M Taipale1, E Jakkula2, O-P Kämäräinen3, P Gao3, S Skarp1, S Barral4, I Kiviranta5, H Kröger6, J Ott7, G-H Wei3, L Ala-Kokko8, M Männikkö9. 1. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland. 2. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. 3. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland. 4. Gertrude H. Sergievsky Center, College for Physicians and Surgeons, Columbia University, New York, USA. 5. Department of Orthopaedics and Traumatology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Department of Orthopaedics and Traumatology, Jyväskylä Central Hospital, Jyväskylä, Finland. 6. Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland; Bone and Cartilage Research Unit, University of Eastern Finland, Kuopio, Finland. 7. Institute of Psychology, Chinese Academy of Sciences, Beijing, China. 8. Connective Tissue Gene Tests, Allentown, PA, USA. 9. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Center for Life Course Epidemiology and Systems Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland. Electronic address: minna.mannikko@oulu.fi.
Abstract
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.
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.
Authors: Sini Skarp; Olli-Pekka Kämäräinen; Gong-Hong Wei; Eveliina Jakkula; Ilkka Kiviranta; Heikki Kröger; Juha Auvinen; Petri Lehenkari; Leena Ala-Kokko; Minna Männikkö Journal: PLoS One Date: 2018-08-29 Impact factor: 3.240