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Background  Rheumatoid 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 Findings  The 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 χ 2  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/Significance  The 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.

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