title: Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis.
abstract: OBJECTIVE
  To define the interaction between cigarette smoking and HLA polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recently identified amino acid-based HLA model for RA susceptibility.
  
  
  METHODS
  We imputed Immunochip data on HLA amino acids and classical alleles from 3 case-control studies (the Swedish Epidemiological Investigation of Rheumatoid Arthritis [EIRA] study [1,654 cases and 1,934 controls], the Nurses' Health Study [NHS] [229 cases and 360 controls], and the Korean RA Cohort Study [1,390 cases and 735 controls]). We examined the interaction effects of heavy smoking (>10 pack-years) and the genetic risk score (GRS) of multiple RA-associated amino acid positions (positions 11, 13, 71, and 74 in HLA-DRβ1, position 9 in HLA-B, and position 9 in HLA-DPβ1), as well as the interaction effects of heavy smoking and the GRS of HLA-DRβ1 4-amino acid haplotypes (assessed via attributable proportion due to interaction [AP] using the additive interaction model).
  
  
  RESULTS
  Heavy smoking and all investigated HLA amino acid positions and haplotypes were associated with RA susceptibility in the 3 populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA-DRβ1 4-amino acid haplotype (AP 0.416, 0.467, and 0.796, in the EIRA, NHS, and Korean studies, respectively). We further identified the key interacting variants as being located at HLA-DRβ1 amino acid positions 11 and 13 but not at any of the other RA risk-associated amino acid positions. For residues in positions 11 and 13, there were similar patterns between RA risk effects and interaction effects.
  
  
  CONCLUSIONS
  Our findings of significant gene-environment interaction effects indicate that a physical interaction between citrullinated autoantigens produced by smoking and HLA-DR molecules is characterized by the HLA-DRβ1 4-amino acid haplotype, primarily by positions 11 and 13.
authors.affiliation: Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Broad Institute, Cambridge, Massachusetts.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Broad Institute, Cambridge, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Bing
authors.initials: B
authors.lastname: Lu
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Costenbader
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sparks
authors.affiliation: Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, Tokyo Medical and Dental University, Tokyo, Japan, and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, and Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
mesh_terms: D000328:Adult; D000483:Alleles; D000596:Amino Acids / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D059868:HLA-DP beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D012213:Rheumatic Fever / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*
chemical_list: D000596:Amino Acids; D015235:HLA-B Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains