Influence of female hormonal factors, in relation to autoantibodies and genetic markers, on the development of rheumatoid arthritis in northern Sweden: a case–control study

Abstract

Objectives: To study the influence of female hormonal factors on the development of rheumatoid arthritis (RA) in relation to the human leucocyte antigen (HLA)-DRB1 shared epitope (SE), the protein tyrosine phosphatase (PTPN22) 1858T variant, anti-citrullinated protein antibodies (ACPAs), and immunoglobulin (Ig)M-rheumatoid factor (IgM-RF).

Methods: A case–control study (1:4) was nested within the Medical Biobank of northern Sweden. Females who had subsequently developed RA (n = 70), median of 2.7 years before the onset of symptoms, and matched controls (n = 280) were identified from among the blood donors. A questionnaire concerning previous exposures until disease onset, including hormonal and reproductive factors, and smoking habits was distributed.

Results: Breastfeeding was significantly associated with the development of RA [odds ratio (OR) 4.8, 95% confidence interval (CI) 1.43–15.8]. Increasing time of breastfeeding increased the risk of RA (OR 5.7, 95% CI 1.83–17.95) for breastfeeding ≥ 17 months. In a multiple logistic regression analysis, increasing time of breastfeeding (OR 9.5, 95% CI 2.14–42.43 for ≥ 17 months), seropositivity for ACPAs (OR 19.5, 95% CI 4.47–84.81), and carriage of the PTPN22 1858T variant (OR 3.2, 95% CI 1.36–7.54) remained significant predictors of RA. Users of oral contraceptives (OC) for ≥ 7 years had a decreased risk for development of RA (OR 0.37, 95% CI 0.15–0.93).

Conclusions: A longer duration of breastfeeding increased the risk of developing RA, especially among individuals seropositive for ACPA or IgM-RF or carrying the PTPN22 1858T variant. Use of OC for ≥ 7 years was associated with a decreased risk.

Acknowledgements

We thank Hans Stenlund (Department of Public Health and Clinical Medicine, Epidemiology) for helpful discussions regarding the statistical analyses, Kåre Eriksson (Department of Public Health and Clinical Medicine, Environmental Medicine) for discussions related to work load, and Göran Wadell (Department of Virology, University Hospital, Umeå, Sweden) for providing samples from the Maternity cohort within the Medical Biobank. This study was supported by grants from the Swedish Research Council (K2003-74XD-14705-01), King Gustaf V's 80-Year Fund, and the Swedish Rheumatism Association, and by research funding from the European Community FP6 funding project 018661 ‘Autocure’.