Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Background/Purpose: Ankylosing spondylitis (AS) is a highly heritable inflammatory arthritis common in both Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease that usually occurs in people of Mediterranean origin. MEFV, a known FMF-associated gene, is a candidate gene for AS, because of increased co-familiality of AS and FMF, and suggestive association of MEFV with AS in candidate gene studies. Here we studied Turkish and Iranian case-control cohorts to identify AS susceptibility loci and also examine the association between MEFV and AS.
Methods: A genome wide association study was performed in 1001 Turkish AS patients and 1011 Turkish controls and also 479 Iranian AS patients and 830 Iranian controls, using Illumina Infinium CoreExome chips. Standard quality control and population stratification identification and control measures were applied (lambda1000 in Turkish, Iranian and combined datasets 1.039, 1.025 and 1.025 respectively).
Results: In this study we identified two non-MHC loci, MEFV and USP8 reaching genome-wide significance (p < 5×10-8), and fourteen suggestive loci (10-5 < p <5×10-8), in the combined cohort. The lead MEFV SNP rs61752717 (M694V, p = 7.6×10-12, OR = 5.3) is a rare coding variant (MAF=0.011 in Turkish controls) and also the most penetrant FMF-associated variant. This lead SNP also shows significant association with AS in Iranian cohort (p = 0.042, OR = 2.9), and in the combined dataset is very strongly AS-associated (p = 1.5×10-13, OR = 4.9). Three coding variants in MEFV were significantly associated with AS (P369S, R408Q and M694V). AS cases with MEFV rs61752717 variants did not themselves have FMF, and had similar disease manifestations to non-carriers. This study confirms the previous identification of USP8 as an AS-associated locus (exm1161045, p = 8.0×10-14, OR = 0.58 in combined dataset), and at previously reported AS-associated loci including HLA-B, ERAP1 and 2p15.
Conclusion: This study provides definitive evidence of the association of rare MEFV variants with AS, and confirms that FMF and AS have overlapping aetiopathogenic mechanisms. The association of MEFV in these populations has the highest odds ratio for AS of any non-MHC genetic variant confirmed at genome-wide significance to date. Functionally important MEFV mutations such as M694V have been demonstrated to lead to dysregulated inflammasome function and excessive IL-1b function. Given that IL-1 inhibition is effective in FMF, it will be interesting to study whether AS cases carrying FMF-associated MEFV variants also benefit from such therapy.
To cite this abstract in AMA style:Li Z, Akar S, Yarkan H, Cetin P, Can G, Kenar G, Pamuk ON, Pehlivan Y, Cremin K, Guzman ED, Harris J, Jamshidi AR, Vojdanian M, Ahmadzadeh N, Mahmoudi M, Brown MA, Akkoc N. Rare Mediterranean Fever (MEFV) Gene Polymorphisms Are Associated with Ankylosing Spondylitis in Turkish and Iranian Population [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/rare-mediterranean-fever-mefv-gene-polymorphisms-are-associated-with-ankylosing-spondylitis-in-turkish-and-iranian-population/. Accessed November 29, 2020.
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