Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis. Issue 4 (April 2016)

• Record Type: Journal Article
• Authors: Taipale, M.; Jakkula, E.; Kämäräinen, O.-P.; Gao, P.; Skarp, S.; Barral, S.; Kiviranta, I.; Kröger, H.; Ott, J.; Wei, G.-H.; Ala-Kokko, L.; Männikkö, M.
• Is Part Of: Osteoarthritis and cartilage. Volume 24:Issue 4(2016)
• Page Start: 655
• Page End: 663
• Publication Date: 2016-04
• Subjects: Osteoarthritis -- Hip -- Knee -- Linkage analysis -- Next generation sequencing -- Enhancer element; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Arthrose -- Périodiques; Articulations -- Maladies -- Périodiques; 616.7223005
• DOI: 10.1016/j.joca.2015.10.019
• Languages: English
• ISSNs: 1063-4584

Abstract

Summary: Objective: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families. Methods: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family. Results: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele. Conclusion: A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.