PDF(Pubmed)
Abstract：
UNASSIGNED: Common genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears (RCTs). We hypothesize that rare variants contribute to symptomatic RCTs and that they can be identified in related cases with a full-thickness tear requiring surgical management.
UNASSIGNED: We used the Utah Population Database to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full-thickness RCT. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full-thickness RCT (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full-thickness RCTs.
UNASSIGNED: A total of 82 rare (minor allele frequency <0.005) coding variants were identified as shared in at least one cousin pair affected with full-thickness rotator cuff tearing belonging to a high-risk pedigree, which included variants in RUNX1, ADAM12, TGFBR2, APBB1, PDLIM7, LTBP1, MAP3K4, and MAP3K1. Analysis of 39 of these variants with data available in the UK Biobank (3899 cases with rotator cuff injury and 11,697 matched controls; mean case age 59.9 years) identified a significant association with the APBB1 gene (OR = 2.37, P = .007, uncorrected). The PDLIM7 allele was found to be in significant excess in RCT cases in a separate cohort of Utah patients with full-thickness RCTs (10 carriers out of 458 independent, unrelated patients; minor allele frequency of 0.022) compared to a minor allele frequency of 0.0058 for the European (non-Finnish) control population rate (749 carriers out of 128612 tested) (chi-square test: 19.3 [P < .001]).
UNASSIGNED: The analysis of closely related individuals with confirmed full-thickness RCTs from high-risk pedigrees has identified 82 rare, shared candidate genetic predisposition coding variants. Association of the PDLIM7 allele with risk for tear was confirmed in an independent cohort of RCTs. Further analysis of the variant alleles is required for confirmation of these genes in rotator cuff tearing.
UNASSIGNED: We used the Utah Population Database to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full-thickness RCT. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full-thickness RCT (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full-thickness RCTs.
UNASSIGNED: A total of 82 rare (minor allele frequency <0.005) coding variants were identified as shared in at least one cousin pair affected with full-thickness rotator cuff tearing belonging to a high-risk pedigree, which included variants in RUNX1, ADAM12, TGFBR2, APBB1, PDLIM7, LTBP1, MAP3K4, and MAP3K1. Analysis of 39 of these variants with data available in the UK Biobank (3899 cases with rotator cuff injury and 11,697 matched controls; mean case age 59.9 years) identified a significant association with the APBB1 gene (OR = 2.37, P = .007, uncorrected). The PDLIM7 allele was found to be in significant excess in RCT cases in a separate cohort of Utah patients with full-thickness RCTs (10 carriers out of 458 independent, unrelated patients; minor allele frequency of 0.022) compared to a minor allele frequency of 0.0058 for the European (non-Finnish) control population rate (749 carriers out of 128612 tested) (chi-square test: 19.3 [P < .001]).
UNASSIGNED: The analysis of closely related individuals with confirmed full-thickness RCTs from high-risk pedigrees has identified 82 rare, shared candidate genetic predisposition coding variants. Association of the PDLIM7 allele with risk for tear was confirmed in an independent cohort of RCTs. Further analysis of the variant alleles is required for confirmation of these genes in rotator cuff tearing.
摘要：
■具有小效应大小的常见遗传变异与肩袖撕裂有关，尽管很少见，已经确定了高度渗透的变体。这项初步研究的目的是确定在肩袖撕裂（RCT）高风险的家系中与受影响个体分离的显性编码变体。我们假设罕见变异有助于有症状的RCT，并且可以在需要手术治疗的全层撕裂的相关病例中识别出它们。
■我们使用犹他州人口数据库来确定已接受全层RCT手术修复的个体的家系。我们分析了整个外显子组序列分析，以鉴定9个独立受影响的表亲对（第一或第二表亲）中的罕见编码变异，这些表亲对接受了关节镜手术以修复全层RCT（诊断时的平均年龄68岁）。利用UKBiobank的数据和单独的全层RCT无关病例队列，验证了候选变体与肩袖撕裂风险的关联。
■总共82个罕见的（次要等位基因频率<0.005）编码变体被鉴定为在至少一个表亲对中共享，患有属于高风险谱系的全厚度肩袖撕裂，其中包括RUNX1、ADAM12、TGFBR2、APBB1、PDLIM7、LTBP1、MAP3K4和MAP3K1中的变体。在英国生物银行（3899例肩袖损伤和11,697个匹配对照；平均病例年龄59.9岁）中，对39种变异进行了分析，发现与APBB1基因存在显着关联（OR=2.37，P=.007，未校正）。PDLIM7等位基因在不同的犹他州全厚度RCT患者的RCT病例中发现明显过量（458个独立携带者中的10个，非相关患者；次要等位基因频率为0.022），而欧洲（非芬兰）对照人群的次要等位基因频率为0.0058（测试128612中有749个携带者）（卡方检验：19.3[P<.001]）。
■对来自高风险家谱的确诊全厚度随机对照试验的密切相关个体进行分析，发现82例罕见，共享候选遗传易感性编码变体。PDLIM7等位基因与撕裂风险的关联在独立的RCT队列中得到证实。需要进一步分析变体等位基因以确认肩袖撕裂中的这些基因。
■我们使用犹他州人口数据库来确定已接受全层RCT手术修复的个体的家系。我们分析了整个外显子组序列分析，以鉴定9个独立受影响的表亲对（第一或第二表亲）中的罕见编码变异，这些表亲对接受了关节镜手术以修复全层RCT（诊断时的平均年龄68岁）。利用UKBiobank的数据和单独的全层RCT无关病例队列，验证了候选变体与肩袖撕裂风险的关联。
■总共82个罕见的（次要等位基因频率<0.005）编码变体被鉴定为在至少一个表亲对中共享，患有属于高风险谱系的全厚度肩袖撕裂，其中包括RUNX1、ADAM12、TGFBR2、APBB1、PDLIM7、LTBP1、MAP3K4和MAP3K1中的变体。在英国生物银行（3899例肩袖损伤和11,697个匹配对照；平均病例年龄59.9岁）中，对39种变异进行了分析，发现与APBB1基因存在显着关联（OR=2.37，P=.007，未校正）。PDLIM7等位基因在不同的犹他州全厚度RCT患者的RCT病例中发现明显过量（458个独立携带者中的10个，非相关患者；次要等位基因频率为0.022），而欧洲（非芬兰）对照人群的次要等位基因频率为0.0058（测试128612中有749个携带者）（卡方检验：19.3[P<.001]）。
■对来自高风险家谱的确诊全厚度随机对照试验的密切相关个体进行分析，发现82例罕见，共享候选遗传易感性编码变体。PDLIM7等位基因与撕裂风险的关联在独立的RCT队列中得到证实。需要进一步分析变体等位基因以确认肩袖撕裂中的这些基因。
