Session Type: Abstract Submissions (ACR)
Background/Purpose: Most genome-wide association (GWA) studies have focused on OA prevalence, but few have focused on OA progression. GWA studies of OA progression may help reveal new biology and drug targets that can be used to develop treatments that slow disease progression in OA patients.
Methods: We used an agnostic GWA analysis of ~8 million 1000 genomes imputed single nucleotide polymorphisms (SNPs) to identify genetic variation associated with structural knee OA progression. Our analyses were conducted in Caucasian participants from the Osteoarthritis Initiative (OAI), a multi-center natural history study of individuals who have or are at high risk for developing radiographic knee OA. A total of 1,756 participants who returned for a follow-up exam and had evidence of radiographic OA (Kellgren-Lawrence (KL) grade ≥ 2) in one or more knees at baseline were included in the analyses (54% female, mean age=67±9 years). We defined progression as worsening of KL grade or progression to total joint replacement (TJR). As a secondary phenotype, we exclusively evaluated progression to TJR. Participants were followed annually for four years. About 27% had worsening of KL grade and 6% had TJR at follow-up. For these analyses, we used logistic regression models adjusted for age, sex, study site, and population stratification and assumed additive genetic models.
Results: We identified two SNPs that reached genome wide significance (P < 5×10-8). One SNP on chromosome 18, rs9964107 (OR=1.6, 95% CI=1.4-1.7, P=3.2×10-8), is associated with worsening of KL grade and another SNP on chromosome 4, rs76964101 (OR=10.8, 95% CI=10.0-11.7, P=4.4×10-8), is associated with progression to TJR. Both SNPs are located within intergenic regions, where rs9964107 is closest to SYT4 and rs76964101 is closest to SRD5A3 and KDR. SYT4 encodes synaptotagamin 4, which is expressed in the brain and may play a role in calcium dependent vesicular trafficking and exocytosis. There is some evidence that this protein may be involved in body weight regulation through negative regulation of oxytocin release. SRD5A3 encodes steroid 5 alpha-reductase 3, which is involved in maintenance of the androgen receptor activation pathway. KDR encodes a kinase insert domain receptor, which is a receptor for vascular endothelial growth factors and promotes proliferation, survival, migration, and differentiation of endothelial cells. There was no evidence for association of either SNP with OA prevalence, suggesting that these SNPs may be uniquely associated with OA progression.
Conclusion: We have identified two genome-wide significant SNPs that may be associated with structural knee OA progression. These SNPs reveal that neuronal regulation of obesity, androgen signaling, and vascular endothelial growth factors may play an important role in OA progression. None of these SNPs are associated with OA prevalence. Further work is ongoing to replicate these associations and identify the causative signal.
M. S. Yau,
L. M. Yerges-Armstrong,
D. J. Duggan,
J. M. Jordan,
B. D. Mitchell,
R. D. Jackson,
M. C. Hochberg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-of-osteoarthritis-progression-results-from-the-osteoarthritis-initiative/