ARA = American Rheumatism Association; EULAR = European League Against Rheumatism; HLA = human leukocyte antigen; IL = interleukin;ILAR = International League of Associations for Rheumatology; JIA = juvenile idiopathic arthritis; JRA = juvenile rheumatoid arthritis; s = siblingrecurrence risk; MIF = macrophage migration inhibitory factor; SNP = single nucleotide polymorphism; TCR = T-cell receptor; TNF = tumour necro-sis factor.
Arthritis Research Vol 4 No 5 Thomson and Donn
IntroductionIt is necessary to define the genetic component of anydisease in order to enhance the understanding of itspathogenesis, imply its aetiology and refine its treatment.The most rapid progress towards such aims is bestachieved when there is homology of the expressed form(phenotype). Unfortunately, progress in defining thegenetic components of childhood arthritis has long provendifficult, for two reasons. Firstly, childhood inflammatoryarthritis is not a single disease but a group of clinical syn-dromes. Secondly, since its first description in the late1890s, classification of the chronic arthritides of child-hood has been problematic. Ansell and Bywaters  firstproposed that classification should be based on the char-acteristics of disease at onset and this basic premise stillremains. This premise has led to the development of tworelated but importantly different classifications, juvenilechronic arthritis as defined by EULAR and juvenilerheumatoid arthritis (JRA) as defined by the AmericanRheumatism Association (ARA). The major differences arethe disease duration (minimum of 3 months for EULAR,6 weeks for ARA) and the fact that the EULAR criteria areinclusive of other forms of juvenile arthritis, such as juve-nile ankylosing spondylitis, inflammatory bowel disease
and juvenile psoriatic arthritis, whereas the ARA criteriaare exclusive.
These problems have hindered genetic studies. In addi-tion, the relatively small patient numbers in some of thedisease subgroups significantly reduces the power of anystudy to detect a real effect. Also, the determination oftrue genetic effects relies heavily on the replication ofresults in identical patient populations but transatlantic dif-ferences in classification have made this virtually impossi-ble. In an attempt to solve these issues, a newclassification system, the ILAR classification, has beendeveloped. It aims both to unify the previous classificationsystems so as to minimise international differences indisease definition and to identify clinically homogenousdisease subgroups within the umbrella term JIA and thusfacilitate research .
Juvenile idiopathic arthritis (JIA) indicates a disease ofchildhood (i.e. less than 16 years of age) of no known aeti-ology, characterised by arthritis persistent for at least6 weeks. Classification is made at 6 months after diagno-sis into one of eight disease categories, each of which hasits own specific characteristics, exclusions and descrip-
Studies have established the magnitude of the genetic basis of juvenile idiopathic arthritis (JIA). JIA is acomplex genetic condition and the genes that influence susceptibility are actively being sought. Acandidate gene approach is being used by several groups. MHC-, cytokine- and T-cell-related geneshave all been positively associated with JIA. Here we review some of the latest genetic data, anddiscuss ways in which JIA genetic research might proceed.
Keywords: candidate genes, cytokines, genetics, juvenile idiopathic arthritis
ReviewGenetic epidemiologyJuvenile idiopathic arthritis genetics Whats new? Whats next?Wendy Thomson and Rachelle Donn
Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester, Stopford Building, OxfordRoad, Manchester M13 9PT, UK
Corresponding author: Wendy Thomson (e-mail: email@example.com)
Received: 19 April 2002 Revisions received: 20 June 2002 Accepted: 25 June 2002 Published: 5 August 2002
Arthritis Res 2002, 4:302-306 2002 BioMed Central Ltd (Print ISSN 1465-9905; Online ISSN 1465-9913)
Available online http://arthritis-research.com/content/4/5/302
tors. Validation of the ILAR classification is still inprogress. Despite these challenges, progress within thearea of JIA genetics is being achieved.
Evidence for a genetic component to juvenileidiopathic arthritisEvidence for a genetic component to a disease can comefrom a variety of sources such as twin studies, familystudies or association studies. As JIA is a relatively raredisease, accounts of twin and family studies are quiteuncommon and often based on small numbers. Recentdata from the USA and Finland, however, suggest that thegenetic contribution to JIA may be quite considerable.
Within the USA, the National Institute of Arthritis and Mus-culoskeletal and Skin Diseases has sponsored a researchregistry for JRA-affected sibling pairs. Initial analysis of 71affected sibling pairs showed that 63% were concordantfor gender and 76% for onset type . This study alsoprovided the first estimate of the sibling recurrence risk(s) for JRA; this was 15 (a value similar to those forinsulin dependent diabetes mellitus and multiple sclero-sis), although this is likely to vary between subgroups.Such a high s is indicative of a factor shared betweensiblings genetic or environmental. In a more recentanalysis of 118 affected sibling pairs, 14 pairs of twinswere identified in which both twins have arthritis. One paircomprises a girl with polyarthritis and a boy with persistentoligoarthritis. The other 13 pairs (11 monozygotic, 2 dizy-gotic and 2 of unknown zygosity) were concordant forgender (nine female, four male), disease onset (10 paucia-rticular, 3 polyarticular) and disease course (eight pauciar-ticular, five polyarticular) .
Within Finland, 41 JIA multicase families with 88 affectedsiblings have been collected over a period of 15 years.This study estimates the s of JIA to be nearer 20 .Within this set of families there were eight sets of monozy-gotic twins, two of which were concordant for JIA. Bothsets of twins were concordant for disease course butwere unexpectedly different for disease onset . A con-cordance rate of 25% for a disease with a populationprevalence of 1 per 1000 implies a relative risk of 250 fora monozygotic twin. All these data (American and Finnish)taken together provide convincing evidence that there is asubstantial genetic component to JIA.
Juvenile idiopathic arthritis and the MHCMuch of the genetic work undertaken in the past threedecades centred round HLA genes. These earlier studiesof HLA and JIA included children classified according toeither the EULAR or the ACR criteria. Numerous studiesof associations of JIA with both HLA class I and class IIgenes have been described, with the class I associationsbeing consistently more limited than those for class II.These studies have been reviewed elsewhere . More
recently, linkage to HLA has now been confirmed in twopopulations [8,9].
Studies of non-HLA genes within the MHC have beenlimited. Positive associations have recently beendescribed, however, between LMP7 and early-onsetpauciarticular JRA, and between the gene encodingTapasin with systemic-onset JRA [10,11].
Candidate gene selection in juvenileidiopathic arthritisSeveral aspects can be considered when selecting genesfor investigation in JIA. The nature of the histopathology ofthe inflamed synovium is one starting point. Evidence forthe underlying driving force for the chronic synovitis of JIAbeing antigen-driven and T-cell mediated has been welldocumented in a recent review by Grom & Hirsch .
Arguably, another important starting point for geneticinvestigation is raised levels of protein expression inaffected children. Keys to the pathogenesis of JIA may beprovided by changes in the secretion patterns of particularproteins, as measured by bioassays; alternatively, theseproteins could simply be present at altered levels as aresult of bystander effects, having little to do with thepathogenic mechanism. Studying the genetic variation ofsuch candidates should help to elucidate this cause oreffect conundrum. To be effective the functional polymor-phism(s) need to be studied. These are generally not pre-determined. Hence to fully investigate a gene it may benecessary to study all the single nucleotide polymor-phisms (SNPs) within it.
Cytokine gene polymorphisms and juvenileidiopathic arthritisTumour necrosis factorThe involvement of tumour necrosis factor (TNF) protein andits receptors in the pathology of JIA has been suggested bymultiple studies. The genetic evidence in support of theseobservations, however, is much scarcer. Date et al. showed the frequencies of polymorphisms at the 1031,863 and 857 positions of the TNF promoter to be signifi-cantly higher in a group of Japanese systemic-onset JIApatients compared with those observed in controls. Also,particular alleles of a microsatellite marker in the TNF-gene were found to be strongly associated with early-onsetpauciarticular juvenile arthritis in German patients .Ozen et al.  studied the TNF 308 and 238 polymor-phisms in Czech and Turkish JIA patients, but found noassociation with either polymorphism. In contrast, Zeggini etal.  have reported positive association with TNF poly-morphisms in a large panel of UK Caucasian oligoarticularJIA patients. The TNF locus is highly polymorphic andseveral of the SNPs that have so far been described havepotential functional significance. Clearly, more studies of thepolymorphisms of TNF in JIA patients are required.
Arthritis Research Vol 4 No 5 Thomson and Donn
Interleukin 6Many of the clinical features of systemic-onset JIA aretypical of excessive IL-6 production, for example fever,hypergammaglo