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  1. Article ; Online: Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort.

    Kazmers, Nikolas H / Meeks, Huong D / Novak, Kendra A / Yu, Zhe / Fulde, Gail L / Thomas, Joy L / Barker, Tyler / Jurynec, Michael J

    Arthritis & rheumatology (Hoboken, N.J.)

    2021  Volume 73, Issue 3, Page(s) 440–447

    Abstract: Objective: Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that ... ...

    Abstract Objective: Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA.
    Methods: Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models.
    Results: We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05).
    Conclusion: Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Cluster Analysis ; Cohort Studies ; Databases, Factual ; Female ; Finger Joint/diagnostic imaging ; Finger Joint/pathology ; Hand Joints/diagnostic imaging ; Hand Joints/pathology ; Humans ; Incidence ; Male ; Middle Aged ; Osteoarthritis/diagnostic imaging ; Osteoarthritis/epidemiology ; Osteoarthritis/genetics ; Osteoarthritis/pathology ; Pedigree ; Proportional Hazards Models ; Risk Factors ; Utah/epidemiology ; Young Adult
    Language English
    Publishing date 2021-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.41520
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility.

    Jurynec, Michael J / Gavile, Catherine M / Honeggar, Matthew / Ma, Ying / Veerabhadraiah, Shivakumar R / Novak, Kendra A / Hoshijima, Kazuyuki / Kazmers, Nikolas H / Grunwald, David J

    Annals of the rheumatic diseases

    2022  Volume 81, Issue 10, Page(s) 1465–1473

    Abstract: Objectives: How 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 ... ...

    Abstract Objectives: How 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
    Methods: Genomic 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
    Results: We 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
    Conclusions: Two types of data support the hypothesis that altered NOD/RIPK2 signalling confers susceptibility to OA.
    MeSH term(s) Alleles ; Animals ; Cytokines/metabolism ; Inflammation/genetics ; Mice ; Osteoarthritis/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism ; Signal Transduction/genetics
    Chemical Substances Cytokines ; Receptor-Interacting Protein Serine-Threonine Kinase 2 (EC 2.7.11.1) ; Ripk2 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2022-06-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/annrheumdis-2022-222497
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort.

    Gavile, Catherine M / Kazmers, Nikolas H / Novak, Kendra A / Meeks, Huong D / Yu, Zhe / Thomas, Joy L / Hansen, Channing / Barker, Tyler / Jurynec, Michael J

    The Journal of hand surgery

    2022  Volume 47, Issue 10, Page(s) 923–933

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Carpometacarpal Joints/surgery ; Chondroitin Sulfates ; Cluster Analysis ; Female ; Genetic Predisposition to Disease ; Humans ; Osteoarthritis/epidemiology ; Thumb
    Chemical Substances Chondroitin Sulfates (9007-28-7)
    Language English
    Publishing date 2022-09-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 605716-0
    ISSN 1531-6564 ; 0363-5023
    ISSN (online) 1531-6564
    ISSN 0363-5023
    DOI 10.1016/j.jhsa.2022.08.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

    Styrkarsdottir, Unnur / Stefansdottir, Lilja / Thorleifsson, Gudmar / Stefansson, Olafur A / Saevarsdottir, Saedis / Lund, Sigrun H / Rafnar, Thorunn / Hoshijima, Kazuyuki / Novak, Kendra / Oreiro, Natividad / Rego-Perez, Ignacio / Hansen, Channing / Kazmers, Nikolas / Kiemeney, Lambertus A / Blanco, Francisco J / Barker, Tyler / Kloppenburg, Margreet / Jurynec, Michael J / Gudbjartsson, Daniel F /
    Jonsson, Helgi / Thorsteinsdottir, Unnur / Stefansson, Kari

    Annals of the rheumatic diseases

    2023  Volume 82, Issue 6, Page(s) 873–880

    Abstract: Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA.: ... ...

    Abstract Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA.
    Methods: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits.
    Results: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (
    Conclusions: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.
    MeSH term(s) Animals ; Hand Joints/diagnostic imaging ; Zebrafish/genetics ; Hand ; Osteoarthritis/complications ; Arthritis, Rheumatoid/complications
    Language English
    Publishing date 2023-03-17
    Publishing country England
    Document type Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/ard-2022-223468
    Database MEDical Literature Analysis and Retrieval System OnLINE

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