PTPN22, PADI-4 and CTLA-4 genetic polymorphisms and risk of rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking

Karen H Costenbader , Shun-Chiao Chang , Immaculata De Vivo , Robert Plenge and Elizabeth W Karlson

Arthritis Research & Therapy 2008, 10:R52doi:10.1186/ar2421


Published:	7 May 2008

Abstract (provisional)

Introduction

PTPN22, PADI-4, and CTLA-4 have been associated with rheumatoid arthritis (RA) risk. We investigated whether polymorphisms in these genes were associated with RA among Caucasian women in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking.

Methods

We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340) and CTLA-4 (rs3087243), in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Participants in NHS were aged 30-55 years at entry in 1976; those in NHSII were 25-42 at entry in 1989. We confirmed incident RA cases through 2002 in NHS and 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants with samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status and postmenopausal hormone use. Genotyping was performed using Taqman SNP allelic discrimination on the ABI 7900HT with published primers. HLA-shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking.

Results

437 incident RA cases were matched to healthy female controls. Mean age at RA diagnosis was 55 (10), 57% of RA cases were RF positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled OR in multivariable dominant model: 1.46 [95% confidence interval (CI) 1.02, 2.08]). The risk was stronger for RF+ than for RF- RA. A significant multiplicative interaction between PTPN22 and smoking > 10 pack-years was observed (p = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled ORs in multivariable dominant models 1.27 [95%CI 0.88 to 1.84] for CTLA-4 and 1.04 [95%CI 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE.

Conclusions

After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking.