Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Joint damage in rheumatoid arthritis (RA) has been shown to be heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the ImmunoChip array to examine whether genetic variants with relevance to susceptibility to multiple autoimmune diseases including RA, influence variation in joint damage in Mexican Americans (MA) and European Americans (EA) with RA.
Methods: We recruited 720 MA and 424 EA patients with RA from public, private, military and VA rheumatology clinics. Joint damage was quantified using a radiograph of both hands and wrists, scored for erosions and joint-space narrowing using Sharp’s technique. The Sharp scores were transformed using inverse normalization to approximate a normal distribution for the subsequent association analyses. To identify ethnic outliers, principal components (PCs) were derived using EIGENSTRAT principal component analysis. We conducted association analyses with the transformed Sharp score as a quantitative trait and single nucleotide polymorphism (SNP) genotypic (i.e., autosomal SNPs) data obtained from the Immunochip in both MA and EA samples using the program PLINK. We used the linear regression additive genetic model which included covariates age, sex, and the first two principal components (PC1 and PC2) to adjust for potential population stratification influences.
Results: After excluding SNPs due to the following reasons: stringent quality control, admixture and cryptic relationship inference analyses, and SNPs with minor allele frequency below 1%, our Sharp score association analyses involved 127,563 and 128,387 autosomal SNPs in MA and EA, respectively. Both phenotypic and genotypic data were available for 666 MAs and 407 EAs. In MAs, the 15 SNPs with the strongest association with joint damage were located in chromosomes 1, 5, 9, 17 and 22 with p-values ranging from p < 1 x 10-5 to p ≤ 1 x 10-6 including the best associated SNP rs7216796 (β ± SE = -0.25 ± 0.05, p = 6.23 x10-6 within the MAP3K14 gene on chromosome 17. In EAs, there were 28 SNPs from chromosomes 1, 4, 6, 9, and 21 with strong p-values ranging from p < 1 x 10-5 to p ≤ 1 x 10-6, showing associations with joint damage. The best associated SNP was rs59902911 (β ± SE = 0.86 ± 0.17, p = 1.01 x 10-6) in the CARD9 gene on chromosome 9. Aside from the above population-specific association signals, we also found evidence for several loci influencing joint damage in both MAs and EAs. However, none of the association signals found in our study reached the Bonferroni-adjusted significance level.
Conclusion: We identified novel loci that influence variation in joint damage on chromosomes 17 (MAP3K14) and 9 (CARD9) strongly associated with joint damage in MAs and EAs with RA, respectively. We also found several ethnic-specific and shared loci showing suggestive associations with joint damage in MAs and EAs. These novel findings, observed in MAs and EAs, may provide new insights into the genetic architecture of joint damage in RA.
Disclosure:
R. Arya,
None;
D. R. Inmaculada,
None;
V. S. Farook,
None;
J. F. Restrepo,
None;
D. A. Winnier,
None;
M. J. Fourcaudot,
None;
D. Battafarano,
None;
S. Kumar,
None;
M. A. de Almeida,
None;
J. E. Curran,
None;
C. P. Jenkinson,
None;
J. Blangero,
None;
R. Duggirala,
None;
A. Escalante,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-variants-influencing-joint-damage-in-mexican-americans-and-european-americans-with-rheumatoid-arthritis/