Session Information
Session Title: Sjogren's Syndrome: Pathophysiology
Session Type: Abstract Submissions (ACR)
Background/Purpose Our goal is to define the contribution of genetic factors to two hallmark manifestations of SS, keratoconjunctivitis sicca (KCS) and focal lymphocytic sialadenitis (FLS), in an international cohort.
Methods We studied 3,334 participants in the Sjögren’s International Collaborative Clinical Alliance (SICCA; contract # HHSN 268201300057C) registry who were characterized for the Illumina HumanOmni 2.5-Quad marker set. SICCA participants were enrolled according to standardized protocols at 9 international sites, including Argentina (n=428), China (n=304), Denmark (n=583), India (n=127), Japan (n=367), the UK (n=296) and the US (total n=1229 from 3 sites). QC measures included filters based on SNP and sample missingness (≥ 2%), unexpected relatedness, non-Mendelian inheritance, and chromosomal regions of anomaly (> 10Mb). SICCA participants were assessed for presence and severity of FLS defined by focus score (FS, positive ≥ 1) on minor salivary gland biopsy and degree of KCS based on ocular staining pattern measured by ocular staining score (OSS, positive ≥ 3). In order to investigate the genetic basis of these manifestations, we compared patients with high values (OSS ≥ 7, FS ≥ 2.5) to patients with normal values (OSS < 3, FS < 1) via logistic regression. Principal components analysis (PCA) was used to characterize each participant for genetic ancestry, and PCs 1 - 5 were included as covariates in all association analyses. We analyzed the entire group and also the two largest strata by ethnicity (European and Asian, with outliers removed outside of PCA clusters).
Results Out of 3284 unrelated subjects with post-QC genotypes and sufficient clinical data, patients were categorized for analysis as follows: high FS (n=636), normal FS (n=1968), high OSS (n=1333), normal OSS (n=857). A total of 1,550,200 SNPs with MAF ≥ 1% passed all QC filters and were fully analyzed. Not surprising in autoimmunity, the MHC was the most significantly associated with both traits in the full dataset (FS p=3e-22; OSS p=6e-12) and in Europeans (FS 375 SNPs p<5e-8, lowest 3e-17; OSS 60 SNPs p<5e-8, lowest p=4e-11). However, in Asians the MHC appears to have much less importance. There was only one suggestive MHC SNP (p=8e-6) for FS; the most associated FS gene in Asians was PTPRD, with 12 SNPs p<5e-6 (lowest p=1.8e-7). Outside of the MHC, some genes appear to influence both phenotypes while others are trait-specific. For example, IRF5 is the highest-associated region for FS (p=2e-7) but not suggestive for OSS. The XYLT1 region is the highest-associated region for OSS (p=1e-6) but is not implicated in FS. On the other hand, STAT4 is among the most-associated regions for both FS (p=1e-6) and OSS (p=3e-6).
Conclusion These results demonstrate that the ocular (OSS) and oral (FS) manifestations of SS are influenced by both shared and trait-specific genetic factors. Furthermore the genetic profile appears to be quite different for both depending on ancestry, in particular when comparing European and Asian SS patients. Additional work including imputed genetic data and more extensive ancestry analysis will provide more power for extending these findings and fully characterizing the genetic contribution to SS.
Disclosure:
L. A. Criswell,
None;
K. E. Taylor,
None;
Q. Wong,
None;
D. M. Levine,
None;
C. McHugh,
None;
C. Laurie,
None;
K. Doheny,
None;
M. Y. Lam,
None;
A. N. Baer,
None;
S. Challacombe,
None;
Y. Dong,
None;
H. Lanfranchi,
None;
M. Schiødt,
None;
M. Srinivasan,
None;
S. Sugai,
None;
H. Umehara,
None;
F. B. Vivino,
None;
Z. Yan,
None;
S. Shiboski,
None;
T. Daniels,
None;
J. S. Greenspan,
None;
C. H. Shiboski,
None;
S. S. C. C. A. (SICCA),
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-genetic-basis-of-sjogrens-syndrome-ss-clinical-manifestations-from-genome-wide-association-analysis-of-subphenotype-extremes-in-an-international-cohort/