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

Gavile, Catherine M.; Kazmers, Nikolas H.; Novak, K.; Meeks, Huong; Yu, Zhe; Thomas, Joy L.; Hansen, Channing; Barker, Tyler; Jurynec, Michael J.

doi:10.1016/j.jhsa.2022.08.004

Cited by 2 publications

(5 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, we used a register-based approach to evade this challenge, assuming that surgical treatment serves as a proxy for disease progression or severity-a strategy which has previously been used rewardingly. 18 The advantage of using surgery as the indicator is that it is a clinically more relevant measure than radiographic changes, for which correlation with symptom intensity is inconsistent and modest, at best. [39][40][41] In contrast, surgery is preceded by an orthopedic assessment, where a surgeon, in cooperation with the patient, has found the objective and subjective symptoms severe enough to justify the associated risks, inconvenience, and expenses of the surgical procedure.…”

Section: Discussionmentioning

confidence: 99%

“…As previously discussed, 38 a challenge of examining the genetics of osteoarthritis progression is the lack of follow‐up data. In our study, we used a register‐based approach to evade this challenge, assuming that surgical treatment serves as a proxy for disease progression or severity—a strategy which has previously been used rewardingly 18 . The advantage of using surgery as the indicator is that it is a clinically more relevant measure than radiographic changes, for which correlation with symptom intensity is inconsistent and modest, at best 39–41 .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, we have previously showed that the genetic associations for knee and hip osteoarthritis differ between patients who had undergone surgical treatment and patients who had not 17 . While a similar approach has successfully been used in a familial clustering study of carpometacarpal osteoarthritis, 18 a genome‐wide analysis of severe rhizarthrosis has not yet been performed. Therefore, we performed a treatment‐stratified GWAS to investigate whether the genetic associations for rhizarthrosis differ between patients who have undergone surgical treatment (trapeziectomy, arthrodesis, or joint replacement) and patients who have not.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetics may affect the risk of undergoing surgery for rhizarthrosis

Henkel,

Erikstrup,

Ostrowski

et al. 2024

Journal Orthopaedic Research

View full text Add to dashboard Cite

Osteoarthritis is a prevalent and severe disease. Involvement of the trapeziometacarpal joint is common and can lead to both pain and disability. Genetics are known to affect the risk of osteoarthritis, but it remains unclear how genetics affect disease trajectories. In this study, we investigated whether the genetic associations of trapeziometacarpal osteoarthritis (rhizarthrosis) vary with the need for surgical treatment. The study was conducted as a case‐control genome‐wide association study using individuals from the Copenhagen Hospital Biobank pain and degenerative musculoskeletal disease study and the Danish Blood Donor Study (N = 208,342). We identified patients diagnosed with rhizarthrosis and grouped them by treatment status, resulting in two case groups: surgical (N = 1083) and nonsurgical (N = 1888). The case groups were tested against osteoarthritis‐free controls in two genome‐wide association studies. We then compared variants suggestive of association (p < 10−6) in either of these analyses directly between the treatment groups (surgical vs. nonsurgical rhizarthrosis). We identified 10 variants suggestive of association with either surgical (seven variants) or nonsurgical (three variants) rhizarthrosis. None of the variants reached nominal significance in the opposite treatment group (p ≥ 0.14), and all 10 variants were significantly different between the treatment groups at a false discovery rate of 5%. These results suggest possible differences in the genetic associations of rhizarthrosis depending on surgical treatment. Clinical significance: Uncovering genetic differences between clinically distinct patient groups can reveal biological determinants of disease trajectories.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetics may affect the risk of undergoing surgery for rhizarthrosis

Henkel,

Erikstrup,

Ostrowski

et al. 2024

Journal Orthopaedic Research

View full text Add to dashboard Cite

show abstract

“…The mutation's location in the substrate-binding domain suggests a potential impact on SIRT5's enzymatic activity, further supported by our functional assays demonstrating Sirt5 F101L has decreased demalonylase activity and disrupts gene expression in chondrocytes. Many (if not all) of the previously identified OA-associated mutations are non-null, even those identified from family studies (44)(45)(46)(47)(48)(49)(50). By studying a hypomorphic human OA-associated allele of Sirt5 F101L , we could potentially uncover novel metabolic and posttranslational effects that we could not detect using a null allele of Sirt5.…”

Section: Discussionmentioning

confidence: 99%

“…We further explored the clinical relevance of our study. Using the Utah Population Database (UPDB), we identified families in which osteoarthritis (OA) segregates as a dominant trait, with multiple members diagnosed with early-onset or severe OA in various joints, including the 1st metatarsophalangeal joint, erosive hand OA, finger interphalangeal joint OA, thumb OA, or shoulder OA (16)(17)(18). We completed genomic analyses for 151 families and identified a rare SIRT5 coding mutation (rs201979175, c.C303G:p.F101L, minor allele frequency -0.00004303) in one family that segregates dominantly with finger interphalangeal joint OA (hand OA).…”

Section: Identification and Functional Analysis Of A Human Oa-associa...mentioning

confidence: 99%

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation

Liu,

Binoy,

Ren

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Objectives: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development. Methods: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5KO and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB). Results: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe, F) to leucine (Leu, L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes. Conclusions: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.

show abstract

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

Cited by 2 publications

References 51 publications

Genetics may affect the risk of undergoing surgery for rhizarthrosis

Genetics may affect the risk of undergoing surgery for rhizarthrosis

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation

Contact Info

Product

Resources

About