title: Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma.
abstract: Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related β1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.
authors.affiliation: Clinical Epidemiology Unit T2, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Baecklund
authors.affiliation: Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.
authors.forename: Jia-Nee
authors.initials: JN
authors.lastname: Foo
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Askling
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Eloranta
authors.affiliation: Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.|Department of Immunology, Genetics and Pathology, Clinical and Experimental Oncology, Uppsala University and Uppsala Akademiska Hospital, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Glimelius
authors.affiliation: School of Health Sciences, Wuhan University, Wuhan, 430071, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Department of Immunology, Genetics and Pathology , Uppsala University , Uppsala , Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Smedby
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000502:physiology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008224:Lymphoma, Follicular / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008297:Male; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D013548:Sweden / Q000453:epidemiology
chemical_list: D059811:HLA-DRB1 Chains
keywords: HLA-DRB1; etiology; follicular lymphoma; interaction; smoking