Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort

Annals of the Rheumatic Diseases

Honeggar

et al. 2022

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ObjectivesHow inflammatory signalling contributes to osteoarthritis (OA) susceptibility is undetermined. An allele encoding a hyperactive form of the Receptor Interacting Protein Kinase 2 (RIPK2) proinflammatory signalling intermediate has been associated with familial OA. To test whether altered nucleotide-binding oligomerisation domain (NOD)/RIPK2 pathway activity causes heightened OA susceptibility, we investigated whether variants affecting additional pathway components are associated with familial OA. To determine whether the Ripk2104Asp disease allele is sufficient to account for the familial phenotype, we determined the effect of the allele on mice.MethodsGenomic analysis of 150 independent families with dominant inheritance of OA affecting diverse joints was used to identify coding variants that segregated strictly with occurrence of OA. Genome editing was used to introduce the OA-associated RIPK2 (p.Asn104Asp) allele into the genome of inbred mice. The consequences of the Ripk2104Asp disease allele on physiology and OA susceptibility in mice were measured by histology, immunohistochemistry, serum cytokine levels and gene expression.ResultsWe identified six novel variants affecting components of the NOD/RIPK2 inflammatory signalling pathway that are associated with familial OA affecting the hand, shoulder or foot. The Ripk2104Asp allele acts dominantly to alter basal physiology and response to trauma in the mouse knee. Whereas the knees of uninjured Ripk2Asp104 mice appear normal histologically, the joints exhibit a set of marked gene expression changes reminiscent of overt OA. Although the Ripk2104Asp mice lack evidence of chronically elevated systemic inflammation, they do exhibit significantly increased susceptibility to post-traumatic OA (PTOA).ConclusionsTwo types of data support the hypothesis that altered NOD/RIPK2 signalling confers susceptibility to OA.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility

Jurynec

Annals of the Rheumatic Diseases

Honeggar

et al. 2022

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“…To determine if there was excess familial clustering of severe CMCJ OA in each pedigree, we utilized a threshold of ≥ 2·0 for the Familial Standardized Incidence Ratio (FSIR). FSIR allows for the quantification of familial risk of a disease by comparing the incidence of a disease in a family to its expected incidence in the general population (Supplemental Data) (25, 28).…”

Section: Methodsmentioning

confidence: 99%

“…Given that few genes have been associated with CMCJ OA, there is clearly a need to identify more pathways that have a strong contribution to disease susceptibility. One way to identify genes with a determinant effect on disease is to study families that have severe forms of disease (23)(24)(25)(26)(27). Our criteria to identify a unique CMCJ OA cohort with potentially severe disease (requiring surgical management and excluding confounding factors) makes identifying large, multigenerational families unambiguous.…”

Section: Introductionmentioning

confidence: 99%

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

Kazmers

Novak

et al. 2022

Preprint

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Objectives: The 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. Methods: We 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. Results: We 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. Conclusions: Familial 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.

“…FSIR allows for the quantification of familial risk of a disease by comparing the incidence of a disease in a family to its expected incidence in the general population. See Kazmers, 2021 and Kazmers, 2020 for detailed methods 45,46 . Pedigrees segregating a dominant pattern of OA inheritance were selected for genomic analysis.…”

Section: Identification Of Families With a Dominant Pattern Of Oa Inh...mentioning

confidence: 99%

The NOD/RIPK2 signaling pathway contributes to osteoarthritis susceptibility

Jurynec

Honeggar

et al. 2022

Preprint

Self Cite

Osteoarthritis (OA) is a debilitating disease characterized by loss of homeostasis of the joint with consequent remodeling of tissue architecture1. The molecular pathways that limit disease onset or progression are unknown, and consequently no disease-modifying drugs are available. We sought genes that contribute to dominant forms of hereditary OA with the aim of identifying pathways whose activity level contributes to OA susceptibility. We found seven independent alleles affecting the NOD/RIPK2 pathway. To determine if altered signaling is sufficient to confer heightened OA susceptibility, mice carrying the OA-associated hyperactive Ripk2104Asp allele were generated. Knees of heterozygous Ripk2104Asp mice exhibit no overt signs of joint remodeling. Nevertheless, the mice respond to injury with markedly advanced post-traumatic OA. Uninjured heterozygous Ripk2104Asp mice appear primed to develop OA: their knees exhibit elevated NOD/RIPK2 pathway activity, localized inflammation, and altered expression of extracellular matrix genes linked to OA. In contrast to the joint, the mice display no evidence of systemic elevated inflammation. Elevated NOD/RIPK2 signaling confers vulnerability to OA.