Kim Stuart K, Khan Condor, Ladd Amy L, Tashjian Robert Z
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
J Shoulder Elbow Surg. 2023 Jan;32(1):174-185. doi: 10.1016/j.jse.2022.07.005. Epub 2022 Aug 17.
The etiology of adhesive capsulitis involves inflammation, thickening, and fibrosis of the shoulder capsule. The underlying genetic factors are poorly understood. The purpose of this study was to identify genetic variants associated with adhesive capsulitis using the UK Biobank (UKB) cohort and compare them with variants associated with Dupuytren disease investigating a common etiology between the 2 fibrotic disorders.
A genome-wide association study (GWAS) was performed using data from UKB with 10,773 cases of adhesive capsulitis, and a second GWAS was performed with 8891 cases of Dupuytren disease. Next, a comparison of association statistics was performed between adhesive capsulitis and Dupuytren disease using the data from both GWAS. Finally, single-nucleotide polymorphisms (SNPs) previously reported from candidate gene studies for adhesive capsulitis and Dupuytren disease were tested for association with adhesive capsulitis and Dupuytren disease using the summary statistics from their respective GWAS.
The UKB GWAS for adhesive capsulitis identified 6 loci that reached genome-wide statistical significance: a cluster of 11 closely linked SNPs on chromosome 1; a single SNP on chromosome 2; a single SNP on chromosome 14; 2 closely linked SNPs on chromosome 21; 33 closely linked SNPs on chromosome 22; and 3 closely linked SNPs on the X chromosome. These SNPs were associated with 8 different genes including TSPAN2/NGF, SATB2, MRPL52/MMP14, ERG, WNT7B, and FGF13. A GWAS for Dupuytren disease was performed and a comparison to the adhesive capsulitis GWAS showed 13 loci significantly associated with both phenotypes. A validation attempt of 6 previously reported SNPs associated with adhesive capsulitis using UKB summary statistics was unable to confirm any of the previously reported SNPs (all P > .19). All 23 previously reported SNPs associated with Dupuytren disease were confirmed using the UKB summary statistics (P < 2.1 × 10) CONCLUSION: This GWAS investigating adhesive capsulitis has identified 6 novel loci involving 8 different genes to be associated with adhesive capsulitis. A GWAS investigating Dupuytren disease was performed and compared to the adhesive capsulitis GWAS, and 13 common loci were identified between the 2 disorders with genes involved in pathologic fibrosis. We were unable to validate the SNPs in candidate genes previously reported to be associated with adhesive capsulitis although we were able to confirm all previously reported SNPs associated with Dupuytren disease. The strong genetic overlap between the adhesive capsulitis and Dupuytren disease loci suggests a similar etiology between the 2 diseases.
粘连性关节囊炎的病因涉及肩关节囊的炎症、增厚和纤维化。其潜在的遗传因素尚不清楚。本研究的目的是利用英国生物银行（UKB）队列确定与粘连性关节囊炎相关的基因变异，并将其与与掌腱膜挛缩症相关的变异进行比较，以研究这两种纤维化疾病之间的共同病因。
使用UKB的数据对10773例粘连性关节囊炎患者进行全基因组关联研究（GWAS），并对8891例掌腱膜挛缩症患者进行第二次GWAS。接下来，利用两个GWAS的数据对粘连性关节囊炎和掌腱膜挛缩症的关联统计进行比较。最后，使用各自GWAS的汇总统计数据，对先前候选基因研究中报道的与粘连性关节囊炎和掌腱膜挛缩症相关的单核苷酸多态性（SNP）进行与粘连性关节囊炎和掌腱膜挛缩症的关联测试。
UKB对粘连性关节囊炎的GWAS确定了6个达到全基因组统计显著性的基因座：1号染色体上一组11个紧密连锁的SNP；2号染色体上1个SNP；14号染色体上1个SNP；21号染色体上2个紧密连锁的SNP；22号染色体上33个紧密连锁的SNP；以及X染色体上3个紧密连锁的SNP。这些SNP与8个不同的基因相关，包括TSPAN2/NGF、SATB2、MRPL52/MMP14、ERG、WNT7B和FGF13。对掌腱膜挛缩症进行了GWAS，并与粘连性关节囊炎的GWAS进行比较，结果显示有13个基因座与两种表型均显著相关。使用UKB汇总统计数据对先前报道的6个与粘连性关节囊炎相关的SNP进行验证，未能确认任何先前报道的SNP（所有P>.19）。使用UKB汇总统计数据确认了先前报道的所有23个与掌腱膜挛缩症相关的SNP（P<2.1×10）。结论：这项针对粘连性关节囊炎的GWAS确定了6个新的基因座，涉及8个不同的基因与粘连性关节囊炎相关。对掌腱膜挛缩症进行了GWAS，并与粘连性关节囊炎的GWAS进行比较，在这两种疾病之间确定了13个共同的基因座，涉及参与病理性纤维化的基因。尽管我们能够确认所有先前报道的与掌腱膜挛缩症相关的SNP，但我们无法验证先前报道的与粘连性关节囊炎相关的候选基因中的SNP。粘连性关节囊炎和掌腱膜挛缩症基因座之间的强烈遗传重叠表明这两种疾病之间病因相似。
