A Review of the MHC Genetics of Rheumatoid Arthritis

REVIEW A review of the MHC genetics of rheumatoid arthritis

JL Newton1, SMJ Harney1, BP Wordsworth1 and MA Brown1 1Institute of Musculoskeletal Sciences, University of Oxford, The Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK

Rheumatoid arthritis is a common complex genetic disease, and, despite a significant genetic element, no gene other than HLA-DRB1 has been clearly demonstrated to be involved in the disease. However, this association accounts for less than half the overall genetic susceptibility. Investigation of other candidate genes, in particular those that reside within the major histocompatibility complex, are hampered by the presence of strong linkage disequilibrium and problems with study design. Genes and Immunity (2004) 5, 151–157. doi:10.1038/sj.gene.6364045 Published online 29 January 2004

Keywords: major histocompatibility complex; rheumatoid arthritis, genetics

The genetic contribution to rheumatoid The shared epitope (SE) hypothesis arthritis (RA) The association of RA with HLA-Dw4 was first reported RA has a strong genetic component but the exact by Stastny in 1976.6 The development of higher resolu- heritability is uncertain. The best estimates of heritability tion HLA-DRB1 genotyping led to the demonstration come from twin studies. The reported concordance rates that different HLA-DR4 alleles are not equally associated have varied between studies, most likely because of with RA. Further, studies in different populations differences in the severity of the cases studied. The MZ demonstrated that non-DR4 HLA-DRB1 alleles were also concordance rate for RA is four times greater than the associated with disease. These findings indicated that the dizygotic (DZ) twin concordance rate, indicating a complexity of the HLA-DRB1 association was greater heritability of 40–60%.1–3 The overall MZ twin concor- than supposed previously. Gregerson and co-workers dance rate is 12–15%. These twin studies provide an first reported a unifying hypothesis for the association of upper limit to the genetic contribution to RA. Studies different HLA-DRB1 specificities associated with RA, including twins with milder disease have found lower termed the ‘SE’ hypothesis. They demonstrated that RA MZ concordance rates, most likely because HLA-DRB1, is associated with specific HLA-DRB1 (DRB1) alleles that clearly the major gene in RA, significantly affects disease encode a conserved sequence of amino acids, severity.4 (70QRRAA74, 70RRRAA74 or 70QKRAA74) comprising residues 70–74 in the third hyper variable region (HVR3) of the DRb1 chain.7 These residues constitute an a helical domain forming one side of the antigen Major histocompatibility complex (MHC) binding site, a site likely to affect antigen presentation. The only region of the genome that has been consistently The alleles carrying this nucleotide sequence are shown to be associated with disease is the MHC. The DRB1*0401, *0404, *0405, *0408, *0101, *0102, *1402, *09 MHC, situated on chromosome 6 (6p21.3), extends and *1001. In different ethnic groups the predominant over 3.6 Mb (Figure 1). It is divided into three regions, RA-associated alleles vary considerably: *0401 and *0404 classes I, II and III. The class I region, at the telomeric end are the predominant RA associated alleles in Caucasians, of the MHC, contains the HLA class 1 genes, HLA-A, -B *0405 in Japanese and *0101 in Israeli Jews. Association and –C, and extends over 2000 kb. In the HLA class II with DRB1*09 has been described in Chilean RA region are the HLA-DR, -DP and -DQ loci, encoding the patients, Japanese and more recently UK Caucasians.8 a and b chains of the various HLA class II molecules. The In contrast, there are other alleles that are negatively class III region lies between the class I and II regions. associated with RA and therefore provide a protective The MHC is a highly gene dense region containing role (DRB1*0103, *0402, *0802, *1302).8 about 220 genes, many of which have immunoregulatory The SE hypothesis assumes that these particular functions.5 class II molecules are directly involved in the pathogen- esis of RA, but the exact mechanism remains unknown. If the pathogenic process is the simple presentation Correspondence: MA Brown, Institute of Musculoskeletal Sciences, of an arthritogenic peptide, a dominant mode of University of Oxford, The Botnar Research Centre, Nuffield Orthopaedic inheritance would be likely. Recurrence risk model- Centre, Windmill Road, Headington, Oxford, UK. E-mail: [email protected] ling has rejected dominant models of inheritance Received 08 September 2003; revised 03 November 2003; accepted and suggests the presence of more than one MHC 04 November 2003 susceptibility gene.9–11 MHC genetics of RA JL Newton et al 152 haplotype bearing SE-positive HLA-DRB1 alleles. While telomeric the DRB1 association with RA is robust, the penetrance of the genotype is low, with B30% of the normal UK Caucasian population being HLA-DRB1*04 positive. Further, in Caucasians, B30% of cases do not carry an Class I HLA - E SE-encoding allele. Indeed, in some studies of patients region 1930kb with mild disease, no association with HLA-DRB1 is FLOT apparent. The absolute risk for developing RA if carrying an SE-encoding allele is one in 35 for *0401, one in 20 for *0404, one in 80 for *0101 and one in 7 for *0401/*0404 HLA- C compound heterozygotes.17 Thus the RR is high but the absolute risk is relatively low, and although the associa- HLA-B tions with the MHC are strong, the presence of the SE is neither necessary nor sufficient for disease to occur. MICA MICB NFKBIL1 TNF Class III HLA-DRB1*04 or HLA-DQB1*03? BAT2 BAT5 region DDAH 2 As with many diseases with MHC associations, the CLIC 1110kb extent and complexity of LD within the MHC has HSPAIL complicated attempts to define precisely the disease- HSP CLUSTER causing genes. The serologically determined specificities, RAGE DQ3 and DR4, encoded at the HLA-DQB1 (DQB1) and - NOTCH4 DRB1 loci, respectively, are both strongly associated with RA in Caucasians. It has been proposed that DQB1*03 and *05 alleles are in fact the true disease-susceptibility 300kb DRB1 alleles in RA, and that the DRB1 associations with DQA1 disease are merely the result of linkage disequilibrium DQB1 Class II region (LD) with these alleles. Support for this hypothesis TAP2 LMP comes from studies in collagen-induced arthritis in HLA- TAP1 DQ transgenic mice. Transfection of susceptible mice centromeric DMA with HLA-DQ8 (DQB1*0302 is the human equivalent) resulted in the development of an inflammatory arthritis similar to RA after immunization with type II collagen. Transcriptional Orientation In contrast, transfection with a non-RA-associated gene, Figure 1 The MHC region. HLA-DQ6, created a phenotype resistant to the development of inflammatory arthritis.18–22 Some association studies in humans have suggested a direct role for DQ A further complexity is that there is a hierarchy of alleles in RA.23 However, further larger studies have not strength of the association of the different SE-positive supported this hypothesis.8,24 Milicic and co-workers HLA-DRB1 alleles and RA, and that some combinations studied 685 RA patients and a total of B14 000 healthy of SE alleles carry greater risk than homozygosity for bone marrow donors, and found no role for DQB1 alleles those alleles. For example, the DRB1*0401/*0404 com- independent of the SE. pound heterozygote genotype is strongly associated with Several studies have, however, demonstrated the early disease onset and a more severe disease phenotype association of the HLA-DRB1*0401-DQB1*0301 haplo- than either DRB1*0401 or DRB1*0404 homozygosity.12–14 type with greater disease severity, positive IgM rheuma- Carriage of DRB1*0401/DRX, where X is a non- toid factor and greater degrees of joint deformity.25 SE-encoding allele, has a relative risk (RR) for developing Therefore, it has been suggested that DR/DQ comple- RA of 4.7, for DRB1*0404/DRX the RR ¼ 5.0, *0401/*0401 mentarity may affect the clinical expression of RA in the RR ¼ 18.8 and for DRB1*0401/DRB1*0404 heterozy- humans as well as mouse models. However, SE-encoding gotes the RR ¼ 31.14,15 The effect size of the association of alleles are also increased in these clinical subgroups, DRB1*0404/*0404 homozygosity has, however, not yet quite likely contributing to their more severe phenotype. been formally compared with DRB1*0401/DRB1*0404 Carefully designed studies, particularly in Felty’s syn- heterozygotes. It is possible that the heterozygote drome, also strongly suggest that the primary association association may prove intermediate between the associa- is with DRB1*04 alleles.26 In conclusion, there is no tion of DRB1*0401 and *0404 homozygotes, contrary to definitive evidence that DQB1 alleles influence suscept- the prediction of the compound heterozygosity theory. In ibility to RA, but there may be an influence on the clinical this regard, it is important to note that the combination expression of the disease from DR–DQ complementarity. *0404,5,8/*0404,5,8 has RR ¼ 36.2, greater than the magnitude of the association of DRB1*0401/DRB1*0404 15 heterozygosity with RA. Other MHC candidate genes Calculations from the extent of sharing of MHC alleles identical by descent within families suggest that the Considerable research has gone into trying to identify the contribution from the MHC is B30% of the total genetic further MHC genes, which are likely to be involved in effect.16 This may be an underestimate, as in many RA (see Table 1 for a summary). The most widely studied families the parents may carry more than one MHC locus is TNF, which lies 1000 kb from HLA-DRB1 within

Genes and Immunity MHC genetics of RA JL Newton et al 153 Table 1 Summary of the previous MHC candidate gene and mapping studies in RA listed in chronological order

Chromosome Year Gene(s) Sample size Result

Angelini et al44 1992 HLA-DP, -DQ, -DR 48 cases, 109 controls Negative Perdriger et al45 1992 HLA-DPB1 71 cases, 148 controls RR ¼ 2.74, Po0.03 Brinkman et al46 1994 TNF 13 cases, 88 controls Negative Vandevyver et al47 1994 TNF 77 cases, 58 controls Negative Singal et al48 1994 TAP2 Suggest a role for TAP polymorphisms in DR4-positive patients Wilson et al49 1995 TNF 147 cases, 135 controls Negative Vandevyver et al50 1995 TAP 82 cases, 66 controls Negative Maksymowych et al51 1995 LMP 2 168 cases, 210 controls Negative Wordsworth et al52 1995 AP genes 60 cases, 60 controls Negative Mulcahy et al53 1996 TNF 50 multiplex families Positive for a TNF effect independent of DRB1 Hillarby et al54 1996 TAP2D 89 cases, 64 controls OR ¼ 2.6 (1.2–5.8) Field et al55 1997 TNF 98 cases, 91 controls Negative Brinkman et al56 1997 TNF 283 cases, 116 controls TNF-238GA OR ¼ 4.1 (1.0–17) Vinasco et al57 1997 TNF 60 cases, 102 controls Negative Vinasco et a758 1997 HSP 70 Negative Singal et al59 1998 MHC microsatellites 97 cases, 100 controls Positive for a second MHC susceptibility locus Tuokko et a860 1998 TAP genes 40 cases, 60 controls P ¼ 0.024 Vinasco et al61 1998 TAP genes 60 cases, 102 controls Negative van Krugten et al62 1999 TNF 112 cases, 138 controls RR ¼ 3.89 Waldron-Lynch et al63 1999 TNF 23 cases, 10 controls Negative Seki et al64 1999 TNF 387 cases, 575 controls Negative Bali et al65 1999 HLA region 60 multiplex families Positive for an independent role of TNF-c alleles Singal et al39 1999 MHC 97 cases, 95 controls Positive for a second MHC susceptibility locus Perdriger et al66 1999 HLA-DMB1 163 cases, 146 controls Possible role for HLA-DM alleles Singal et al67 1999 HLA-D region 20 cases, 20 controls DRB1and/or inappropriate expression of certain DR genes contributes to RA development Martinez et al28 2000 TNF 52 families TNFa6b5 positively associated with disease Hajeer et al27 2000 TNF 179 cases, 145 controls Negative Shibue et al68 2000 TNF 545 cases, 265 controls Negative Singal et al69 2000 HLA class III region 97 cases, 95 controls Positive for a second MHC susceptibility locus Vejbaesya et al70 2000 TAP genes 82 cases, 100 controls Negative Jenkins et al71 2000 HSP 70 60 families P ¼ 0.003 Castro et al72 2001 TNF 79 cases, 69 controls TNFa6 Po0.0076 Waldron-Lynch et al30 2001 TNF 33 multiplex families Positive for À308 and À857 depending on the SE status Hadj Kacem et al73 2001 HLA-DQB1 CAR1/CAR2 60 cases, 150 controls Negative for TNF, positive for HLA-DQB1, CAR1/CAR2 Ota et al74 2001 70kb region telomeric of 120 cases, 248 controls Positive for a second susceptibility locus telomeric TNF of TNF Tuokko et al75 2001 HLA haplotypes in RA 67 cases, 77 controls Suggest loci outside DRB1 contribute to RA susceptibility Zanelli et al35 2001 HLA region 132 cases, 254 controls Positive for a second susceptibility locus in the telomeric HLA region Singal et al76 2001 MICA 90 cases, 85 controls Negative Martinez et al77 2001 MICA 54 families, 211 cases, OR ¼ 0.39, P ¼ 0.007(TDT), P ¼ 0.0005 (case control) 200 controls Low et al78 2002 TNF 238 cases, 217 controls Negative Udalova et al79 2002 TNF 81 cases, 176 controls P ¼ 0.02–863, OR ¼ 1.89 (1.04–3.41) Cvetkovic et al80 2002 TNF 154 cases and controls Allele 1 Po0.01 (OR ¼ 1.62) Jawaheer et al38 2002 HLA complex 469 multi-case families Positive for two additional genetic effects to DRB1 Pascual et al81 2002 HLA haplotypes 147 cases, 202 controls Positive for a second RA susceptibility factor Okamoto et al37 2003 I kappa BL 116 cases, 100 controls P ¼ 0.0062 Newton et al34 2003 TNF 300 cases, 300 controls P ¼ 0.007 with one haplotype

the MHC class III region. These studies have reported they were designed to investigate. These two effects may conflicting findings, and very few of them have followed be indistinguishable.27–30 designs that would control fully for LD with DRB1. A These problems are not unique to RA, affecting studies common approach has been to match cases and controls of any disease with strong MHC associations. Several either for the carriage of DRB1*04or for carriage of SE- different approaches have been taken to overcoming this containing DRB1 alleles. The distribution of SE carrying problem. Using within-family association, studies have DRB1 alleles, or DR4 alleles, may then differ between compared the transmission of haplotypes within families cases and controls, because of their differential strength where the parents carry more than one copy of an HLA- of the association with RA. Thus, previous studies of DRB1 susceptibility allele (the ‘Homozygous Parent other MHC markers in RA may have been affected by LD Test’31 (Figure 2). Thus, for example, if there are as well as by the effects of the disease association that two parental haplotypes carrying HLA-DRB1*0401, the

Genes and Immunity MHC genetics of RA JL Newton et al 154 a Using this method, we have recently studied the role DRB1*0401-TNF*2 DRB1*0404-TNF*2 of the TNF gene in RA. Studying only DR4-positive cases and controls, the frequencies of different LTA-TNF DRB1*0403-TNF*3 DRB1*0701-TNF*4 haplotypes were compared between cases and control haplotypes carrying the same DRB1*04 allele. A single LTA-TNF haplotype (termed LTA-TNF2) was identified as modifying the DRB1 associations with RA; being over- represented on case *0404 haplotypes (P ¼ 0.007) and DRB1*0401-TNF*2 under-represented on case *0401 haplotypes (P ¼ 0.007). DRB1*0404-TNF*2 These results strongly support the presence of an b additional MHC susceptibility locus or loci outside of the TNF region.34 However, as the knowledge of the DRB1*0401-TNF*3 DRB1*0403-TNF*4 haplotype structure of this area is currently limited DRB1*0401-TNF*2 DRB1*0403-TNF*3 further, large studies are necessary to rule out the LT- TNF region definitively. There is an increasing body of evidence implicating the region telomeric to TNF of harboring additional RA- susceptibility elements.35,36 Ota et al, using 18 micro- DRB1*0401-TNF*3 satellite markers across a 3.6 Mb region of the MHC and five TNF SNPs, in 120 patients and 248 controls, DRB1*0403-TNF*4 identified a 70 kb region telomeric of TNF that demon- Figure 2 TDT studies of the MHC. Standard TDT compares the strated association with RA. No LD was seen with transmitted and untransmitted allele frequencies. In (a), if looking at DRB1*0405, but this was only assessed on the basis of the TNF alleles only, there may appear to be an overtransmission of carriage of *0405 rather than at a haplotypic level, and no TNF*2, but when the DRB1 data are included it becomes clear that assessment was carried out of other RA-associated DRB1 this is likely just to represent overtransmission of DRB1 SE carrying alleles. In (b), each parent is homozygous for the same DRB1 allele alleles. Thus this study may still be affected by LD with so the role of the TNF alleles can be specifically examined. DRB1. A subsequent paper by Okamoto et al concluded that the true disease-associated variant was an SNP (SNP 96452) within the IkBL gene.37 No LD studies between the SNPs and DRB1 were reported. It appears that the results preferential transmission of one of those haplotypes from the preceding paper, showing that the microsatel- compared with the other may indicate the presence of a lites were not in LD with DRB1, were extrapolated to further susceptibility allele on the overtransmitted conclude that the SNPs in this region were also not in haplotype. This approach has been used with success LD. In British Caucasians, this SNP is in significant LD in type I diabetes, but requires very large sample sizes to with the DRB1 locus (unpublished data). Okamota and obtain sufficient informative families. A further ap- co-workers also demonstrated stronger association of a proach is to pool on the basis of carriage of specific haplotype of three markers than with SNP 96452. If the DRB1 alleles (ie ‘antigen positivity’), but this assumes conclusion is that this SNP is directly involved in the that both cases and controls are in Hardy–Weinberg susceptibility to RA, then the strongest association equilibrium. In RA cases, the DRB1 alleles are not in should have been with this SNP alone. The results do Hardy–Weinberg equilibrium due to the strong disease provide evidence of an additional susceptibility region association of this locus, and therefore such studies are for RA, but do not necessarily implicate SNP 96452 still susceptible to bias due to LD with DRB1. Lastly, a specifically. form of logistic regression applied to the transmission Further evidence as to the complexity of the MHC disequilibrium test has been developed, which allows associations of RA came from the work of Jawaheer et al38 comparison of transmission rates of haplotypes identical who genotyped a total of 54 microsatellite markers across at the candidate locus, but different at the secondary the MHC in 469 multicase RA families. There was locus. This method loses power rapidly with increasing significant association with one microsatellite haplotype LD such as one would expect across the MHC, and is on the background of the ancestral A1-B8-DRB1*03 therefore not ideal for this application.32 haplotype, a non-SE-encoding haplotype. The region of Full matching of haplotypes in cases and controls at association covered a B500 kb segment of the central HLA-DRB1 does effectively control for LD. Until MHC, which did not include DRB1. There was also recently, such haplotypic studies have required the use evidence of an additional susceptibility element on of families for both cases and controls. Although the the background of DRB1*0404 in the class I region of nontransmitted parental haplotypes could be used as the MHC. These findings are in keeping with our results controls, this method requires large data sets to obtain showing different disease-modifying elements on the sufficient power. Further, as described below, the non- background of DRB1*0401 and DRB1*0404. Singal et al39 transmitted maternal SE-bearing haplotypes may not provided evidence for an additional susceptibility region be randomly distributed, and may influence disease in the Bat2-Hsp region of the class III MHC in SE- susceptibility themselves, thereby invalidating their negative patients. This study using B100 cases and use as a control group. The development of accurate controls confirmed LD between these microsatellites and Bayesian approaches to determining haplotype frequen- DRB1. There was not sufficient matching to control for cies in unrelated cases and controls has permitted a this confounding effect when analyzing the SE-positive novel powerful and efficient method that overcomes this group, but analyses on the SE-negative group demon- problem.33 strated association with the Bat2 138 allele and the

Genes and Immunity MHC genetics of RA JL Newton et al 155 D6S273 138 allele. Zanelli et al genotyped six micro- design to eliminate as many confounding factors as satellites residing in the class III region and the possible. centromeric portion of the class I region in 132 RA patients and 254 controls. There was evidence for a susceptibility factor in the region telomeric to TNF independent of DRB1.35 References In conclusion, there is compelling evidence against a direct role for polymorphisms in the TNF gene 1 Silman AJ, MacGregor AJ, Thomson W et al. Twin concor- contributing directly to RA susceptibility and an dance rates for rheumatoid arthritis: results from a nationwide increasing body of support for additional susceptibility study. Br J Rheumatol 1993; 32: 903–907. elements elsewhere in the MHC, in particular, the 2 Aho K, Koskenvuo M, Tuominen J, Kaprio J. Occurrence regions telomeric to the TNF gene. 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