Genetics in TNF TNFR pathway: A complex network causing spondyloarthritis and conditioning response to anti TNFa therapy
Objectives We investigated whether polymorphisms (SNPs) in the promoter region of TNFA, or in the autoinflammatory TNFRSF1A and MEFV genes, concur with HLA B27 in enhancing the risk of Spondyloarthritis (SpA) and/or in predicting the response to anti TNFa treatment. Methods 373 controls and 137 SpA (82 with Psoriatic Arthritis PsA and 55 with Ankylosing Spondylitis AS; 98/137 under TNFa inhibitor therapy) from the Veneto Region (Italy) were studied. TNFA polymorphisms 1031T>C; 857C>T; 376G>A; 308G>A; 238G>A) and HLA B27 were assayed by RT PCR. Direct sequencing of MEFV (exons 2,3,5 and 10) and TNFRSF1A (exons 2,3,4 and 6) genes were performed. Results HLA B27 was associated with AS (kh2 120.1; p 0.000) Only the TNFA 1031T>C was singly associated with SpA, and the haplotype C/G, resulting from 1031T>C/ 308G>A combination, was significantly associated with a reduced risk of SpA (OR: 0.67, CI: 0.46 0.97; p 0.035) Two SNPs were identified in TNFRSF1A, the R92Q (Minor allele frequency MAF 0.034) and c.625+10A>G (MAF 0.479) None of them was associated with SpA (p>0.05) The TNFRSF1A c.625+10 G allele was associated with late response to anti TNFa therapy (p 0.031) Twenty one SNPs were identified in MEFV gene, 10 with a known potential functional significance. Variant alleles were extremely rare in our population (MAF<0.025) except for R202Q (MAF 0.27) None was associated with SpA diagnosis (p>0.05) Conclusion TNFRSF1A and MEFV gene SNPs are not associated with SpA in the North East of Italy. AS risk appears to depend not only on HLA B27, but also on the protective TNFA haplotype 1031C/ 308G. The TNFRSF1A c.625+10A>G impacts on the response to anti TNFa therapy.
PloS one