Background/Purpose: Erosive osteoarthritis (EOA) of the hand is a characterized radiographically with centrally-located interphalangeal joint erosions, and clinically by its rapid onset, rapid rate of progression, and potential for substantial disability and deformity.  Although an association between a single nucleotide polymorphism in the interleukin-1β gene has been demonstrated for EOA in a small case-control study, it remains unclear whether this condition has a genetic basis and there remains a lack of understanding of the underlying pathophysiology. Our purpose was to determine whether EOA clusters in families, which would suggest a genetic etiologic contribution.  Secondarily, we performed genomic analyses on one high-risk family with EOA to identify candidate genes that have a significant contribution to the onset and progression of EOA.

Methods: EOA patients were identified by ICD-10 code (M15.4), then mapped to pedigrees using methods developed by the Utah Population Database (UPDB).   The UPDB is a collection of >10 million individuals in multigenerational pedigrees dating back to the late 1700’s which are linked to >30 million medical records.  High-risk families with excess clustering of EOA were identified using the Familial Standardized Incidence Ratio (FSIR) threshold of ≥ 2.0. The magnitude of familial risk was calculated using relative risk from Cox regression models to determine the relative risk of EOA in related individuals using a ratio of 1:10 affected individuals to controls.  Genomic analyses were performed as previously reported.

Results: We identified 231 unrelated high-risk pedigrees with an FSIR ≥ 2.0 (top pedigrees illustrated in Table 1).  Of the 580 affected individuals within these pedigrees, mean age at diagnosis was 66 ± 11.0 years and 80.1% were female. The relative risk of developing EOA was significantly elevated in first-degree relatives (RR 30.51; 95% confidence interval 3.3 – 282.4; p = 0.0026).  Genomic analyses in one EOA family consisting of two distantly related affected individuals and one unaffected sibling (Figure 1) identified a rare coding variant in the procollagen galactosyltransferase COLGALT1 (Arg326Cys, AF – 0.00009)  (Figure 2).

Conclusion: Our finding of excess familial clustering of hand EOA patients indicates a significant genetic contribution to the etiology of the disease.  Although functional testing is still underway, we have identified a coding  variant associated with EOA – namely COLGALT1, a gene involved with glycosylation of hydroxylated lysines in procollagen.⁶  These results, and those to be gained through whole-exome sequencing of additional identified high-risk pedigrees, may lead to an improved understanding of EOA pathophysiology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-genetic-variants-associated-with-erosive-hand-osteoarthritis-using-pedigrees-from-a-state-wide-population-based-cohort/