POS0345 CLINICOGENETIC STUDY OF FIVE NOVEL SUSCEPTIBILITY LOCI FOR TAKAYASU ARTERITIS: SUSCEPTIBILITY LOCI IN THE IL12B AND PTK2B REGION, BUT NOT THE LILRA3, DUSP22, KLHL33 REGIONS, ARE ASSOCIATED WITH VASCULAR DAMAGE IN TAKAYASU ARTERITIS
Authors: K. Kadoba, R. Watanabe, T. Iwasaki, K. Kitagori, S. Akizuki, K. Murakami, R. Nakashima, M. Hashimoto, M. Tanaka, K. Ohmura, A. Morinobu, C. Terao, H. Yoshifuji
Journal: Annals of the Rheumatic Diseases (2021)

Background: We have previously identified single nucleotide polymorphism (SNP) rs6871626 in IL12B , rs103294 in LILRA3 , rs17133698 in DUSP22 , rs2322599 in PTK2B , and rs1713450 in KLHL33 as non-HLA susceptibility loci in Takayasu arteritis (TAK) [1, 2]. However, the association of these SNPs with clinical features has scarcely investigated. Objectives: In this study, we aimed to examine how these SNPs contribute to clinical features and vascular damage in TAK. Methods: We enrolled 99 TAK patients who were enrolled in our previous genome-wide association study (GWAS) [2]. To assess vascular damage, Takayasu Arteritis Damage Score (TADS) and Vasculitis Damage Index (VDI) were measured at the last visit before November 2020. As for organ damages, the presence or absence of aortic regurgitation (AR), hypertension, ischemic heart disease, cerebrovascular event, visual loss, end-stage renal failure, and inflammatory bowel disease were evaluated. Treatment profiles including immunosuppressive drugs and vascular interventions were also reviewed. Results: The incidence of AR was positively associated with the risk allele of IL12B rs6871626 (p=0.0052; odds ratio (OR) 2.45, 95% confidence interval (CI) 1.27-4.73), and so was the proportion of patients who underwent aortic valve replacement (p=0.023; OR 3.64, 95% CI 1.08-12.24) (table 1). The incidence of hypertension was associated with the risk allele of IL12B rs6871626 (p=0.049; OR 1.82, 95% CI 0.99-3.36) and PTK2B rs2322599 (p=0.044; OR 2.52, 95% CI 0.97-6.54) (table 1). The proportion of biologic users tended to be higher in the risk genotypes of IL12B rs6871626 (p=0.15; OR1.80, 95% CI 0.79-3.99). Regarding vascular damage, there was positive correlation between TADS and the risk allele of IL12B rs6871626 (p=0.0035; β= 1.35) (Figure 1). Moreover, VDI was also positively correlated with the allele (p=0.0054; β= 0.96) (Figure 1). No other clinicogenetic associations were observed between five SNPs and vasculitis-associated damages. Table 1. The association of the five SNPs with aortic regurgitation and hypertension Aortic regurgitation Hypertension OR (95% CI) p value OR (95% CI) p value IL12B rs6871626 2.45 (1.27-4.73) 0.0052* 1.82 (0.99-3.36) 0.049* PTK2B rs2322599 1.21 (0.51-2.86) 0.67 2.51 (0.97-6.54) 0.044* LILRA3 rs103294 1.16 (0.52-2.61) 0.71 1.20 (0.55-1.64) 0.64 DUSP22 rs17133698 0.56 (0.28-1.13) 0.090 0.87 (0.46-1.63) 0.66 KLHL33 rs1713450 0.89 (0.42-1.91) 0.77 1.48 (0.68-3.22) 0.31 SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval Conclusion: In the present study, IL12B rs6871626 was closely correlated with vascular damage. We also found association between PTK2B rs2322599 and hypertension. There was no significant relevance between vascular damage and LILRA3 rs103294, DUSP22 rs17133698, or KLHL33 rs1713450. References: [1]Terao C et al. Am J Hum Genet. 2013;93(2):289-97. [2]Terao C et al. Proc Natl Acad Sci U S A. 2018;115(51):13045-50. Disclosure of Interests: Keiichiro Kadoba: None declared, Ryu Watanabe Speakers bureau: I have received speaker’s fee from Mitsubishi Tanabe Pharma, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Eli Lilly, Bristol-Myers Squibb, and Janssen., Takeshi Iwasaki: None declared, Koji Kitagori Grant/research support from: KK has received research grants from GlaxoSmithKline., Syuji Akizuki: None declared, Kosaku Murakami Speakers bureau: I have received speaking fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Ran Nakashima: None declared, Motomu Hashimoto Speakers bureau: I have received a research grant and/or speaker fee from Bristol-Myers, Eisai, Ely Lilly, Mitsubishi Tanabe Pharma., Grant/research support from: I have received a research grant and/or speaker fee from Bristol-Myers, Eisai, Ely Lilly, Mitsubishi Tanabe Pharma., Masao Tanaka Speakers bureau: I have received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Taisho Pharma Co., Ltd, and Takeda Pharmaceutical Company Limited., Koichiro Ohmura Speakers bureau: I have received speaker’s fee from Abbvie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi and Takeda., Grant/research support from: I have received research grants from GlaxoSmithKline., Akio Morinobu Speakers bureau: I have received speaking fees from Chugai Pharmaceutical Co. Ltd., Grant/research support from: I have received research grants from Chugai Pharmaceutical Co. Ltd., Chikashi Terao: None declared, Hajime Yoshifuji Speakers bureau: I have received lecture fees from Chugai., Consultant of: I have been an advisory board for a clinical trial conducted by Janssen.