From the Institute of Environmental Medicine, Division of Cardiovascular Epidemiology, Karolinska Institutet, Stockholm, Sweden in collaboration with the Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden ROLE OF GENES AND ENVIRONMENT 

Rheumatoid arthritis (RA) is a complex disease with autoimmune features primarily causing destruction in the joints of the body. Knowledge regarding risk indicators and causes are increasing but so far only a few genetic and very few environmental risk factors have been consistently identified. The overall aim of this thesis is to investigate interaction between genetic and environmental factors for different phenotypes of RA. Specific aims are to investigate: 1. gene-environment interaction between HLA-DRB1 SE alleles and smoking. 2. Gene-gene interaction between HLA-DRB1 SE and R620W PTPN22 alleles. 3. Interaction between alcohol consumption, smoking and HLA-DRB1 SE alleles. 4. Dose dependency between smoking and risk of developing RA with consideration taken to interaction between smoking and HLA-DRB1 SE alleles. In all the above aims different phenotypes for RA as defined by presence or absence of antibodies to citrullinated protein antigens (ACPA+, ACPARA respectively) is considered. This thesis is primarily based on data from a Swedish study named Epidemiological Investigation of Rheumatoid Arthritis (EIRA). EIRA is a population based case-control study which consists of information from incident cases and controls matched on age, sex and living area. Cases and controls were given the opportunity to fill in an extensive questionnaire and to provide a blood sample for genetic and serological analysis. In paper II additional studies from USA (the NARAC study) and the Netherlands (Leiden EAC) was used to investigate potential gene-gene interaction between HLA-DRB1 SE and R620W PTPN22 alleles. In paper III information from the Danish case-control study of rheumatoid arthritis (the CACORA study) in addition to EIRA, was used to investigate interaction between alcohol consumption, smoking and HLA-DRB1 SE alleles. Smoking and alcohol consumption patterns and dosage were estimated through selfreported information in questionnaires. Interaction was primarily defined in terms of deviance from additivity of effects. A strong interaction between smoking and HLA-DRB1 SE alleles was observed regarding risk of developing ACPA+ RA. The most pronounced interaction was observed for the combination of smoking and homozygosity for HLA-DRB1 SE alleles. Smoking was also associated, in a dose dependent manner with increased risks of developing ACPA+ RA with consideration taken to HLA-DRB1 SE alleles. Interaction between HLA-DRB1 SE and R620W PTPN22 alleles regarding risk of developing ACPA+ RA was observed in three different studies (EIRA, NARAC and Leiden EAC). No associations between HLA-DRB1 SE or R620W PTPN22, and only a minor association for smoking regarding risk of ACPARA were observed. Alcohol consumption was inversely associated with risk of developing RA in a dose dependent manner in both EIRA and CACORA. Lack of alcohol consumption was also associated with interaction with smoking and HLA-DRB1 SE alleles regarding risk of developing ACPA+ RA.