Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort

Abstract ObjectivesThe objectives of this study are to 1) identify individuals that required surgery for thumb carpometacarpal osteoarthritis (CMCJ OA), 2) determine if CMCJ OA clusters in multigenerational families, 3) define the magnitude of familial risk of CMCJ OA, 4) identify risk factors associated with CMCJ OA and 5) identify rare genetic variants that segregate with familial CMCJ OA. MethodsWe searched the Utah Population Database to identify a cohort of CMCJ OA patients that required a surgical procedure (CMC fusion or arthroplasty). Affected individuals were mapped to pedigrees to identify high-risk multigenerational families with excess clustering of CMCJ OA. Cox regression models were used to calculate familial risk of CMCJ OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify a rare coding variant associated with familial CMCJ OA. ResultsWe identified 550 pedigrees with excess clustering of severe CMCJ OA. The relative risk of developing CMCJ OA requiring surgical treatment was significantly elevated in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. A dominantly segregating, rare variant in CHSY3 was associated with familial CMCJ OA. ConclusionsFamilial clustering of severe CMCJ OA was observed in a statewide population. Identification of a candidate gene indicates a genetic contribution to the etiology of the disease. Our data indicate the genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease. Key messagesWe study a unique cohort of individuals requiring surgical management of CMCJ OA.Severe CMCJ OA clusters in large, multigenerational families indicating a genetic contribution to the disease..We discovered a dominant coding variant in CHSY3 in a family with severe CMCJ OA.