TNFAIP3 polymorphisms and age at onset are associated with response to tumour necrosis factor blockade in psoriasis

Abstract

The TNFAIP3 gene has been associated with psoriasis, rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus and celiac disease. TNFAIP3 encodes A20, a tumour necrosis factor (TNF)-inducible zinc finger protein thought to limit NF-jB-mediated immune responses. In this study we report association of response of psoriasis to TNF blockers with two TNFAIP3 single nucleotide polymorphisms (SNPs) (rs2230926 in exon 7 and rs610604 in intron 3) and their haplotypes. Treatment response was self-evaluated using a 0-5 visual analogue scale in 433 psoriasis patients who received TNF blockers. Confirmation was sought in 199 psoriasis and psoriatic arthritis patients from Toronto who were followed prospectively. Response variables were dichotomized separately in the two cohorts, yielding similar proportions of good responses. Covariate analyses with age at onset, body mass index and presence of psoriatic arthritis (PsA) were analysed in both cohorts, along with worst-ever total body surface area in the Michigan cohort. While significant associations were observed only for the Michigan cohort, fixed-effects metaanalysis retained significant association between dosage of the G allele of rs610604 and good combined response to all TNF blockers [odds ratio (OR) 1Æ50, Pcorr = 0Æ050] and etanercept (OR 1Æ64, Pcorr = 0Æ016). The rs2230926 T-rs610604 G haplotype was similarly associated with good combined response to all TNF blockers (OR 1Æ55, Pcorr = 0Æ031) and etanercept (OR 1Æ71, Pcorr = 0Æ011). Age at onset was significantly and negatively associated with response to TNF blockers in the Michigan cohort (OR 0Æ973, P = 0Æ00016). Although not reaching nominal significance, age at onset also trended towards negative association with all four-drug responses in the Toronto sample (OR 0Æ982) for all TNF blockers com- bined. Age at onset of disease was included as a covariate in all association models and the nested logistic regression models testing association for each combination of SNP and drug revealed that the associations of age at onset and SNP rs610604 with drug response were independent of each other (no significant interaction). By demonstrating an association with therapeutic response, these results provide a clinically relevant functional correlate to the recently described genetic association between psoriasis and TNFAIP3. The novel association with age at onset suggests that people with early onset have a form of disease more amenable to treatment with TNF blockers than people with later onset, which may be a result of different genetic risk factors.