Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study

Abstract

ObjectivesHLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic inflammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM.MethodsIIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation.Results557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure.ConclusionSmoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.

Distinct profiles of myositis-specific autoantibodies in Chinese and Japanese patients with polymyositis/dermatomyositis

“…In addition to genetic factors, some environmental factors may also affect MSA expression. Chinoy et al demonstrated an interaction between DRB1*03 and smoking in the development of anti-Jo-1 antibodies [17]. A study in central Japan showed that from 1994 to 2010, the relative prevalence of CADM and anti-MDA-5-antibody-positive patients increased significantly, and the presence of anti-MDA-5 antibodies was inversely associated with the population of the patients' city of residence [18].…”

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

“…While the IIM, like other autoimmune diseases, are thought to develop as a consequence of chronic inflammation resulting from environmental exposures in genetically susceptible individuals, few examples of such gene-environment interactions have been reported 30,31 , and none have explained the strong association between AH8.1 and the different myositis phenotypes. The facts that HLA genes: (a) are important in responses to many infectious and noninfectious environmental exposures 32 ; and (b) determine one’s capacity to produce antibodies including many autoantibodies 33 , could explain why specific combinations of HLA alleles are important to the pathogenesis of myositis.…”

Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case–control study

“…Evidence has accumulated that smoking is a triggering factor for the development of anticitrullinated peptide antibodies in RA 13. In IIM, anti-Jo-1 antibody positive cases are more likely to be smokers, which suggests that smoking and the lung play important roles in IIM development as well 14. A recent case–control study showed that a history of lung disease (sarcoidosis, pneumonia or tuberculosis) reported via questionnaire was associated with IIM, providing further evidence that IIM could start in the lung 15…”