Abstract
IntroductionOsteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. The heritability of OA has been estimated to be 60% for hip OA and 39% for knee OA. Genetic factors behind OA are still largely unknown. Studying families with strong history of OA, facilitates examining the co-segregation of genetic variation and OA. The aim of this study was to identify new, rare genetic factors and novel candidate genes for OA.MethodsEight patients from three Finnish families with hip and knee OA were studied using whole exome sequencing. We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions. Expression of identified candidate genes were studied in bone and cartilage tissues and the observed variants were investigated using bioinformatic analyses.ResultsTwo rare variants co-segregated with OA in two families. In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the OLIG3 gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis. The Arg210Gly variant was estimated to be pathogenic by Polyphen-2 and Mutation taster and the locus is conserved among mammals. In Family 12 the observed variant (c.-127G>T) was located in the transcription start site of the FIP1L1 gene. FIP1L1 participates in the regulation of polyadenylation. The c.-127G>T is located in the transcription start site and may alter the DNA-binding of transcription factors. Both, OLIG3 and FIP1L1 were observed in human bone and cartilage.ConclusionThe identified variants revealed novel candidate genes for OA. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to OA.
Highlights
Osteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide
We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions
In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the Oligodendrocyte transcription factor 3 (OLIG3) gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis
Summary
Osteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. OA is characterized by progressive degradation of the joint cartilage It includes synovial inflammation and bone remodeling causing pain, and eventually leading to loss of joint function. Most often it affects the joints in the knee, hip, or hand, but can affect any joint. OA is a complex disease that has a strong genetic background with heritability estimations of 39% and 65% for hand and knee OA, respectively [3,4] and 60% for hip OA [5]
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