Purpose
Our goals were to identify individuals who required surgery for thumb carpometacarpal
(CMC) joint osteoarthritis (OA), determine if CMC joint OA clusters in families, define
the magnitude of familial risk of CMC joint OA, identify risk factors associated with
CMC joint OA, and identify rare genetic variants that segregate with familial CMC
joint OA.
Methods
We searched the Utah Population Database to identify a cohort of CMC joint OA patients
who required surgery. Affected individuals were mapped to pedigrees to identify high-risk
families with excess clustering of CMC joint OA. Cox regression models were used to
calculate familial risk of CMC joint OA in related individuals. Risk factors were
evaluated using logistic regression models. Whole exome sequencing was used to identify
rare coding variants associated with familial CMC joint OA.
Results
We identified 550 pedigrees with excess clustering of severe CMC joint OA. The relative
risk of CMC joint OA requiring surgical treatment was elevated significantly in first-
and third-degree relatives of affected individuals, and significant associations with
advanced age, female sex, obesity, and tobacco use were observed. We discovered candidate
genes that dominantly segregate with severe CMC joint OA in 4 independent families,
including a rare variant in Chondroitin Sulfate Synthase 3 (CHSY3).
Conclusions
Familial clustering of severe CMC joint OA was observed in a statewide population.
Our data indicate that genetic and environmental factors contribute to the disease
process, further highlighting the multifactorial nature of the disease. Genomic analyses
suggest distinct biological processes are involved in CMC joint OA pathogenesis.
Clinical relevance
Awareness of associated comorbidities may guide the diagnosis of CMC joint OA in at-risk
populations and help identify individuals who may not do well with nonoperative treatment.
Further pursuit of the genes associated with severe CMC joint OA may lead to assays
for detection of early stages of disease and have therapeutic potential.
Key words
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Article info
Publication history
Accepted:
August 4,
2022
Received:
June 24,
2022
Footnotes
C.M.G and N.H.K contributed equally to the manuscript.
Supported by the Skaggs Foundation for Research (M.J.J. and N.H.K.), the Arthritis National Research Foundation (M.J.J.), the Utah Genome Project (M.J.J. and N.H.K.), and National Institutes of Health R21AG063534-01A1 (M.J.J.). The UPDB is supported by the Pedigree and Population Resource, the Program in Personalized Health and Center for Clinical and Translational Science, and the National Cancer Institute at the National Institutes of Health (P30CA2014).
No benefits in any form have been received or will be received related directly or indirectly to the subject of this article.
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