Interaction between Smoking and HLA-DRB1*04 Gene Is Associated with a High Cardiovascular Risk in Brazilian Amazon Patients with Rheumatoid Arthritis

Abstract

BackgroundRheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints that affects approximately 1% of the population worldwide. The HLA-DRB1 gene locus plays a major role in genetic susceptibility to RA, a condition that has been associated with a high cardiovascular morbidity and mortality in many studies.Methodology/Principal FindingsThe aim of this work was to investigate which types of HLA class II genes are associated with RA in patients from the Brazilian Amazon and their influence on high cardiovascular risk status in this population. For this purpose, a case-control study was carried out with a total of 350 non-Indian individuals made up of a cohort of 132 consecutive RA sufferers and 218 healthy controls. A χ2 test showed that HLADRB1*04 (p<0.0016; OR = 1.89; 95% CI = 1.29–2.79) and HLADRB1*10 (p = 0.0377; OR = 3.81; 95% CI = 1.16–12.50) are the major HLA genes associated with susceptibility to RA. A logistic regression model also showed that the interaction between HLADRB1*04 (p = 0.027; OR = 6.02; 95% CI = 1.21–29.7), age (p = 0.0001; OR = 1.26; 95% CI = 1.13–1.39) and smoking (p = 0.0001; OR = 23.6; 95% CI = 4.25–32.1) is associated with a probability of a high cardiovascular risk status at an early age.Conclusions/SignificanceThe results of this study show for the first time that HLA class II type is associated with RA in Brazilian Amazon populations and that a specific interaction between the HLA-DRB1*04 gene and smoking is associated with a high cardiovascular risk status, as initially reported in the European population. This study therefore contributes to an understanding of gene-environment interactions in RA patients.

HLA class II alleles influence rheumatoid arthritis susceptibility and autoantibody status in South Indian Tamil population

“…This is in line with the previous observations in South Indian migrants to Malaysia and similar to that observed in other distinct population groups viz Spanish, Basque and Israelis . This contrasts with the HLA allele pattern observed in Caucasians, Japanese, Chinese and also in Asian Indians from the north and western regions of India where specific subtypes of HLA‐DRB1*04 emerged as the major RA susceptibility allele followed by HLA‐DRB1*10 . Although the susceptibility alleles of HLA‐DRB1*04 differed among these populations they all (along with DRB1*10 ) share a conserved 5‐aminoacid sequence called ‘shared epitopes’ (SE) in the antigen‐binding groove of HLA molecule.…”

“…The frequency of DRB1*04 and DRB1*10 alleles varies significantly across populations. In populations where the DRB1*04 alleles are prevalent, the DRB1*10 allele is underrepresented and vice versa, both in RA patients and controls (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Depending upon their population prevalence, one of these alleles is likely to be a major RA susceptibility allele.…”

Pooled analysis of the HLA‐DRB1 by smoking interaction in Parkinson disease

“…43 In MS patients, smoking influenced the proliferation of immune cells in the lung; the magnitude of the increase in alveolar macrophage concentration was associated with HLA-DRB1 alleles. 4 In RA sufferers, smoking and HLA-DRB1*04 interacted to influence their risk of cardiovascular disease; 44 the hypothesized mechanism was that both HLA-DRB1*04 and smoking enhanced T-cell activation in the lung, which may lead to inflammatory processes in the endothelial cells of the vessel walls and subsequent development of cardiovascular disease. Regarding lymphoma, a recent study showed a positive association with HLA-DRB1 shared epitope alleles (including HLA-DRB1*04 ) as well as a positive additive interaction between HLA-DRB1 shared epitope alleles and smoking, such that there was no association with smoking in subjects without shared epitope alleles and a significant positive association in those who carried two shared epitope alleles.…”

Alleles of HLA-DRB1*04 Associated with Pulmonary Tuberculosis in Amazon Brazilian Population

“…The HLA-DRB1*04 gene are associated with Rheumatoid arthritis (RA) [ 57 – 59 ]. However, the subtypes reported to be associated with RA are DRB1*0401 , DRB1*0404 , DRB1*0405 , DRB1*0408 , DRB1*0409 [ 60 ].…”