A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis
Journal
International journal of molecular sciences
Journal Volume
24
Journal Issue
3
Date Issued
2023-02-03
Author(s)
Khosasih, Vivia
Liu, Kai-Ming
Huang, Chung-Ming
Liou, Lieh-Bang
Hsieh, Ming-Shium
Lee, Chian-Her
Tsai, Chang-Youh
Kuo, San-Yuan
Hwa, Su-Yang
Lin, Cheng-Jyh
Cheng, Chun-Ying
Chen, Wei-Ming
Chen, Liang-Kuang
Chuang, Hui-Ping
Chen, Ying-Ting
Tsai, Pei-Chun
Lu, Liang-Suei
H'ng, Weng-Siong
Zhang, Yanfei
Chen, Hsiang-Cheng
Chen, Chien-Hsiun
Lee, Ming Ta Michael
Wu, Jer-Yuarn
Abstract
While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.
Subjects
CYP26B1; Han Chinese; genome-wide association study; hand osteoarthritis; polymorphisms; retinoic acid
SDGs
Publisher
MDPI
Type
journal article