title: Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers.
abstract: BACKGROUND
  Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA.
  
  
  METHODS
  In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking.
  
  
  RESULTS
  MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers.
  
  
  CONCLUSIONS
  High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, D2:01, 17176 Stockholm, Sweden. saedis.saevarsdottir@karolinska.se
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Kristjan
authors.initials: K
authors.lastname: Steinsson
authors.forename: Gerdur
authors.initials: G
authors.lastname: Grondal
authors.forename: Helgi
authors.initials: H
authors.lastname: Valdimarsson
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D037601:Mannose-Binding Lectin / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D012217:Rheumatoid Factor / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking; D055815:Young Adult
chemical_list: D037601:Mannose-Binding Lectin; D012217:Rheumatoid Factor