Identification of a Novel Genetic Marker for Risk of Degenerative Rotator Cuff Disease Surgery in the UK Biobank

J Bone Joint Surg Am. 2021 Jul 21;103(14):1259-1267. doi: 10.2106/JBJS.20.01474.

Abstract

Background: While evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data.

Methods: Cases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis of traumatic injury had been made during the same hospital visit. For each case, up to 5 controls matched by age, sex, and follow-up time were chosen from the UK Biobank. Analyses were limited to European-ancestry individuals who were not third-degree or closer relations. We used logistic regression to test for genetic association of 674,405 typed and >10 million imputed markers, after adjusting for age, sex, population principal components, and follow-up.

Results: We identified 2,917 RCD surgery cases and 14,158 matched controls. We observed 1 genome-wide significant signal (p < 5 × 10-8) for a novel locus tagged by rs2237352 in the CREB5 gene on chromosome 7 (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.11 to 1.24). The single-nucleotide polymorphism (SNP) rs2237352 was imputed with a high degree of confidence (info score = 0.9847) and is common, with a minor allele frequency of 47%. After expanding the control sample to include additional unmatched non-cases, rs2237352 and another SNP in the CREB5 gene, rs12700903, were genome-wide significant. We did not detect genome-wide significant signals at loci associated with RCD in previous studies.

Conclusions: We identified a novel association between a variant in the CREB5 gene and RCD surgery. Validation of this finding in studies with imaging data to confirm diagnoses will be an important next step.

Clinical relevance: Identification of genetic RCD susceptibility markers can guide understanding of biological processes in rotator cuff degeneration and help inform disease risk in the clinical setting.

Level of evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Biological Specimen Banks / statistics & numerical data
  • Biomarkers / analysis
  • Case-Control Studies
  • Cyclic AMP Response Element-Binding Protein A / genetics*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Orthopedic Procedures / statistics & numerical data*
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Risk Assessment / methods
  • Risk Assessment / statistics & numerical data
  • Rotator Cuff / pathology*
  • Rotator Cuff / surgery
  • Rotator Cuff Injuries / epidemiology
  • Rotator Cuff Injuries / genetics*
  • Rotator Cuff Injuries / pathology
  • Rotator Cuff Injuries / surgery
  • United Kingdom

Substances

  • Biomarkers
  • CREB5 protein, human
  • Cyclic AMP Response Element-Binding Protein A