Association of a Non-Synonymous, Loss-of-Function, Variant in NOD2 with Reduced Tissue Damage in ACPA +Ve RA

Ricardo Segurado¹, Denis Shields¹, Rachel Knevel², Annette H.M. van der Helm-van Mil³, Tom W.J. Huizinga⁴ and Anthony G. Wilson⁵, ¹University College Dublin, Dublin, Ireland, ²Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, ³Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁴Department of Rheumatology, LUMC, Leiden, Netherlands, Leiden, Netherlands, ⁵UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland

Meeting: ACR/ARHP Annual Meeting 2017

Date of first publication: September 18, 2017

Keywords: Genetic Biomarkers, joint damage and rheumatoid arthritis (RA)

Session Information

Date: Monday, November 6, 2017

Title: Genetics, Genomics and Proteomics Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

The functional capacity of individuals with rheumatoid arthritis (RA) is related to the severity of damage to bone and cartilage within joints. This is a highly variable trait that is known to have a significant genetic component. A loss-of-function non-synonymous variant (rs2066844, Arg702Trp) in nucleotide-binding oligomerization domain containing 2 (NOD2) gene, results in lower activation of NF-kB-mediated inflammation and tissue damage in RA. Our hypothesis was that the 702Trp variant is, as a result of reduced inflammatory load, be associated with lower radiological damage in RA.

Methods:

The initial study was performed in the British Genetics of RA (GORA) cross-sectional population (N=914), radiological damage was assessed by the Modified Larsen Score (MLS). Genotyping was performed using either the Illumina HumanCoreExome array (N=568) or the Illumina HumanCNV370 Quad v3 array (N=346). Genotypes for rs2066844 were imputed for individuals typed on latter platform using IMPUTE v2. Replication was performed in the Leiden EAC (N=597), with damage assessed at baseline and yearly thereafter using the Sharp-van der Heijde score (SHS) and samples were genotyped on the Illumina iScan platform (Immunochip). RF and ACPA status was available for both populations. Analyses were conducted in R v3.4.0 and SPSS v20. For the combined meta-analysis, we used the most recent measurement on each patient in a zero-inflated negative binomial model adjusted for sex and age at assessment, followed by a fixed-effects meta-analysis of the two summary statistics.

Results:

In the discovery GORA population the minor rs2066844 (702Trp) frequency was 5%, similar to the 1000 genomes European frequency (5.1%), genotypes fitted Hardy-Weinberg equilibrium. The minor allele carriage was associated with lower MLS: incidence ratio risk 0.75 (95% CI: 0.60-0.93), p=0.009. The association was only significant in RF+ (p=0.008) or ACPA+ (p=0.013) subgroups. The proportion of variance explained by rs2066844 was 0.007. In the replication Leiden cohort we observed a similar lower yearly progression of SHS score for each minor allele, by 0.95 SHS (95% CI: 0.92-0.99, p=0.006) in all patient and in ACPA positive patients (0.92, 95% CI: 0.87-0.97, p=0.004). Meta-analysis of the two cohorts revealed a significant pooled effect with an IRR of 0.76 (95% CI: 0.64-0.91 , p=0.003).

Conclusion: These data reveal a protective effect of rs2066844 minor allele with severity of sero-positive RA that is likely a consequence of the lower inflammatory activity associated with this genotype. Although the overall influence on the variance of tissue damage is modest, in combination with established prognostic biomarkers, it may contribute to the development of prognostic algorithm for RA.

Disclosure: R. Segurado, None; D. Shields, None; R. Knevel, None; A. H. M. van der Helm-van Mil, None; T. W. J. Huizinga, None; A. G. Wilson, None.

To cite this abstract in AMA style:

Segurado R, Shields D, Knevel R, van der Helm-van Mil AHM, Huizinga TWJ, Wilson AG. Association of a Non-Synonymous, Loss-of-Function, Variant in NOD2 with Reduced Tissue Damage in ACPA +Ve RA [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/association-of-a-non-synonymous-loss-of-function-variant-in-nod2-with-reduced-tissue-damage-in-acpa-ve-ra/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-a-non-synonymous-loss-of-function-variant-in-nod2-with-reduced-tissue-damage-in-acpa-ve-ra/