Increased frequency of DRB1*11:01 in anti–hydroxymethylglutaryl‐coenzyme A reductase–associated autoimmune myopathy

Objective

To investigate the association of anti–hydroxymethylglutaryl‐coenzyme A reductase (anti‐HMGCR) myopathy with HLA class I and II antigens.

Methods

HLA antigens were determined in 1) 20 white and 8 African American anti‐HMGCR patients, 2) 487 white and 167 African American controls, and 3) 51 white subjects with mild self‐limited statin intolerance.

Results

White anti‐HMGCR patients had a higher frequency of the combination HLA–DR11, DQA5, and DQB7 than controls or statin‐intolerant subjects (70% versus 17%; odds ratio [OR] 11.7 [95% confidence interval (95% CI) 4.0–35.3], P = 4.1 × 10^?7 and 70% versus 21%; OR 8.3 [95% CI 2.2–33.9], P = 5.4 × 10^?4, respectively). This combination was not increased in African American anti‐HMGCR subjects compared to controls (13% versus 3%; OR 4.6 [95% CI 0.2–53.3], P = 0.2). However, DR11 was increased in African American anti‐HMGCR patients compared to controls (88% versus 21%; OR 26.4 [95% CI 3.1–590.3], P = 0.0002). High‐resolution mapping showed that 95% with DR11 had DRB1*11:01. DQA1 and DQB6 were less frequent in white anti‐HMGCR–positive patients compared to controls (25% versus 65%; OR 0.2 [95% CI 0.1–0.5], P = 5.5 × 10^?4 and 0% versus 45%; OR 0.0 [95% CI 0.0–0.3], P = 2.1 × 10^?5, respectively). DRB11 was not associated with particular disease features.

Conclusion

DRB1*11:01 is associated with an increased risk of anti‐HMGCR myopathy in whites and African Americans. These findings suggest a mechanistic link between statin exposure, increased HMGCR expression, and the possible presentation of HMGCR‐derived peptide(s) by DRB1*11:01.

     

Evidence for linkage of HLA loci in juvenile idiopathic oligoarthritis: Independent effects of HLA–A and HLA–DRB1

Objective

Although multiple associations between HLA loci and juvenile oligoarthritis have previously been documented, evidence for linkage of HLA loci in oligoarthritis in UK Caucasians with juvenile idiopathic arthritis (JIA) has not been described. The aim of this study was to investigate linkage of HLA–A, B, and DRB1 in UK Caucasian JIA patients with oligoarthritis.

Methods

One hundred forty‐two families comprising affected offspring and their parents (45 with one parent available and 97 with both parents available) were typed for HLA–A, B, and DRB1 by polymerase chain reaction–sequence‐specific oligonucleotide probe. Single‐point and multipoint analyses were performed using various modifications of the extended transmission disequilibrium test. Linkage disequilibrium (LD) analysis was performed using the EH‐Plus system.

Results

Linkage to HLA–A and HLA–DRB1 was seen in oligoarthritis and in the International League of Associations for Rheumatology–defined subgroups of persistent oligoarthritis and extended oligoarthritis. Linkage to HLA–A, B, and DRB1 was also observed in female patients with oligoarthritis. Linkage of the HLA loci seemed to be attributable to maternal preferential transmission of alleles. Furthermore, LD patterns between the HLA–A, B, and DRB1 loci were investigated. HLA–A and HLA–DRB1 were confirmed as independent susceptibility loci for oligoarthritis.

Conclusion

This is the first study to establish linkage of HLA–A and HLA–DRB1 in oligoarthritis and to show that the 2 loci contribute independently to disease. Further studies are being performed to determine whether it is these loci or other genes in LD with them that are responsible for susceptibility to oligoarthritis in UK Caucasian patients with JIA.

     

Influence of shared epitope–negative HLA–DRB1 alleles on genetic susceptibility to rheumatoid arthritis

Objective

Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE‐negative HLA–DRB1 alleles influence the development of RA. This study examined the influence of SE‐negative HLA–DR alleles (DRB1*X) on the development of RA in 3 different French populations.

Methods

HLA–DRB1 alleles were defined by polymerase chain reaction with sequence‐specific oligonucleotide hybridization or sequence‐specific primers. SE‐negative alleles were classified according to the electric charge of their P4 pocket. HLA–DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA–DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p.

Results

Among the SE‐negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single‐dose SE–positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients.

Conclusion

The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.

     

Interferon-β1A–induced polyarthritis in a patient with the HLA–DRB1*0404 allele

Human interferon-α (IFNα) and IFNβ are administered for treatment of several diseases, including viral infections, malignancies, and multiple sclerosis (MS). IFNα therapy has been associated with the production of autoantibodies and the development of a variety of autoimmune disorders, including polyarthritis. This report describes the development of seronegative, symmetric polyarthritis in a patient with relapsing-remitting MS, after 8 weeks of therapy with IFNβ1a. HLA phenotyping analysis of the patient revealed the presence of HLA–DRB1*0404, an allele known to be associated with the development of rheumatoid arthritis. Therefore, IFNβ1a may have induced arthritis in a patient who was genetically predisposed to develop arthritis on the basis of HLA determinants. The English-language literature regarding IFNα- and IFNβ-induced polyarthritis is reviewed, and possible mechanisms for IFNα- and IFNβ-induced autoimmunity, including the contribution of HLA determinants and nitric oxide overproduction, are discussed.     

Ethnic variation in the clinical manifestations of rheumatoid arthritis: Role of HLA–DRB1 alleles

Objective

To assess the extent of ethnic variation in the clinical expression of rheumatoid arthritis (RA) and the role of HLA–DRB1 alleles in this variation.

Methods

We assessed consecutive RA patients for joint findings, subcutaneous nodules, laboratory and radiographic findings, and treatment. We typed HLA–DRB1 alleles to identify those that contain the shared epitope (SE). We adjusted ethnic comparisons for age and sex, and tested for ethnic heterogeneity in the effect of the SE.

Results

We studied 777 RA patients, 498 of whom were women (64%), 432 were Hispanic (56%), 272 were non‐Hispanic white (NHW; 35%), 53 were African American (AA; 7%), and 20 were Asian (3%). Compared with NHW, Hispanics had significantly more tender joints (17 versus 11), more swollen joints (8 versus 7), more frequent rheumatoid factor (RF) positivity (93% versus 84%), higher erythrocyte sedimentation rate (ESR; 45 versus 36 mm/hr), and a lower number of lifetime disease‐modifying antirheumatic drugs (1.9 versus 2.5). AA were older at onset (46 versus 44 years), had less frequent subcutaneous nodules (18% versus 28%), and higher ESR (42 versus 36 mm/hour) than did NHW. Hispanics and AA were more likely than NHW to be null for the SE (odds ratio [OR] = 4.59 for AA; and OR = 1.61 for Hispanics), and less likely to have 2 SE‐carrying alleles (OR = 0.59 for Hispanics and OR = 0.25 for AA). The number of SE copies was associated with subcutaneous nodules, ESR, RF, and radiographic changes. Ethnic heterogeneity in the effect of the SE was modest.

Conclusions

There is ethnic variation in the clinical expression of RA and in both the frequency and types of SE‐carrying HLA–DRB1 alleles. Some ethnic variation in clinical findings is associated with differences in SE frequency. However, we found that the effect of the SE on the clinical features of RA varies little between ethnic groups.

     

Chronic periaortitis and HLA–DRB1*03: Another clue to an autoimmune origin

Objective

Patients with chronic periaortitis (CP) often show clinical and laboratory findings of a systemic autoimmune disorder. The aim of the present study was to investigate the role of the HLA system in CP.

Methods

Low‐resolution genotyping for HLA–A, HLA–B, and HLA–DRB1 loci and genotyping of TNFA(‐238)A/G and TNFA(‐308)A/G single nucleotide polymorphisms were performed in 35 consecutive patients with CP and 350 healthy controls.

Results

The HLA–DRB1*03 allele frequency was strikingly higher in patients with CP than in controls (24.28% versus 9.14%; χ² = 15.50, P = 0.000084, corrected P [P_corr] = 0.0012, odds ratio [OR] 3.187, 95% confidence interval [95% CI] 1.74–5.83); the HLA–B*08 allele frequency was also higher in patients than in controls (17.14% versus 6.28%; χ²=11.12, P = 0.0008, P_corr = 0.0269, OR 3.085, 95% CI 1.54–6.16). The A*01 allele frequency was significantly different (P = 0.0463), but the statistical significance was lost after correction for multiple testing (P_corr = 0.5088). TNFA(‐238)A allele and TNFA(‐308)A allele frequencies were not significantly different (P = 0.512 and P = 0.445, respectively). Comparison of the main clinical and laboratory findings suggestive of a systemic autoimmune disease (e.g., acute‐phase reactants, constitutional symptoms, other autoimmune diseases associated with CP) between the HLA–DRB1*03–positive and the HLA–DRB1*03–negative patients showed that the former group had significantly higher levels of C‐reactive protein (P = 0.045) at disease onset, although this difference was not statistically significant after correction for multiple tests (P_corr = 0.369).

Conclusion

The HLA system plays a role in susceptibility to CP. The strong association between CP and HLA–DRB1*03, an allele linked to a wide range of autoimmune conditions, further supports the view that CP may represent a clinical manifestation of an autoimmune disease.

     

Brief Report: Association of HLA–DRB1*0101/*0405 with susceptibility to anti–melanoma differentiation–associated gene 5 antibody–positive dermatomyositis in the Japanese population

Objective

The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti–aminoacyl–transfer RNA synthetase (anti‐aaRS) antibody or anti–melanoma differentiation–associated gene 5 (anti–MDA‐5) antibody positivity. Anti–MDA‐5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti–MDA‐5 antibody–positive DM is unclear. This study was undertaken to investigate the HLA–DRB1 genotype in patients with anti–MDA‐5 antibody–positive DM.

Methods

We examined genetic differences among 17 patients with anti–MDA‐5 antibody–positive DM, 33 patients with anti‐aaRS antibody–positive PM/DM, 33 patients with PM/DM without anti‐aaRS antibody or ILD, and 265 healthy controls.

Results

The frequencies of HLA–DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti–MDA‐5 antibody–positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti–MDA‐5 antibody–positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti–MDA‐5 antibody–positive DM than in patients with PM/DM without anti‐aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9–370.2) (P = 1.1 × 10⁻⁵), or in patients with anti‐aaRS antibody–positive PM/DM (OR 13.3 [95% CI 1.6–112.6], P = 4.5 × 10⁻³).

Conclusion

Our findings indicate that HLA–DRB1*0101/*0405 is associated with susceptibility to anti–MDA‐5 antibody–positive DM in the Japanese population.

     

Particular HLA–DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis

Objective

To examine the relationship of the HLA–DRB1 shared epitope (SE) to rheumatoid vasculitis, using individual patient data (IPD) meta‐analytic methods.

Methods

Published studies that enrolled adult patients with rheumatoid arthritis (RA) were identified by searches of Medline and Embase, and by manual searches of medical journals. All authors were contacted for IPD. Meta‐analyses were performed to assess the association of SE presence, dose, and genotype with rheumatoid vasculitis.

Results

A total of 14 studies and 1,568 patients (129 with vasculitis) were included in the analysis. RA patients with vasculitis were significantly more likely to have rheumatoid nodules (odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.5–3.9], but there was no significant association with male sex, rheumatoid factor positivity, or erosive disease. No significant association was observed between the presence of the SE (i.e., 1 or 2 alleles versus 0 alleles) and rheumatoid vasculitis (summary OR 1.4, 95% CI 0.7–2.7). Analysis by SE genotype, however, demonstrated a striking relationship of vasculitis to 3 genotypes containing a double dose of the SE, specifically HLA–DRB1*0401/*0401 (OR 6.2, 95% CI 1.01–37.9), *0401/*0404 (OR 4.1, 95% CI 1.1–16.2), and *0101/*0401 (OR 4.0, 95% CI 1.4–11.6).

Conclusion

The HLA–DRB1 SE genotypes *0401/*0401, *0401/*0404, and *0101/*0401 may be of particular importance to rheumatoid vasculitis. It is hoped that additional investigation of these and other SE genotypes will lead to improved insight into the mechanisms influencing the clinical expression of RA.

     

Gene–environment interaction between the DRB1 shared epitope and smoking in the risk of anti–citrullinated protein antibody–positive rheumatoid arthritis: All alleles are important

Objective

An interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA–DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anti–citrullinated protein antibodies (ACPAs).

Methods

We used data regarding smoking habits and HLA–DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs.

Results

A strong interaction between smoking and SE alleles in the development of ACPA‐positive RA was observed for all DRB1*04 SE alleles taken as a group (relative risk [RR] 8.7 [95% CI 5.7–13.1]) and for the *0401 and *0404 alleles (RR 8.9 [95% CI 5.8–13.5]) and the *01 and *10 alleles (RR 4.9 [95% CI 3.0–7.8]) as specific, separate groups, with similar strength of interaction for the different groups (attributable proportion due to interaction 0.4 [95% CI 0.2–0.6], 0.5 [95% CI 0.3–0.7], and 0.6 [95% CI 0.4–0.8], respectively).

Conclusion

There is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA‐positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA‐positive RA.

     

Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Objective

The effect of non–shared epitope HLA–DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA–DRB1 alleles, independent of the shared epitope, on the risk of developing anti–citrullinated protein antibody (ACPA)–positive or ACPA‐negative RA in a large case–control study.

Methods

HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results

DRB1*13 was found to protect against ACPA‐positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26–0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA‐positive RA (RR 3.91 [95% CI 3.04–5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81–1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA‐negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91–1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA‐negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6–2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA‐negative RA (RR 2.07 [95% CI 1.17–3.67]).

Conclusion

Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA‐positive RA but, in combination with DRB1*03, increasing the risk of ACPA‐negative RA.