Identification of a Novel Genetic Marker for Risk of Degenerative Rotator Cuff Disease Surgery in the UK Biobank.
Identification of a Novel Genetic Marker for Risk of Degenerative Rotator Cuff Disease Surgery in the UK Biobank.
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DOI：
10.2106/jbjs.20.01474
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发表时间：
2021-07-21
期刊：
影响因子：
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通讯作者：
Saccone NL
中科院分区：
文献类型：
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作者：
Yanik EL;Keener JD;Lin SJ;Colditz GA;Wright RW;Evanoff BA;Jain NB;Saccone NL
虽然有证据表明，家族易感性影响退行性肩袖病(RCD)的风险，但对特定遗传标记的了解有限。我们使用英国生物库进行了一项关于RCD手术的全基因组相关性研究，这是一组年龄在40-69岁之间的500,000人的前瞻性队列，在登记时使用了基因数据。使用相关的医院记录识别退行性RCD手术病例。病例被定义为存在ICD-10代码M75.1，由创伤/骨科专家诊断，并伴随与RCD治疗一致的手术。如果创伤诊断是在同一医院就诊，则排除这些病例。对于每个病例，从英国生物库中选择了最多五个年龄、性别和随访时间匹配的对照组。分析仅限于不是三级或更接近的欧洲血统的人。我们使用Logistic回归来检验674,405个类型和>；1000万个归类标记的遗传关联性，这些标记调整了年龄、性别、人群主成分和随访。我们确定了2917例RCD手术病例和14,158名匹配的对照组。我们在第7染色体上的−基因rs2237352标记的一个新的基因座上观察到一个全基因组显著信号(p值和lt；5×10 CREB8)(OR=1.17，95%CI=1.11-1.24)。单核苷酸多态(Rs2237352)具有较高的置信度(INFO分数=0.9847)，具有较高的可信度，其等位基因频率为47%。在扩大对照样本以包括其他不匹配的非病例后，rs2237352和CREB5基因上的另一个SNP rs12700903在全基因组范围内具有显著意义。在以前的研究中，我们没有在与RCD相关的基因座上检测到全基因组的显著信号。我们发现CREB5基因的一个变异与RCD手术之间存在一种新的关联。在用成像数据确认诊断的研究中验证这一发现将是重要的。识别遗传的RCD易感标记可以指导对袖带退变的生物学过程的理解，并有助于在临床环境中告知疾病风险。
While evidence indicates that familial predisposition influences degenerative rotator cuff disease (RCD) risk, knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using UK Biobank, a prospective cohort of 500,000 people aged 40–69 at enrollment with genotype data. Degenerative RCD surgery cases were identified using linked hospital records. Cases were defined as presence of ICD-10 code M75.1 diagnosed by a trauma/orthopedic specialist with accompanying surgery consistent with RCD treatment. Cases were excluded if traumatic injury diagnoses were made during the same hospital visit. For each case up to five controls were chosen from UK Biobank matched by age, sex, and follow-up time. Analyses were limited to European-ancestry individuals who were not third degree or closer. We used logistic regression to test for genetic association of 674,405 typed and >10 million imputed markers adjusting for age, sex, population principal components, and follow-up. We identified 2,917 RCD surgery cases and 14,158 matched controls. We observed one genome-wide significant signal (p-value<5×10−8) for a novel locus tagged by rs2237352 in the CREB5 gene on chromosome 7 (OR=1.17, 95%CI=1.11–1.24). 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 on the CREB5 gene, rs12700903, were genome-wide significant. We did not detect genome-wide significant signals at loci associated with RCD in previous studies. 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 important. Identification of genetic RCD susceptibility markers can guide understanding of biological processes in cuff degeneration and help inform disease risk in the clinical setting.