Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis

• Published in: Osteoarthritis and cartilage 2016-04, Vol.24 (4), p.655-663
• Main 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
• Format: Article
• Language: English
• Subjects: Chromosomes, Human, Pair 2 - genetics; Enhancer element; Exome - genetics; Female; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing - methods; Hip; Humans; Knee; Linkage analysis; Lod Score; Male; Middle Aged; Next generation sequencing; Osteoarthritis; Osteoarthritis, Hip - genetics; Osteoarthritis, Knee - genetics; Pedigree; Rheumatology
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2015.10.019

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.