Editor's Choice| Volume 47, ISSUE 10, P923-933, October 2022

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


      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.


      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.


      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).


      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

      JHS Podcast

      October 3, 2022

      JHS Podcast Episode 79

      Dr. Graham interviews Drs. Mick Jurynec and Nik Kazmers about their paper “Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort”, which is the lead article in the October 2022 issue of the Journal of Hand Surgery.

      Loading ...
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hand Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Marshall M.
        • Watt F.E.
        • Vincent T.L.
        • Dziedzic K.
        Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management.
        Nat Rev Rheumatol. 2018; 14: 641-656
        • Kloppenburg M.
        • Kwok W.Y.
        Hand osteoarthritis--a heterogeneous disorder.
        Nat Rev Rheumatol. 2011; 8: 22-31
        • Kloppenburg M.
        • van Beest S.
        • Kroon F.P.B.
        Thumb base osteoarthritis: a hand osteoarthritis subset requiring a distinct approach.
        Best Pract Res Clin Rheumatol. 2017; 31: 649-660
        • Gillis J.
        • Calder K.
        • Williams J.
        Review of thumb carpometacarpal arthritis classification, treatment and outcomes.
        Can J Plast Surg. 2011; 19: 134-138
        • Zhang Y.
        • Niu J.
        • Kelly-Hayes M.
        • Chaisson C.E.
        • Aliabadi P.
        • Felson D.T.
        Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: the Framingham Study.
        Am J Epidemiol. 2002; 156: 1021-1027
        • Moriatis Wolf J.
        • Turkiewicz A.
        • Atroshi I.
        • Englund M.
        Prevalence of doctor-diagnosed thumb carpometacarpal joint osteoarthritis: an analysis of Swedish health care.
        Arthritis Care Res (Hoboken). 2014; 66: 961-965
        • Wilder F.V.
        • Barrett J.P.
        • Farina E.J.
        Joint-specific prevalence of osteoarthritis of the hand.
        Osteoarthr Cartil. 2006; 14: 953-957
        • Jonsson H.
        • Valtysdottir S.T.
        • Kjartansson O.
        • Brekkan A.
        Hypermobility associated with osteoarthritis of the thumb base: a clinical and radiological subset of hand osteoarthritis.
        Ann Rheum Dis. 1996; 55: 540-543
        • Jonsson H.
        • Eliasson G.J.
        • Jonsson A.
        • et al.
        High hand joint mobility is associated with radiological CMC1 osteoarthritis: the AGES-Reykjavik study.
        Osteoarthr Cartil. 2009; 17: 592-595
        • Rydberg M.
        • Dahlin L.B.
        • Gottsater A.
        • Nilsson P.M.
        • Melander O.
        • Zimmerman M.
        High body mass index is associated with increased risk for osteoarthritis of the first carpometacarpal joint during more than 30 years of follow-up.
        RMD Open. 2020; 6e001368
        • Halilaj E.
        • Moore D.C.
        • Patel T.K.
        • Ladd A.L.
        • Weiss A.P.
        • Crisco J.J.
        Early osteoarthritis of the trapeziometacarpal joint is not associated with joint instability during typical isometric loading.
        J Orthop Res. 2015; 33: 1639-1645
        • Ramos Y.F.
        • Meulenbelt I.
        Implementation of functional genomics for bench-to-bedside transition in osteoarthritis.
        Curr Rheumatol Rep. 2015; 17: 53
        • Thysen S.
        • Luyten F.P.
        • Lories R.J.
        Targets, models and challenges in osteoarthritis research.
        Dis Model Mech. 2015; 8: 17-30
        • Hirsch R.
        • Lethbridge-Cejku M.
        • Hanson R.
        • et al.
        Familial aggregation of osteoarthritis: data from the Baltimore Longitudinal Study on Aging.
        Arthritis Rheum. 1998; 41: 1227-1232
        • Spector T.D.
        • Cicuttini F.
        • Baker J.
        • et al.
        Genetic influences on osteoarthritis in women: a twin study.
        BMJ. 1996; 312: 940-943
        • Jonsson H.
        • Manolescu I.
        • Stefansson S.E.
        • Ingvarsson T.
        • et al.
        The inheritance of hand osteoarthritis in Iceland.
        Arthritis Rheum. 2003; 48: 391-395
        • Stefansson S.E.
        • Jonsson H.
        • Ingvarsson T.
        • et al.
        Genomewide scan for hand osteoarthritis:a novel mutation in matrilin-3.
        Am J Hum Genet. 2003; 72: 1448-1459
        • Boer C.G.
        • Yau M.S.
        • Rice S.J.
        • et al.
        Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene.
        Ann Rheum Dis. 2020;
        • Hunter D.J.
        • Demissie S.
        • Cupples L.A.
        • Aliabadi P.
        • Felson D.T.
        A genome scan for joint-specific hand osteoarthritis susceptibility: the Framingham Study.
        Arthritis Rheum. 2004; 50: 2489-2496
        • Boer C.G.
        • Hatzikotoulas K.
        • Southam L.
        • Stefansdottir L.
        • Zhang Y.
        • Coutinho de Almeida R.
        • et al.
        Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
        Cell. 2021; 184: 4784-4818.e17
        • den Hollander W.
        • Boer C.G.
        • Hart D.J.
        • et al.
        Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.
        Ann Rheum Dis. 2017; 76: 2046-2053
        • Styrkarsdottir U.
        • Thorleifsson G.
        • Helgadottir H.T.
        • et al.
        Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.
        Nat Genet. 2014; 46: 498-502
        • Ramos Y.F.
        • Bos S.D.
        • van der Breggen R.
        • et al.
        A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis.
        Ann Rheum Dis. 2015; 74: 1756-1762
        • Jurynec M.J.
        • Sawitzke A.D.
        • Beals T.C.
        • et al.
        A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.
        Hum Mol Genet. 2018; 27: 2406
        • Kazmers N.H.
        • Meeks H.D.
        • Novak K.A.
        • Yu Z.
        • Fulde G.L.
        • Thomas J.L.
        • et al.
        Familial clustering of erosive hand osteoarthritis in a large statewide cohort.
        Arthritis Rheumatol. 2020;
        • Freund M.K.
        • Burch K.S.
        • Shi H.
        • et al.
        Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits.
        Am J Hum Genet. 2018; 103: 535-552
        • Kazmers N.H.
        • Yu Z.
        • Barker T.
        • Abraham T.
        • Romero R.
        • Jurynec M.J.
        Evaluation for Kienbock disease familial clustering: a population-based cohort study.
        J Hand Surg Am. 2020; 45: 1-8 e1
        • Kerber R.A.
        Method for calculating risk associated with family history of a disease.
        Genet Epidemiol. 1995; 12: 291-301
        • Haugen I.K.
        • Englund M.
        • Aliabadi P.
        • et al.
        Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham osteoarthritis study.
        Ann Rheum Dis. 2011; 70: 1581-1586
        • Haugen I.K.
        • Magnusson K.
        • Turkiewicz A.
        • Englund M.
        The prevalence, incidence, and progression of hand osteoarthritis in relation to body mass index, smoking, and alcohol consumption.
        J Rheumatol. 2017; 44: 1402-1409
        • Marshall M.
        • Peat G.
        • Nicholls E.
        • van der Windt D.
        • Myers H.
        • Dziedzic K.
        Subsets of symptomatic hand osteoarthritis in community-dwelling older adults in the United Kingdom: prevalence, inter-relationships, risk factor profiles and clinical characteristics at baseline and 3-years.
        Osteoarthritis Cartilage. 2013; 21: 1674-1684
        • Soul J.
        • Hardingham T.E.
        • Boot-Handford R.P.
        • Schwartz J.M.
        SkeletalVis: an exploration and meta-analysis data portal of cross-species skeletal transcriptomics data.
        Bioinformatics. 2019; 35: 2283-2290
        • Yada T.
        • Sato T.
        • Kaseyama H.
        al. Chondroitin sulfate synthase-3. Molecular cloning and characterization.
        J Biol Chem. 2003; 278: 39711-39725
        • Aubourg G.
        • Rice S.J.
        • Bruce-Wootton P.
        • Loughlin J.
        Genetics of osteoarthritis.
        Osteoarthritis Cartilage. 2022; 30: 636-649
        • Ruault V.
        • Yauy K.
        • Fabre A.
        • et al.
        Clinical and molecular spectrum of nonsyndromic early-onset osteoarthritis.
        Arthritis Rheumatol. 2020; 72: 1689-1693
        • Sliz E.
        • Taipale M.
        • Welling M.
        • et al.
        TUFT1, a novel candidate gene for metatarsophalangeal osteoarthritis, plays a role in chondrogenesis on a calcium-related pathway.
        PLoS One. 2017; 12e0175474
        • Ishimaru D.
        • Sugiura N.
        • Akiyama H.
        • Watanabe H.
        • Matsumoto K.
        Alterations in the chondroitin sulfate chain in human osteoarthritic cartilage of the knee.
        Osteoarthritis Cartilage. 2014; 22: 250-258
        • Wei L.
        • Cao P.
        • Xu C.
        • et al.
        Chondroitin synthase-3 regulates nucleus pulposus degeneration through actin-induced YAP signaling.
        FASEB J. 2020; 34: 16581-16600
        • arc O.C.
        • arc O.C.
        • Zeggini E.
        • et al.
        Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.
        Lancet. 2012; 380: 815-823
        • Sebastian A.
        • Chang J.C.
        • Mendez M.E.
        • et al.
        Comparative transcriptomics identifies novel genes and pathways involved in post-traumatic osteoarthritis development and progression.
        Int J Mol Sci. 2018; 19: 2657
        • Naot D.
        • Grey A.
        • Reid I.R.
        • Cornish J.
        Lactoferrin--a novel bone growth factor.
        Clin Med Res. 2005; 3: 93-101
        • Yang Z.
        • Ni J.
        • Kuang L.
        • Gao Y.
        • Tao S.
        Identification of genes and pathways associated with subchondral bone in osteoarthritis via bioinformatic analysis.
        Medicine (Baltimore). 2020; 99e22142
        • Walker J.G.
        • Ahern M.J.
        • Coleman M.
        • et al.
        Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis.
        Ann Rheum Dis. 2006; 65: 149-156
        • Rai M.F.
        • Schmidt E.J.
        • Hashimoto S.
        • Cheverud J.M.
        • Sandell L.J.
        Genetic loci that regulate ectopic calcification in response to knee trauma in LG/J by SM/J advanced intercross mice.
        J Orthop Res. 2015; 33: 1412-1423
        • Kang D.
        • Shin J.
        • Cho Y.
        • et al.
        Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development.
        Sci Transl Med. 2019; 11: eaar6659
        • Waterborg C.E.J.
        • Koenders M.I.
        • van Lent P.
        • van der Kraan P.M.
        • van de Loo F.A.J.
        Tyro3/Axl/Mertk-deficient mice develop bone marrow edema which is an early pathological marker in rheumatoid arthritis.
        PLoS One. 2018; 13e0205902
        • van den Brand B.T.
        • Abdollahi-Roodsaz S.
        • Vermeij E.A.
        • et al.
        Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.
        Arthritis Rheum. 2013; 65: 671-680
        • Cai X.
        • Xing J.
        • Long C.L.
        • Peng Q.
        • Humphrey M.B.
        DOK3 Modulates Bone Remodeling by Negatively Regulating Osteoclastogenesis and Positively Regulating Osteoblastogenesis.
        J Bone Miner Res. 2017; 32: 2207-2218
        • Jurynec M.J.
        • Gavile C.M.
        • Honeggar M.
        • et al.
        NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility.
        Ann Rheum Dis. 2022; 81: 1465-1473