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

Abstract

Objective Inflammatory response plays an important role in Parkinson’s disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in three population-based case-control studies from Denmark and France. Methods We included 2,056 cases and 2,723 controls from three PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions. Results Both carrying rs660895-G (AG vs. AA: OR= 0.81; GG vs. AA: OR= 0.56; p-trend=0.003) and ever smoking (OR=0.56, p<0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter=1.37, p=0.005), and dominant (interaction parameter=1.54, p=0.001) genetic models without any heterogeneity (I2=0.0%): the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR=0.64, p<0.001) disappeared among ever smokers (OR=1.00, p=0.99). Similar interactions were observed when we investigated light and heavy smokers separately. Interpretation Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation.

Risky behaviors and Parkinson disease

“…2 Other epidemiologic studies suggested significant gene-by-smoking interaction effects in PD. 47,48 In our study, we observed a PD risk reduction of 31% for ever smokers vs never smokers. Although risk reduction effects demonstrated in an observational study and in an MR study may not be comparable, a consistency in the direction of protective associations by both the approaches is an important finding.…”

“…The identified associated phenotypes were then investigated for association with PD through a thorough literature search. Using this strategy, we identified rheumatoid arthritis, years of educational attainment, adiposity-related traits, age at menarche, and type 1 diabetes mellitus as potential confounders [45][46][47][48][49] (figure 2). We identified 8 genetic variants or loci from our genetic instrument for the tendency to smoke phenotype associated with different confounding traits.…”

Risky behaviors and Parkinson’s disease: A Mendelian randomization study in up to 1 million study participants

“…A meta-analysis merging smoking status trait from 33 different populations demonstrated a risk reduction by 36% for ever-vs never-smokers with consistent results in both case-control and cohort studies 2 . Other epidemiological studies suggested significant gene-by-smoking interaction effects in PD 46, 47 . In our study, we observed a PD risk reduction of 31% for ever smokers vs never smokers.…”

Effects of smoking on the association of human leukocyte antigen with ulcerative colitis

“…In rheumatoid arthritis, the risk of developing antibodies to citrullinated proteins has been associated with gene–environment interactions between HLA‐DRB1 shared epitope alleles and smoking . Other diseases showing associations between HLA and smoking include idiopathic inflammatory myopathies, Parkinson disease, multiple sclerosis, and lymphoma …”

“…30 In rheumatoid arthritis, the risk of developing antibodies to citrullinated proteins has been associated with gene-environment interactions between HLA-DRB1 shared epitope alleles and smoking. [30][31][32][33][34] Other diseases showing associations between HLA and smoking include idiopathic inflammatory myopathies, 35 Parkinson disease, 36,37 multiple sclerosis, [38][39][40][41] and lymphoma. 42 In the current study, the strong effects of HLA-DRB1*15:02 on the risk of UC were observed in never smokers.…”