title: Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis.
abstract: Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA--the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele--in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP-positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.
authors: Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. henrik.kallberg@ki.se
authors: Henrik
authors: H
authors: Kallberg
authors: Leonid
authors: L
authors: Padyukov
authors: Robert M
authors: RM
authors: Plenge
authors: Johan
authors: J
authors: Ronnelid
authors: Peter K
authors: PK
authors: Gregersen
authors: Annette H M
authors: AH
authors: van der Helm-van Mil
authors: Rene E M
authors: RE
authors: Toes
authors: Tom W
authors: TW
authors: Huizinga
authors: Lars
authors: L
authors: Klareskog
authors: Lars
authors: L
authors: Alfredsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000145:classification / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D010641:Phenotype; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
chemical_list: D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases