Although the etiology of JIA is complex, genetic factors have long been implicated in its causation.(1
) Besides descriptions of twins(12
) and sibling pairs(14
) with JIA, there are very few descriptions of extended multiplex families of JIA. The few case-series of twins concordant for JIA indicate a monozygotic twin concordance rate of 25–40%(4
), which implies a RR of 250–400 for a monozygotic twin of a proband with JIA.(4
) A limited number of studies have estimated RR for siblings of JIA probands, ranging from ~15 (1
) from the United States, to ~20 in Finland (4
). The denominators in these studies used extrapolated figures, and these studies did not provide confidence intervals or statistical significance levels for the RR estimates.
We have also previously calculated RR for siblings of JIA probands, with an estimated value of 30.(3
). However, the confidence intervals of this estimate were wide (7.0 to infinity) reflecting the small sample size of only 8 individuals with JIA among relatives of probands. Furthermore, in our earlier study we stratified relatives by degree of relationship which combines individuals of different generations in a kinclass. This is likely to have biased our estimates since only children seen in the pediatric rheumatology clinics were included in the ISDCRD, and if earlier generations such as parents, aunts or grandparents had JIA, they would not have been included in the database. By using classes of relatives who are all in the same generation such as siblings and cousins, we have minimized this potential bias. Thus we have now provided reliable estimates with robust confidence intervals for the RR of JIA among siblings. We have also shown that first-cousins of probands with JIA also have a significant excessive risk of JIA, (RR = 6). We believe ours is the first description of RR for relatives beyond siblings and twins. Such estimates would be difficult if not impossible to obtain without resources such as the UPDB, making our study unique. The observed decline in the magnitude of risk between siblings and cousins supports the notion that JIA is influenced by at least several shared genetic factors. Our study also provides a population-based estimate of the prevalence of JIA at 1.2/1000 individuals.
The majority of studies investigating genetic factors in JIA have been case-control association studies. This has been due in part to a lack of large extended multiplex families with multiple JIA cases. Besides reports of affected sibling pairs with JIA, there have only been limited descriptions of JIA multiplex families. Earlier, we had described four clusters of 5 cases of JIA each.(3
) The UPDB is a dynamic database and receives annual updates of new records. Adding more individuals to a hierarchical database has a multiplicative effect on connections. The present study used twice the number of JIA cases. These factors increased the number of familial links and increased the probability of clustering beyond random associations which allowed to us pick more clusters of interest. Thus our present study expands our earlier findings with the identification of several additional and larger case-clusters of JIA which could aid in the search for genes underlying susceptibility to this condition. The affected relatives in these clusters share common ancestors and in many instances are distantly related.
We also calculated, to our knowledge, the first estimates of PAR for familial factors in JIA. Familial factors account for ~13% of JIA. This is modest compared to 39% in carcinoma of the breast, or 35% in colon carcinoma, and is similar to the PAR of 10% estimated in Mullerian anomalies.(7
) We are not aware of PAR estimates for other rheumatic diseases.
While it is possible that there are additional cases of JIA that were not included in our database, we believe our study includes most cases of JIA given that they were seen in the only tertiary pediatric center in the State of Utah. The diagnosis of JIA was made by pediatric rheumatologists who examined these children, thereby assuring the validity of the diagnosis. Our well characterized JIA cohort resembles other published JIA cohorts, suggesting that our results can be generalized to other JIA cohorts.
We acknowledge that our cases come from one hospital system and hence our RR estimates might be inflated by referral bias. However, our PAR calculation is population-based and computes the percent of risk for JIA associated with being a member of an extended family. Also, since we included only JIA cases seen at the Pediatric Rheumatology clinics at the Univeristy of Utah, our observed PAR might be lower than the actual value as some cases with JIA in the population may have sought care at other facilities.
The subtypes of JIA have distinct clinical and genetic associations. However, since clinically distinct autoimmune phenotypes share common susceptibility factors, we treated JIA as a combined phenotype. We did analyze the oligoarticular and polyarticular JIA subtypes separately, and demonstrate that the sibling RR of oligoarticular JIA is also statistically significantly elevated.
Our study provides insight into the familial distribution of JIA based on the analysis of a large number of affected individuals using a unique resource, the Utah Population Database. Comprehensive identification and characterization of JIA within kinships would allow genetic linkage analysis to help identify potentially important genes underlying this common pediatric rheumatic disease.