Association of the HLA–DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis

Abstract

ObjectiveTo examine the role of the variants of the PTPN22 and HLA–DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA).MethodsPatients were recruited from a primary care–based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA–DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti–cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex.ResultsDNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1–2.2]) and from CVD (HR 1.68 [95% CI 1.1–2.7]). This effect was most marked for individuals with the HLA–DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6–23.2]). No association of the PTPN22 gene with mortality was detected.ConclusionSE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis: Results from two Swedish population‐based rheumatoid arthritis cohorts

“…This interpretation receives some support from our observation, at least in the EIRA study, of higher, yet statistically nonsignificant, risks of IHD in the 5 years before the onset of RA symptoms. Recently, the SE has been suggested to be an independent risk factor for IHD in patients with manifest RA (10,11). In our study, there was no difference in the occurrence of IHD before the onset of RA symptoms between SE-positive and SE-negative individuals, which would indicate that the SE per se, although a marker of IHD risk after the onset of RA (10,11), does not constitute a risk factor for IHD independently of RA disease.…”

“…These observations point to the presence and importance of other risk factors for IHD in patients with RA but do not define what risk factors these are or whether the risk that cannot be attributed to traditional risk factors could be a consequence of RA. Thus, although a cause-andeffect association between the inflammatory burden imposed by RA and the occurrence of IHD has been suggested (7,8), findings such as shared genetic risk factors for RA and IHD (9) and an independent link between the HLA-DRB1 shared epitope (SE) and IHD risk in RA (10,11) suggest that the increased risk of IHD in RA might also reflect shared etiologies of RA and IHD. A correct attribution for the increased RA-related risk of IHD not only is etiologically important but also has important clinical implications.…”

“…In these cohorts, we set out to confirm an increased risk of IHD after a diagnosis of RA and to investigate the relative risk and phenotype of IHD up until the onset of RA symptoms. Because there have been indications of marked etiologic heterogeneity in different RA subsets (14), we moreover assessed the occurrence of IHD prior to the onset of RA symptoms in subsets of patients with RA defined by the presence or absence of rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPAs), and with consideration of the major genetic RA risk variant, the SE, for which an independent link with cardiovascular disease risk in RA has been reported (10,11).…”

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

“…20 Compound heterozygosity (*0401/*0404 heterozygosity) has been associated with a maximal genotypic risk for RA susceptibility and severity, [21][22][23][24][25] including vasculitis 26 and cardiovascular mortality. 27 It has also been proposed that certain HLA-DRB1 alleles protect against development of RA, compared with other HLA-DRB1 non-SE alleles. Proposed protective motifs include: the 70 DERAA 74 sequence, [28][29][30][31] aspartic acid at position 70 (D 70 ), 32,33 , isoleucine at position 67 (I 67 ) 34 or S 1 ( 71 ERAA 74 (S 1E ) with 71 ARAA 74 (S 1A )).…”

Association between two polymorphisms in the HLA-G gene and angiographic coronary artery disease

“…From this first report of association between the 14-bp polymorphism in exon 8 of the HLA-G gene and CAD, it cannot be excluded that the association may be a consequence of linkage disequilibrium with other gene loci in the human MHC region. It is well described that the extended HLA-haplotype, including the HLA-DRB1 * 01/ * 04 combination, is associated with cardiovascular disease and mortality (32). Of interest, an association between HLA-G polymorphisms and other chronic inflammatory disorders, such as inflammatory bowel disease (33,34), asthma (35,36) and multiple sclerosis (37)(38)(39), has been repeatedly reported.…”