Endothelial dysfunction in rheumatoid arthritis: influence of HLA-DRB1 alleles

Cardiovascular disease is the commonest cause of premature mortality in rheumatoid arthritis (RA) patients. Vascular endothelial injury is the primary event in atherosclerosis. It has been associated with endothelial dysfunction. We have recently observed that actively treated RA patients had endothelial dysfunction. HLA-DRB1 shared epitope alleles, in particular HLA-DRB1*0404, seem to be implicated in the development of endothelial dysfunction. These results underline the influence of genetic factors in the risk of atherosclerosis in RA patients.     

HLA-DRB1 alleles and HLA-DRB1 shared epitopes are markers for juvenile rheumatoid arthritis subgroups in Colombian mestizos

We studied the association of human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 alleles and HLA haplotypes with juvenile rheumatoid arthritis (JRA) in 65 patients and 65 controls from Colombia. The JRA subsets were distinguished on the basis of criteria established by the American College of Rheumatology. Two alleles were associated with protection, HLA-DRB1*1501 (p = 0.002) and HLA-DRB1*1402 (p = 0.01). HLA-DRB1*1602 (p = 0.0000002) was associated with susceptibility for systemic JRA and HLA-DRB1*1104 (p = 0.0002) for pauciarticular JRA. Amino acid sequences at residues 70-74 of DRB1 chain shared by HLA-DRB1 alleles (shared epitomes) were also informative. The polyarticular JRA subset revealed association with (70)QRRAA(74), which includes HLA-DRB1*04, 01, and (70)DRRAA(74), which includes DRB1*1601, 1602, 1101, and 1104. Two new findings of interest were the association of the haplotypes DRB1*1104, DQB1*0301(p = 0.0002) with pauciarticular JRA and DRB1*1602, DQB1*0301 (p = 0.0000002) association with systemic JRA. The DRB1 alleles of these two haplotypes share the epitope (70)DRRAA(74)and were associated with both the pauciarticular and the systemic subset of JRA. Our results suggest that studies of disease susceptibility in populations of admixed genetic background should take into account the contribution of different ethnic groups or nationalities in the recruitment of controls and patients studied in order to rule out genetic stratification.     

HLA-DRB1*04 alleles in psoriatic arthritis: comparison with rheumatoid arthritis and healthy controls.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor. An increased frequency of HLA-DR4 has been noted in PsA, particularly among patients with a rheumatoid arthritis like (RA) arthritis. The aim of the current investigation was to compare HLA-DRB1*04 alleles in patients with PsA, patients with RA, and healthy controls. Sample size calculations based on the frequency of HLA-DR4 suggested that 90 individuals in each patient group would be sufficient to address our question. Therefore, 90 HLA-DRB1*04 positive patients from each patient group underwent high resolution molecular typing and were included in this study. Although HLA-DRB1*0401 was the most frequent allele in all groups, its frequency among the PsA patients was lower than that of RA patients and controls. HLA-DRB1*0402 was higher among patients with PsA. Patients with RA were more likely to have more than one shared epitope allele than either PsA or the healthy control group. HLA-DQB1 alleles did not contribute further information. We suggest that the differences in the class II HLA epitope(s) may also be related to interaction specificity with another molecule functioning in the immune response to a putative arthritogenic antigen and result in differences in disease expression.     

HLA-DRB1*01 and DRB1*04 alleles in Sardinian rheumatoid arthritis patients

In Sardinia, like in other Caucasoid populations, rheumatoid arthritis (RA) is significantly associated with HLA-DR4 and DR1 antigens. To discover which DR4 and DR1 alleles were associated with the disease we selected 22 Sardinian patients affected by RA. Fifty DR4+ and 28 DR1+ healthy individuals coming from the same geographical area were used as controls. In the Sardinian patients only two DRB1*04 alleles were observed: DRB1*0405 in 11 and DRB1*0403 in three patients. The DRB1*0102 allele was observed in two patients and DRB1*0101 in six patients. Hereditary predisposition to RA in Sardinia therefore seems to be almost exclusively associated with the DRB1*0405 and DRB1*0101 alleles which share the 67LLEQRRAA74-85VG86 epitope in the peptide binding groove.     

HLA-DRB1 alleles encoding the "shared epitope" are associated with susceptibility to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic acid at position 70 of the beta-chain are protective in Mexican Mestizos

The risk to develop rheumatoid arthritis (RA) has been associated with the presence of HLA-DRB1 alleles encoding the "shared epitope" (SE). Additionally, HLA-DRB1 alleles encoding an aspartic acid at position 70 (D70+ ) have been associated with protection against the development of RA. In this study we tested the association between either SE or D70+ and rheumatoid arthritis in Mexican Mestizos. We included 84 unrelated Mexican Mestizos patients with RA and 99 unrelated healthy controls. The HLA-typing was performed by PCR-SSO and PCR-SSP. We used the chi-squared test to detect differences in proportions of individuals carrying at least one SE or D70+ between patients and controls. We found that the proportion of individuals carrying at least one HLA-DRB1 allele encoding the SE was significantly increased in RA cases as compared to controls (p(c) = 0.0004, OR = 4.1, 95% CI = 2.2-7.7). The most frequently occurring allele was HLA-DRB1*0404 (0.161 vs 0.045). Moreover, we observed a significantly increased proportion of HLA-DRB1 SE+ cases with RF titers above the median (p = 0.005). Conversely, the proportion of individuals carrying at least one HLA-DRB1 allele encoding the D70+ was significantly decreased (p(c) = 0.004, OR = 0.4, 95% CI 0.2-0.7) among RA patients compared with controls. In conclusion, the SE is associated with RA in Mexican Mestizos as well as with the highest titers of RF.     

中国人类风湿关节炎与PAD14功能基因多态性及部分HLA-DRB1等位基因相关性研究

目的 分析类风湿关节炎(rheumatoid arthritis,RA)中4型肽精氨酸转亚胺基酶(peptidylarginine deiminase IV,PAD14)功能基因多态性,探讨PAD14基因多态性与RA易感性的关系,以及编码与RA易感性相关HLA共同表位(shared epitope,SE)的HLA-DRB1等位基因与PAD14基因多态性的相关性.方法 采用逆转录合成cDNA、DNA测序和T载体克隆方法 分析67例RA患者、81名正常人PAD14基因外显子4个单核苷酸多态性(single nucleotide polymorphisms,SNPs),包括PADH_89*A/G,PADl4 90*C/T,PAD1492*C/G,PAD14 104*C/T;采用PCR-序列特异性引物方法 分析HLA-DRB1.*-01、*04、* 10基因型.结果 RA患者PAD14 89、90、104位基因多态性分布与正常对照组比差异有统计学意义,携带PAD14少见等位基因者对RA的危险性较携带常见等位基因者显著增加;分析编码SE等位基因与PAD14 SNPs的相关性发现,SE+/PAD14_89G-携带者较SE-/PAD14_89G-携带者发生RA的危险性高4.7倍(OR=4.7,95%CI:1.6～13.4,P=0.003),携带SE+/PAD14 89G+者高5.6倍(OR=5.6,95%CI:2.0～15.7,P=0.003).在PAD14 90、92、104位均出现相似的情况.结论 PAD14功能基因多态性与中国人RA的易感性相关,编码SE的HLA-DRB1等位基因仍然是RA的重要遗传标记,而且HLA-DRB1等位基因与PAD14的少见等位基因间可能存在一定的协同作用.     

HLA-DRB1 motifs and heat shock proteins in rheumatoid arthritis

Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved amino acid motif expressed in the third hypervariable region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA helps the development of RA by an unknown mechanism. In the past ten years, we have extensively studied the unique properties of the QKRAA motif of HLA-DRB1*0401 and have found: (1) That it can constitute B and T cell epitopes on many infectious agents; (2) That it can shape the T cell repertoire; (3) That it is overrepresented in protein databases; (4) That it constitutes a binding motif for the highly conserved family of 70 kD heat shock proteins. This may cause abnormal trafficking of HLA-DRB1*0401 in B cells and/or abnormal T cell responses to bacterial and human 70 kD heat shock proteins in people who express HLA-DRB1*0401.     

HLA-DRB1 and anti-cyclic citrullinated peptide antibody production in rheumatoid arthritis

Anti-cyclic citrullinated peptide antibodies (anti-CCP) are a new diagnostic marker for rheumatoid arthritis (RA), which shows a specificity of 97% and a sensitivity of 81% in the second generation assay. About 61% of RA patients express HLA-DRB1*0401. In a cohort of patients with RA we investigated whether the expression of anti-CCP correlates with the carriage of certain genes on the HLA-DRB1 locus. Our data reveal a highly significant association between anti-CCP and HLA-DR4, and a weaker but still significant association with HLA-DR1. HLA-DRB1*0401 is not a prerequisite for anti-CCP production, but if HLA-DRB1*0401 was present, 90% of our RA patients were anti-CCP positive.     

HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic clues emerging from a meta-analysis

Juvenile Idiopathic Arthritis (JIA) is characterized with a variable pattern of articular involvement and systemic symptoms and, thus, it has been classified in several subtypes. Genetic predisposition to JIA is mainly due to HLA class II molecules (HLA-DRB1, HLA-DPB1), although HLA class I molecules and non-HLA genes have been implicated, too. Here, we carried out a meta-analysis including selected studies designed to assess HLA genetic background of JIA patients, compared to healthy controls; particularly, we focused our attention on HLA-DRB1. In summary, our meta-analysis showed four main findings regarding HLA-DRB1 locus as a genetic factor of JIA: i) HLA-DRB1*08 is a strong factor predisposing to JIA, both for oligo-articular and poly-articular forms (oJIA > pJIA); ii) HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetic predisposition of Rheumatoid Factor (RF) positive forms of JIA; iii) HLA-DRB1*11 was confirmed to be predisposing to oligo-articular JIA; iv) HLA-DRB1*04 was confirmed to have a role in systemic JIA. Importantly, RF positivity seems to select the JIA clinical subset with the strongest immunogenetic similarities with adult rheumatoid arthritis.     

Meta-analysis of HLA-DRB1 polymorphism in Latin American patients with rheumatoid arthritis

OBJECTIVES: To estimate the common effect size of HLA-DRB1 alleles on rheumatoid arthritis (RA) susceptibility across Latin America populations through a meta-analysis combining the results of published data. METHODS: Case-control studies on HLA-DRB1 association with RA in Latin America were searched up to October 2006. Genotype frequencies were extracted according to both shared epitope (SE) and HLA-DR4 positive or negative alleles. The effect summary odds ratio (OR) and 95% confidence intervals was obtained. Heterogeneity and publication bias were assessed. RESULTS: Eight studies containing 684 cases and 1015 controls were included. Under the random effects model, the common OR was 3.28 (1.93, 5.60) (p<0.0001) and 3.54 (2.47, 5.05) (p=4.22 x 10(-12)) for HLA-DR4 and SE, respectively. There was no evidence of publication bias according to Funnel plot and Egger's regression test (p=0,445 for DR4 and p=0,464 for SE meta-analysis). Significant heterogeneity was observed for HLA-DR4 (I2=81.06%, Q=36.96, p=0.000005) but not for the SE meta-analysis. CONCLUSIONS: HLA-DR4 and SE positive HLA-DRB1 alleles (mainly HLA-DRB10404) are associated with RA in Latin Americans. Heterogeneity is expected owing to the diverse degree of admixture between the examined populations. Our findings support the HLA as a major susceptibility locus for RA and validate the SE hypothesis in Latin America.     

DQCAR 113 and DQCAR 115 in combination with HLA-DRB1 alleles are significant markers of susceptibility to rheumatoid arthritis in the Korean population

We have investigated HLA region microsatellite polymorphisms in rheumatoid arthritis (RA) which are known to be associated with HLA class II alleles in the Korean population. Ninety patients with RA and 106 controls were employed for this study, in which TAP1CA, DQCAR, D6S273, HLA-DRB1, -DQA1 and -DQB1 allele typing were performed. DQCAR 113 (RR = 3.2, P<0.0002), DQCAR 115 (RR = 3.6, P<0.0001) and heterozygous DQCAR 113/115 (RR = 11.2, P<0.0001) frequencies were significantly increased in the RA group compared with the control group. The HLA-DRB1 genotypes of patients who had DQCAR 113/115 alleles were defined as DRB1*04 and/or DRB1*09. There was no significant difference between RA and controls in D6S273 and TAP1CA allele frequencies. We demonstrated that HLA-DRB1*0405 (RR = 6.6, P<10(-6)), DQA1*03 (RR = 5.2, P<10(-6)), DQB1*04 (RR = 3.5, P<0.002) alleles were useful markers of susceptibility to RA in Koreans. The frequency of HLA-DRB1*0405 was higher in DQCAR 113 allele-positive RA (68.1%) than in DQCAR 113 allele-negative (16.3%) and total RA (43.3%) groups, and the susceptibility risk of DQCAR 113 allele to RA was more increased in the DRB1*0405-positive group (RR = 5.5, P<0.04). On the other hand, DQCAR 115 allele was more significantly associated with susceptibility to RA in HLA-DRB1*0405-negative patients (RR = 5.1, P<0.0005), and the association between RA and HLA-DRB1*0405 was also significantly associated with DQCAR 115 allele-negative patients (RR = 13.2, P<0.00001) as compared with DQCAR 115 allele-negative control groups. HLA-DRB1*0405-DQA1*03-DQCAR113-DQB1*03 haplotype showed high relative risk value (RR= 17.7, P<0.0002). In conclusion, the DQCAR allele in combination with HLA class II, especially DR, is probably a useful risk marker for RA susceptibility in the Korean population.     

HLA-DRB1 in eight Finnish monozygotic twin pairs concordant for rheumatoid arthritis

This study presents the results of HLA-DRB1 typing of the eight monozygotic twin pairs with both members affected by rheumatoid arthritis (RA), sampled in the nationwide Finnish twin cohort. The shared epitope, associated with RA in case-control studies, was present in all eight twin pairs, being significantly more frequent than among RA patients in a recent Dutch case-control study. Furthermore, 4 out of 8 twin pairs were homozygous for the shared epitope, while in 73 Dutch healthy controls encoding the shared epitope only 13 (18%) were homozygous; this suggests a gene dose effect in RA susceptibility. Combining these results with data from other sources may help to clarify the contribution of HLA alleles in the genetic predisposition to RA.     

Contribution of LILRB1 polymorphism and HLA-DRB1-shared epitope to rheumatoid arthritis

Objectives

The LILRB1 gene has recently been associated with rheumatoid arthritis (RA) susceptibility in HLA-DRB1-shared epitope (SE) negative Japanese individuals. Since the contribution of the LILRB1 polymorphism to RA susceptibility may vary among ethnic populations, we examined this association in a group of Caucasian patients. The frequency of LILRB1 alleles was also determined in patients according to the presence of DRB1-SE.

Methods

Samples from 103 RA patients and 107 healthy controls were randomly collected. Polymorphism of the LILRB1 gene was analyzed by sequencing with primers that amplified intron 3 and exon 4.

Results

The frequencies of LILRB1 alleles in RA patients did not differ from those of controls. However, when patients and controls were grouped according to SE, the PE-01/01 genotype was less frequent in negative-SE patients than in controls. Whereas SE is associated with higher anti-CCP antibody levels, as expected, the production of anti-CCP antibodies was lower in negative-SE patients with PE-01/01 genotype. Moreover, radiographic damage in hand and feet of SE-negative PE-01/01 patients was less severe than in patients with other genotypes.

Conclusions

The participation of this LILRB1 polymorphism in the RA pathogenesis of this Caucasian cohort differed from that reported in a Japanese sample. Our findings suggest that the LILRB1-PE-01/01 genotype could exert a protective role in RA susceptibility and disease severity in the absence of SE.     

HLA DPB1 alleles and susceptibility to rheumatoid arthritis.

HLA-DPB1 genotypic and phenotypic frequencies were investigated in a series of 35 adult rheumatoid arthritis (RA) patients and 42 controls. No significant associations between DPB1 alleles and susceptibility to RA were demonstrated, although some non-significant differences in DPB1*0301 and 0401 allele frequencies between patients and controls were observed.     

Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.     

Meta-analysis of the association between HLA-DRB1 allele and rheumatoid arthritis susceptibility in Asian populations

The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the metaanalysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, p<0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, p<0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1* 0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR beta71 and beta74, not by beta71 alone.     

Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRAA alleles

In most ethnic groups genetic susceptibility to rheumatoid arthritis (RA) is associated with certain HLA-DRB1 alleles encoding a similar sequence motif called the 'shared epitope' (SE) spanning amino acid positions 70 to 74 in the third diversity region of the outermost domain of the HLA-DRB1 molecule. We examined the association of the SE and RA in 83 Colombian women with established RA and 90 healthy controls. The group HLA-DRB1*04 was associated with RA with respect to controls (47% vs 18%, respectively. OR: 4.1, 95%CI: 2.1-8.2, P < 0.001). HLA-DRB1 alleles carrying the SE QRRAA, but not those carrying QKRAA or RRRAA, were associated with disease (OR: 3.7, 95%CI: 1.73-7.83, P = 0.0009). This association was stronger among HLA-DRB1*04 carriers (OR: 23, 95%CI: 1.3-414, P = 0.002). In our population, the SE QRRAA expressed in DRB1*04 alleles appears critical in identifying women with increased susceptibility to RA.     

Identification of two new HLA-DRB1 alleles: HLA-DRB1*1350 and DRB1*140502

Two new HLA-DRB1 alleles have been found by using high-resolution sequence-based typing. The two sequences have been officially named DRB1*1350 (HWS10001327-AY048687) and DRB1*140502 (HWS10001790-AY129430). DRB1*1350 differs from DRB1*110101 by two amino acids at positions 37 (Y-->N) and 58 (A-->E). This allele may arise from gene conversion between DRB1*110101 and DRB1*130201 or DRB1*030101, which are commonly found in Taiwan populations. The other allele, DRB1*140502, obtained from a patient with rheumatoid arthritis, differs from DRB1*140501 at codon 58 (GCC-->GCT). However, it causes no change in amino acid sequence and would therefore not have direct clinical implications.