supported in part by grants from the National Institute of Child Health and Human Development (K12HD01410) and from The Val A. Browning Charitable Foundation, the Primary Children’s Medical Center Foundation, the Clinical Genetics Research Program, and The Children’s Health Research Center, Salt Lake City, Utah. Database support to the Utah Population Database was provided by the Huntsman Cancer Foundation. Sampath Prahalad, MD, Elizabeth O’Brien, PhD, Alison M. Fraser, MSPH, Richard A. Kerber, PhD, Geraldine P. Mineau, PhD, David Pratt, MD, David Donaldson, MD, Michael J. Bamshad, MD, John Bohnsack, MD: University of Utah School of Medicine, Salt Lake City. Address correspondence and reprint requests to Sampath Prahalad, MD, Division of Immunology and Rheumatology, Depart- ment of Pediatrics, University of Utah School of Medicine, 30 North, 1900 East, Salt Lake City, UT 84132-2206. E-mail: sampath.prahalad@hsc.utah.edu. Submitted for publication May 4, 2004; accepted in revised form August 26, 2004. 4022