Revealing the genetics of osteoarthritis in families

Abstract

Osteoarthritis (OA) is the most common and debilitating joint disease worldwide and frequent cause of disability in elderly. In Brazil, OA is also considered the most prevalent rheumatic disease being joint replacement the only effective treatment offered to several affected patients. The genetic component of hip OA and knee OA have been estimated to be around 40-60% using twin studies and it is considered that at least 30% of the risk of OA is genetically determined. Till date, only around 10% of the genetic component have been explained. Next generation exome sequencing (NGE), has been highly successful in identifying likely causal mutations in patients with familial, more severe, phenotypes or Mendelian disorders. Due to their strong effect, these mutations can provide direct clues to genotype-phenotype relations. Both parts of this proposal, the "Molecular Epidemiology and the department of Biomedical Data Sciences" from Leiden University and the "Laboratory of Genetics Epidemiology" from FMJ-Brazil focus a significant part of their research efforts in finding those mutations in genes from affected families with OA. At the moment, the Leiden partner has performed exome sequencing dataset (50x coverage; Beijing Technology Institute) in a cohort (GARP) from 43 patients and early onset of OA in 7 families. The GARP study involves sibling pairs with symptomatic OA at multiple joint sites hence representing familial OA patients at the severe end of the OA spectrum. On the other side, FMJ-Sao Paulo count with DNA extracted from 60 individuals affected with OA and with family history of OA and 30 family members (affected or unaffected with OA), conforming aproximately a total of 6-8 families that are going to be sequenced. In addition, Leiden has available paired preserved and OA affected cartilage samples for around 500 donors undergoing joint replacement surgery for primary OA, in the RAAK study. These cartilage samples will allow to perform functional studies, that will help to determine the expression of the identified genes in this tissue, between others. The objective of this proposal is to establish a mutual collaboration in this research line to be able to detect and replicate findings in families from both studies (Leiden and Sao Paulo) through the use of an Exome-sequencing approach and functional studies to verify expression and function of these genes in cartilage. (AU)