Title: CARD15: a Pleiotropic Autoimmune Gene That Confers Susceptibility to Psoriatic Arthritis
Abstract: A recent genomewide scan in psoriatic arthritis (PsA) revealed a susceptibility locus at 16q. This region overlaps CARD15, a susceptibility gene in Crohn disease. The possibility of a common susceptibility gene between PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis in subjects with Crohn. We screened 187 patients with PsA and 136 healthy controls, all from Newfoundland, for the three common, independent sequence variants of CARD15 (R702W, leu1007fsinsC, and G908R), which were detected by polymerase chain reaction by use of allele-specific primers and visualized through gel electrophoresis. In total, 53/187 (28.3%) probands with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (odds ratio 2.97; 95% confidence interval 1.61–5.47; P=.0005). Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to PsA independent of HLA-Cw*0602. Thus, CARD15 represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with PsA. A recent genomewide scan in psoriatic arthritis (PsA) revealed a susceptibility locus at 16q. This region overlaps CARD15, a susceptibility gene in Crohn disease. The possibility of a common susceptibility gene between PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis in subjects with Crohn. We screened 187 patients with PsA and 136 healthy controls, all from Newfoundland, for the three common, independent sequence variants of CARD15 (R702W, leu1007fsinsC, and G908R), which were detected by polymerase chain reaction by use of allele-specific primers and visualized through gel electrophoresis. In total, 53/187 (28.3%) probands with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (odds ratio 2.97; 95% confidence interval 1.61–5.47; P=.0005). Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to PsA independent of HLA-Cw*0602. Thus, CARD15 represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with PsA. Psoriasis (MIM 177900) is a chronic inflammatory hyperproliferative skin disorder that affects 1%–3% of the population (Goodfield Goodfield, 1994Goodfield M Skin lesions in psoriasis.Baillieres Clin Rheumatol. 1994; 8: 295-316Abstract Full Text PDF PubMed Scopus (15) Google Scholar). Psoriatic arthritis (PsA) has been defined as an inflammatory arthritis associated with psoriasis that occurs in up to one-third of the patients with psoriasis (Wright and Moll Wright and Moll, 1976Wright V Moll JMH Psoriatic arthritis.in: Wright V Moll JMH Seronegative polyarthritis. North Holland Publishing, Amsterdam1976: 169-223Google Scholar; Gladman et al. Gladman et al., 1987Gladman DD Schuckett R Russell ML Thorne JC Schacter RK Psoriatic arthritis: clinical and laboratory analysis of 220 patients.QJM. 1987; 62: 127-141PubMed Google Scholar). The etiology of PsA remains unknown but likely results from an interplay between genetic, immunological, and environmental factors (Gladman Gladman, 2002Gladman DD Current concepts in psoriatic arthritis.Curr Opin Rheumatol. 2002; 14: 361-366Crossref PubMed Scopus (49) Google Scholar). Multiple lines of evidence support a genetic basis of PsA. A large epidemiological study in the United Kingdom reported strong familial clustering of PsA with a relative risk of 55% for affected first-degree relatives (Moll and Wight Moll and Wright, 1973Moll JM Wright V Familial occurrence of psoriatic arthritis.Ann Rheum Dis. 1973; 32: 181-201Crossref PubMed Scopus (250) Google Scholar). Association studies implicate the HLA loci of the major histocompatibility complex (MHC) in psoriasis and PsA (Gladman Gladman, 2002Gladman DD Current concepts in psoriatic arthritis.Curr Opin Rheumatol. 2002; 14: 361-366Crossref PubMed Scopus (49) Google Scholar). The strongest association is between psoriasis and HLA-Cw*0602, with lesser associations with HLA-B13, HLA-B17, and HLA-B57. In PsA, the association with HLA-Cw*0602 is less profound and is most evident in patients with PsA with an early onset of psoriasis (Enerback et al. Enerback et al., 1997Enerback C Martinsson T Inerot A Wahlstrom J Enlund F Yhr M Swanbeck G Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP).Acta Derm Venereol. 1997; 77: 273-276PubMed Google Scholar; Gladman et al. Gladman et al., 1999Gladman DD Cheung C Ng CM Wade JA HLA C-locus alleles in psoriatic arthritis.Hum Immunol. 1999; 60: 259-261Crossref PubMed Scopus (80) Google Scholar). Recent completion of the first-ever genomewide linkage scan in PsA, by use of 1,000 microsatellite markers in 178 patients with PsA from 39 Icelandic families, revealed a LOD score of 2.17 on chromosome 16q (Karason et al. Karason et al., 2003Karason A Gudjonsson JE Upmanyu R Antonsdottir AA Hauksson VB Runasdottir EH Jonsson HH Gudbjartsson DF Frigge ML Kong A Stefansson K Valdimarsson H Gulcher JR A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting.Am J Hum Genet. 2003; 72: 125-131Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Further analysis, conditional on paternal transmission to affected individuals, resulted in a LOD score of 4.19. The peak of this LOD score is within 20 Mb of the CARD15 gene (MIM 605956; GenBank accession number 64127). It is interesting that a region overlapping CARD15 has also been implicated by a genomewide scan in psoriasis, in which a LOD score of 2.5 was reported (Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (357) Google Scholar). The CARD15 gene has convincingly been shown to confer susceptibility to Crohn disease (MIM 266600) (Hugot et al. Hugot et al., 2001Hugot J-P Chamaillard M Zouali H Lesage S Cézard J-P Belaiche J Almer S Tysk C O'Morain C Gassull M Binder V Finkel Y Cortot A Modigliani R Laurent-Puig P Gower-Rousseau C Macry J Colombel J-F Sahbatou M Thomas G Association of NOD2 leucine rich repeat variants with susceptibility to Crohn's disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4486) Google Scholar; Ogura et al. Ogura et al., 2001Ogura Y Bonen DK Inohara N Nicolae DL Chen FF Ramos R Britton H Moran T Karaliuskas R Duerr RH Achkar JP Brant SR Bayless TM Kirschner BS Hanauer SB Nunez G Cho JH A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (3993) Google Scholar). The possibility of a common susceptibility gene between psoriasis/PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis and PsA in subjects with Crohn disease (Lee et al. Lee et al., 1990Lee FI Bellary SV Francis C Increased occurrence of psoriasis in patients with Crohn's disease and their relatives.Am J Gastroenterol. 1990; 85: 962-963PubMed Google Scholar; Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (357) Google Scholar). In this study, we set out to determine the prevalence of the three common independent sequence variants of CARD15 mutations, arg702 to trp (R702W), leu1007fsinsC, and gly908 to arg (G908R) in PsA. The study was approved by the local ethics committee, and informed consent was obtained from all patients. All subjects were identified from the province of Newfoundland and were examined by a single rheumatologist (P.R.). PsA was diagnosed as an inflammatory arthritis in patients with psoriasis, in the absence of other etiologies for inflammatory arthritis. Information collected included variables related to disease pattern, joint damage, extent of psoriasis, extra-articular features, medication history, and surgeries. The control subjects were not related and were all examined to ensure that they had no autoimmune disease. Genomic DNA was isolated from peripheral whole blood collected in EDTA by use of a salting-out technique (Promega Wizard Genomic DNA Purification Kit). For the CARD15 genotyping, 50 ng of DNA was used for each PCR reaction. All subjects were genotyped for the R702W (SNP8; exon 4), G908R (SNP12; exon 8), and Leu1007fsinsC (SNP13; exon 11) variants. Reaction products were visualized using agarose gel electrophoresis. All samples were scored as wild type/wild type, wild type/mutated, or mutated/mutated. The laboratory scientist was blind to the clinical diagnosis. The R702W (Hugot SNP8 [GenBank accession number G67950]) variant of the CARD15 gene was genotyped by use of the PCR-ARMS technique (Vermeire et al. Vermeire et al., 2002Vermeire S Wild G Kocher K Cousineau J Dufresne L Bitton A Langelier Pare P Lapointe G Cohen A Daly MJ Rioux JD CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure.Am J Hum Genet. 2002; 71: 74-83Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). Appropriate internal, water, and known controls were used for each R702W reaction (Lesage et al. Lesage et al., 2002Lesage S Zouali H Cézard J-P EPWG-IBD group Colombel JF EPIMAD group Belaiche J GETAID group Almer S Tysk C O'Morain C Gassull M Binder V Finkel Y Modigliani R Gower-Rousseau C Macry J Merlin F Chamaillard M Jannot A-S Thomas G Hugot J-P CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.Am J Hum Genet. 2002; 70: 845-857Abstract Full Text Full Text PDF PubMed Scopus (833) Google Scholar). The primers were wild-type forward (5′-ATCTGAGAAGGCCCTGCTCC-3′), mutated forward (5′-ATCTGAGAAGGCCCTGCTCT-3′), reverse (5′-CCCACACTTAGCCTTGATG-3′), constant forward (5′-GCAGACATTGATTTTACACAG-3′), and constant reverse (5′-TGAGGCAAAACAACTGAGAC-3′). These primers were synthesized by Integrated DNA Technologies. The PCR conditions are available from the authors on request. The missense mutation G908R (Hugot SNP12 [GenBank accession number G67951]) creates a restriction endonuclease site for HhaI. The double-stranded DNA fragment was amplified using primers 5′-CCCAGCTCCTCCCTCTTC-3′ and 5′-AAGTCTGTAATGTAAAGCCAC-3′. The presence of a variant allele produces two bands of 138 bp and 242 bp, and a wild-type allele results in one band of 380 bp following DNA amplification and digestion with HhaI. The Leu1007fsinsC (Hugot SNP13 [GenBank accession number G67955]) was genotyped using multiplex PCR. The primers were 5′-CTG AGC CTT TGT TGA TGA GC-3′ (forward), 5′-TCT TCA ACC ACA TCC CCA TT-3′ (reverse), 5′-CAG AAG CCC TCC TGC AGG CCC T-3′ (wild type), and 5′-CGC GTG TCA TTC CTT TCA TGG GGC-3′ (mutated). The wild-type allele produced a band of 319 bp, and the mutation produced a band of 214 bp. For HLA genotyping, 200 ng of genomic DNA was amplified using the Dynal RELI SSO HLA-Cw* typing kit. PCR amplicons were identified by a reverse line assay by use of sequence-specific oligonucleotide probes. Assay results were interpreted by use of the Pattern Matching Program provided by Dynal. Logistic regression was used to calculate odds ratio (OR) estimates and corresponding 95% CIs that relate CARD15 mutations and PsA, as well as to examine the joint risk associated with CARD15 mutations and HLA-Cw*0602. Fisher's exact test was used to test for the presence of linkage disequilibrium between all possible combinations of the CARD15 variants. Cox's semiparametric method (Cox Cox, 1972Cox DR Regression models and life tables.J R Statist Soc. 1972; 34: 187-220Google Scholar) was used to examine the association between age at onset of psoriasis and age at onset of PsA and the CARD15 and HLA-CW*0602 genotypes. For the genotype/phenotype correlations, Fisher's exact test was used to examine associations between CARD15 mutations and selected binary variables. Since the genotype/phenotype correlations were an exploratory analysis for future studies with larger samples of patients with PsA and the appropriate error structure for multiplicity adjustments in the rheumatological context is not well defined (Cook and Farewell Cook and Farewell, 1996Cook RJ Farewell VT Multiplicity considerations in the design and analysis of clinical trials.J R Statist Soc. 1996; 159: 93-110Crossref Scopus (161) Google Scholar), formal adjustments were not made for multiple testing. Thus, no definitive conclusions can be drawn regarding the genotype/phenotype correlations. In total, 187 unrelated white patients with PsA (100 males and 87 females) were assessed. For one patient, G908R information was missing. The mean age and disease duration of patients with PsA were 47.93 years (SD 10.83) and 10.94 years (SD 8.50), respectively, and the mean age for the 136 white controls (56 males and 80 females) was 44.87 years (SD 14.01). All subjects were "native Newfoundlanders" who were whites of Northern European ancestry. Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the 136 control patients (table 1). There was no evidence against the assumption of Hardy-Weinberg equilibrium in the controls for all CARD15 variants.Table 1Genotypes of CARD15 Variants in Patients with PsA and Healthy ControlsAllele Frequency ofR702W inleu1007FsinsC inG908R inGenotypeSubjects with PsAControlsSubjects with PsAControlsSubjects with PsAControlsMutated/mutated400000Mutated/wild type31912761Wild type/wild type152127175129180134 Total187136187136186135 Open table in a new tab Tables 2 and 3 provide results of univariate logistic regressions of case/control status for models, including variables defined by any CARD15 mutation and the separate CARD15 mutations. Only four patients were homozygous for any CARD15 mutation (all R702W), and none of the controls were homozygous for any CARD15 mutation (table 1). A formal dominance test provided no evidence of differential risk for heterozygotes and homozygotes. Therefore, all analyses combine individuals homozygous and heterozygous for allele R702W. The OR for the R702W variant was 3.50 (95% CI 1.51–7.01), P=.0027; for the leu1007fsinsC variant, the OR was 1.26 (95% CI 0.48–3.30), P=.63; and for the G908R variant, the OR was 4.47 (95% CI 0.53–7.52), P=.17 (table 2). There was no evidence of any linkage disequilibrium among the three analyzed polymorphisms. Only a single control individual had two CARD15 mutations (leu1007fsinsC and R702W). There was no evidence, however, that this was inconsistent with independence assumptions in cases or controls for any pair of mutations (minimum P value .13). In total, 53/187 (28.3%) patients with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (OR 2.97; 95% CI 1.61–5.47; P=.0005). The prevalence of the CARD15 mutation was similar in familial PsA (14/54; 25.9%), defined as at least one other affected first-degree relative, as compared with sporadic PsA (39/133; 29.3%).Table 2Logistic Regression for Univariate CARD15 VariantsSequence VariantOR95% CIPR702W3.501.51–7.01.002710071.26.48–3.30.63G908R4.47.53–7.52.17CARD152.971.61–5.47.0005 Open table in a new tab Table 3Logistic Regression for Multivariate CARD15 VariantsSequence VariantOR95% CIPR702W3.91 (3.70)1.45–10.54 (1.82–7.54).0071 (.0003)10071.50 (3.79).50–4.47 (1.87–7.68).47 (.0002)G908R3.68 (3.68).43–31.56 (1.82–7.46).23 (.0003)CARD153.57 (4.00)1.69–7.54 (1.96–8.17).0009 (.0001)Note.—All values are in comparison with HLAc6. Open table in a new tab Note.— All values are in comparison with HLAc6. In total, 176 subjects with PsA were genotyped for HLA-Cw*0602. Of the 176 subjects with PsA, 60 (34.1%) had at least one HLA-Cw*0602 allele, as compared with 11/90 (12.2%) of the controls for whom HLA information was available (OR 3.72; 95% CI 1.84–7.51; P<.001). Table 4 shows the relationship between the presence of HLA-Cw*0602 and the three CARD15 mutations in patients with PsA. As can be seen from the table, there was no correlation noted between these variables. The ORs associated with the CARD15 variants in the multivariate models that include the HLA-Cw*0602 variable differ little from those in the univariate models. In addition, there was no evidence of interaction effects on disease incidence between the CARD15 variables and the HLA-Cw*0602 indicator. In particular, the 15 individuals with both an HLA-Cw*0602 allele and CARD15 gene were all patients with PsA, but there was no evidence that this was inconsistent with a multiplicative effect of the two factors (P=.15).Table 4Relationship between HLA-Cw*0602 and CARD15 VariantsNo. of Affected Subjects with VariantR702WaP=.841007bP=.22G908RcP=.66HLACw*0602 StatusAbsentPresentAbsentPresentAbsentPresentAbsent9521106101115Present4812582581a P=.84b P=.22c P=.66 Open table in a new tab One of the most consistent associations reported to date on psoriasis and PsA is the early age at onset of psoriasis in subjects carrying HLA-Cw*0602 (Enerback et al. Enerback et al., 1997Enerback C Martinsson T Inerot A Wahlstrom J Enlund F Yhr M Swanbeck G Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP).Acta Derm Venereol. 1997; 77: 273-276PubMed Google Scholar; Gladman et al. Gladman et al., 1999Gladman DD Cheung C Ng CM Wade JA HLA C-locus alleles in psoriatic arthritis.Hum Immunol. 1999; 60: 259-261Crossref PubMed Scopus (80) Google Scholar). On the basis of a Cox regression model for onset times and explanatory variables coding for HLA-Cw*0602 and the CARD15 genes, we noted a strong relationship between an earlier age at the onset of psoriasis and the presence of HLA-Cw*0602 (P<.001). There is some evidence that G908R is associated with a later age at onset of psoriasis (P=.045), with slightly less evidence in the presence of HLA-Cw*0602 (P=.061). No other relationship was noted between the CARD15 mutations and onset of psoriasis or PsA. With respect to genotype/phenotype correlations, those carrying the R702W mutation had greater tendency for corticosteroid use (9/35 vs. 17/152 [P=.03]) and joint surgeries related to PsA (5/34 vs. 7/151 [P=.05]). No associations were noted between CARD15 mutations and disease pattern, damaged joints, extent of psoriasis, extra-articular features, and/or use of disease-modifying agents. Of note, Crohn disease was identified in 2/187 (1.1%) probands with PsA, of whom 1 carried a CARD15 mutation (R702W heterozygote). To our knowledge, this is the first study to examine the prevalence of CARD15 mutations in PsA. It is interesting that a recent Italian study failed to demonstrate a strong association between the same three CARD15 variants and uncomplicated psoriasis (Borgiani et al. Borgiani et al., 2002Borgiani P Vallo L D'Apice MR Giardina E Pucci S Capon F Nistic S Chimenti S Pallone F Novelli G Exclusion of CARD15/NOD2 as a candidate susceptibility gene to psoriasis in the Italian population.Eur J Dermatol. 2002; 12: 540-542PubMed Google Scholar). Lack of association between NOD2 3020InsC frameshift mutation and psoriasis has also been reported by Nair et al. (Nair et al., 2001Nair RP Stuart P Ogura Y Inohara N Chia NVC Young L Henseler T Jenisch S Christophers E Voorhees JJ Nunez G Elder JT Lack of association between NOD2 3020 InsC frameshift mutation and psoriasis.J Invest Dermatol. 2001; 117: 1671-1672Crossref PubMed Scopus (50) Google Scholar). It is conceivable that the CARD15 mutation is more specific to PsA than uncomplicated psoriasis. Alternatively, an enhanced signal-to-noise ratio, like that in Newfoundland, may be necessary to establish this association. Newfoundland is a well-recognized genetic isolate, the homogeneity of which resembles that of religious isolates such as the Hutterites and the Amish (Bear et al. Bear et al., 1988Bear JC Nemec TF Kennedy JC Marshall WH Power AA Kolonel VM Burke GB Inbreeding in outport Newfoundland.Am J Med Genet. 1988; 29: 649-660Crossref PubMed Scopus (30) Google Scholar). Thus, the genetic homogeneity of the Newfoundland population, coupled with the relative environmental/cultural homogeneity, may offer the opportunity to detect modest signals. Given the uniqueness of said population, confirmation of our finding in another population or ethnic group is prudent prior to generalizing that CARD15 confers susceptibility to PsA. The CARD15 gene may shed further light on the pathogenesis of PsA, as the CARD15 mutations have been implicated in altering recognition of the bacterial lipopolysaccharide (LPS) (Ogura et al. Ogura et al., 2001Ogura Y Bonen DK Inohara N Nicolae DL Chen FF Ramos R Britton H Moran T Karaliuskas R Duerr RH Achkar JP Brant SR Bayless TM Kirschner BS Hanauer SB Nunez G Cho JH A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (3993) Google Scholar). This hypothesis has been supported by functional experiments, as 1007fs mutations decreased the NF-κB activation by the LPS (Hugot and Cho Hugot and Cho, 2002Hugot J-P Cho JH Update on genetics of inflammatory bowel disease.Curr Opin Gastroenterol. 2002; 18: 410-415Crossref PubMed Scopus (9) Google Scholar). This is intriguing, in that a temporal relationship has long been noted between bacterial infections (such as Streptococcus) and the development and exacerbation of psoriasis and PsA (Vasey Vasey, 1985Vasey FB Etiology and pathogenesis of psoriatic arthritis.in: Gerber LH Espinoza LR Psoriatic arthritis. Grune & Stratton, Orlando, FL1985: 45-57Google Scholar). In summary, CARD15 is the first candidate gene identified in PsA that resides outside the MHC. The risk for CARD15 to be associated in our population with PsA (OR 2.97) is comparable with that seen for HLA-Cw*0602 (OR 3.72), the allele most consistently recognized to be associated with psoriasis and PsA. CARD15 confers its disease risk independent of HLA-Cw*0602, as no relationship between CARD15 mutations and HLA-Cw*0602 was noted. Finally, our study suggests that CARD15 is a pleiotropic autoimmune gene, since it confers susceptibility to Crohn disease (Hugot et al. Hugot et al., 2001Hugot J-P Chamaillard M Zouali H Lesage S Cézard J-P Belaiche J Almer S Tysk C O'Morain C Gassull M Binder V Finkel Y Cortot A Modigliani R Laurent-Puig P Gower-Rousseau C Macry J Colombel J-F Sahbatou M Thomas G Association of NOD2 leucine rich repeat variants with susceptibility to Crohn's disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4486) Google Scholar; Ogura et al. Ogura et al., 2001Ogura Y Bonen DK Inohara N Nicolae DL Chen FF Ramos R Britton H Moran T Karaliuskas R Duerr RH Achkar JP Brant SR Bayless TM Kirschner BS Hanauer SB Nunez G Cho JH A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (3993) Google Scholar), Blau syndrome (Miceli-Richard et al. Miceli-Richard et al., 2001Miceli-Richard C Lesage S Rybojad M Prieur AM Manouvrier-Hanu S Hafner R Chamaillard M Zouali H Thomas G Hugot J-P CARD15 mutations in Blau syndrome.Nat Genet. 2001; 29: 19-20Crossref PubMed Scopus (751) Google Scholar), and, now, PsA. One of the central genetic factors in autoimmune diseases is the MHC; however, it is unlikely that this locus solely accounts for the similar genetic predisposition. CARD15 may represent a non-MHC genetic locus that results in susceptibility to multiple autoimmune diseases. We thank the countless number of volunteers from Newfoundland who participated in this study, the staff at St. Clare's Mercy Hospital, and Newfound Genomics. Grant support was received from Canadian Institute of Health Research (CIHR) and The Arthritis Society of Canada (TAS). P.R. is a CIHR new investigator and TAS scholar.