THU0012 IMPACT OF RS12107036 POLYMORPHISM OF TP63 ON THE RISK OF RAPID PROGRESSIVE OSTEOARTHRITIS OF THE KNEE. DATA FROM THE OSTEOARTHRITIS INITIATIVE
Authors: A. Durán-Sotuela, M. Fernandez-Moreno, M. E. Vazquez Mosquera, P. Ramos-Louro, A. Dalmao-Fernandez, S. Relaño-Fernandez, N. Oreiro, F. J. Blanco, I. Rego-Perez
Journal: Annals of the Rheumatic Diseases (2020)

Background: There is a need to identify patients with the rapid progressive phenotype of Osteoarthritis (RPOA) to include them in clinical trials and to implement prevention strategies. During the last years, nuclear single nucleotide polymorphisms (SNPs) were associated with susceptibility and progression of the disease, but not with the rapid progression phenotype. Objectives: Analyze the influence of previously knee OA-associated nuclear SNPs on the risk of RPOA in patients of the OAI. Methods: Caucasian patients from the OAI were selected and assigned into three different groups (N=252/group) based on the following criteria: A.rapid progressors; baseline KL grade 0-1 in at least one knee and increase up to KL≥ 3 during a 48-month period; or baseline KL grade 2 in at least one knee and increase up to KL 4 or total knee replacement during the follow-up. B.no-rapid progressors; baseline KL grade 0-1 in at least one knee and increase up to KL 2 during 48-month period; or baseline KL grade 2 in at least one knee and increase up to KL 3 during the follow-up. C.no-progressors; KL grade 0-2 at baseline in at least one knee and bilaterally stable during 48-month period. Groups were re-categorized into two groups: non-progressors and progressors (pooling A and B). Nuclear SNPs were previously assigned by mini-sequencing techniques. Preliminary chi-square analyses and binary and multinomial logistic regression models adjusted by gender, age, body mass index (BMI), contralateral OA, previous injury in target knee and WOMAC pain, were performed with IBM SPSS Statistics v24. Results: We analyzed the effect of 7 SNPs that had been strongly associated with knee OA susceptibility in different GWAS studies: rs11177, rs4730250, rs11842874, rs12107036, rs8044769, rs10948172 and rs143383. Chi-square analyses only showed differences in the frequency distribution of rs12107036 between groups (p=0,028), being the GG genotype over-represented in the rapid progressors group and the AA genotype in the non-progressors group (Figure 1). The binary logistic regression showed that G allele was significantly over-represented in the (pooled) progressors group when compared with non-progressors (p=0,008) (Table 1). And the multinomial logistic regression showed that, in addition to age and previous injury in target knee, the GG genotype (p=0,032) emerged as a potential risk factor for the RPOA when compared with non-rapid progressors (Table 2). Table 1. Binary regression model comparing progressors pool vs. no-progress Variables p-value OR C.I. 95% Min. Max. Age 0,217 1,012 0,993 1,030 Sex (Female ) 0,000 # 2,049 1,478 2,842 BMI 0,000 # 1,085 1,044 1,127 Contralateral OA (Yes ) 0,044 # 1,400 1,009 1,942 Previous Injury (Yes ) 0,002 # 1,723 1,223 2,429 WOMAC pain 0,003 # 1,102 1,033 1,177 rs12107036 G (Yes ) 0,008# 1,682 1,148 2,463 CI: confidence interval; OR: Odd Ratio; #: statistical significance declared at P ≤ 0.05 Table 2. Multinomial regression model comparing rapid vs. no-rapid progressors. Variables p-value OR C.I. 95% Min. Max. Age 0,000 # 1,064 1,041 1,088 Sex (Female ) 0,498 0,875 0,595 1,287 BMI 0,096 1,034 0,994 1,077 Contralateral OA (Yes ) 0,792 1,052 0,719 1,539 Previous Injury (Yes ) 0,028 # 1,523 1,047 2,216 WOMAC pain 0,091 1,055 0,992 1,123 rs12107036 GG (Yes ) 0,032 # 1,574 1,039 2,382 CI: confidence interval; OR: Odd Ratio; #: statistical significance declared at P ≤ 0.05 Conclusion: The G allele of the nuclear SNP rs12107036 of TP63 gen increases the risk of knee OA progression. Depending on the number of risk allele copies the level of progression varies, being the GG genotype a risk factor for the RPOA of the knee. The assignment of this nuclear polymorphism could be useful as complementary genetic biomarker for the early identification of this phenotype. Disclosure of Interests: Alejandro Durán-Sotuela: None declared, Mercedes Fernandez-Moreno: None declared, Maria Eugenia Vazquez Mosquera: None declared, Paula Ramos-Louro: None declared, Andrea Dalmao-Fernandez: None declared, Sara Relaño-Fernandez: None declared, Natividad Oreiro: None declared, Francisco J. Blanco Grant/research support from: Sanofi-Aventis, Lilly, Bristol MS, Amgen, Pfizer, Abbvie, TRB Chemedica International, Glaxo SmithKline, Archigen Biotech Limited, Novartis, Nichi-iko pharmaceutical Co, Genentech, Jannsen Research &amp; Development, UCB Biopharma, Centrexion Theurapeutics, Celgene, Roche, Regeneron Pharmaceuticals Inc, Biohope, Corbus Pharmaceutical, Tedec Meiji Pharma, Kiniksa Pharmaceuticals, Ltd, Gilead Sciences Inc, Consultant of: Lilly, Bristol MS, Pfizer, Ignacio Rego-Perez: None declared