Table_2_Diseases of the musculoskeletal system and connective tissue and risk of breast cancer: Mendelian randomization study in European and East Asian populations.docx

ObjectiveAssociations between diseases of the musculoskeletal system and connective tissue (MSCTD) and breast cancer (BC) have not been elucidated completely. The purpose of this study was to investigate the associations of MSCTD, rheumatoid arthritis (RA), Sjogren syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), osteoarthritis (OA) of hip or knee, and ankylosing spondylitis (AS) with BC in European populations and East Asian populations using Mendelian randomized (MR) analysis.
MethodsThe genetic instruments linked to MSCTD, RA, SS, SLE, SSc, DM, PM, OA, and AS were chosen from the EBI database of complete genome-wide association studies (GWAS) summary data and the FinnGen consortium. The associations of genetic variants with BC were extracted from the Breast Cancer Association Consortium (BCAC). Two Sample MR was performed using summary data from GWAS, principally using the inverse variant weighted (IVW) method. Heterogeneity, pleiotropy, and sensitivity analyses were performed to evaluate the robustness of the results by weighted median, MR Egger, simple mode, weighted mode, and leave-one-out analysis.
ResultsIn the European population, causal relationships between RA and BC (OR=1.04, 95%CI: 1.01-1.07, P=0.023), AS and BC (OR=1.21, 95%CI: 1.06-1.36, P=0.013) were confirmed. IVW analysis showed DM (OR=0.98, 95%CI: 0.96-0.99, P=0.026) and PM (OR=0.98, 95%CI: 0.97-0.99, P=0.002) were associated with slightly decreased risks of estrogen receptor (ER)+ BC, and MSCTD was associated with an increased risk of ER- BC (OR=1.85, 95%CI: 1.27-2.44, P=0.039). There was no causal relationship between SLE, SS, SSc, OA, and BC, neither ER+ BC nor ER- BC. However, in the East Asian population, IVW analysis showed that RA (OR=0.94, 95%CI: 0.89-0.99, P=0.0096) and SLE (OR=0.95, 95%CI: 0.92-0.99, P=0.0058) was associated with decreased risks of BC.
ConclusionsThis study suggests that causal relationships between patients with MSCTD and BC in the European population are different from those in the East Asian population, patients with RA and AS in the European population have an increased risk of BC, patients with MSCTD have increased risk of ER- BC in the European population, while patients with RA and SLE in the East Asian population have decreased risk of BC.

研究目的：肌肉骨骼系统与结缔组织疾病（musculoskeletal system and connective tissue diseases, MSCTD）与乳腺癌（breast cancer, BC）之间的关联尚未完全阐明。本研究旨在利用孟德尔随机化（Mendelian randomized, MR）分析，探究欧洲人群与东亚人群中，MSCTD、类风湿关节炎（rheumatoid arthritis, RA）、干燥综合征（Sjogren syndrome, SS）、系统性红斑狼疮（systemic lupus erythematosus, SLE）、系统性硬化症（systemic sclerosis, SSc）、皮肌炎（dermatomyositis, DM）、多发性肌炎（polymyositis, PM）、髋/膝骨关节炎（osteoarthritis of hip or knee, OA）以及强直性脊柱炎（ankylosing spondylitis, AS）与BC的关联。
研究方法：本研究从全基因组关联研究（genome-wide association studies, GWAS）汇总数据的欧洲生物信息研究所（European Bioinformatics Institute, EBI）数据库以及FinnGen联盟中选取与MSCTD、RA、SS、SLE、SSc、DM、PM、OA及AS相关的遗传工具变量。乳腺癌关联联盟（Breast Cancer Association Consortium, BCAC）中提取了遗传变异与BC的关联数据。本研究采用基于GWAS汇总数据的两样本孟德尔随机化分析，主要采用逆方差加权（inverse variant weighted, IVW）法。通过加权中位数法、MR Egger法、简单众数法、加权众数法以及留一法分析进行异质性、多效性及敏感性分析，以评估研究结果的稳健性。
研究结果：在欧洲人群中，RA与BC、AS与BC的因果关联得到证实（OR=1.04，95%CI：1.01-1.07，P=0.023；OR=1.21，95%CI：1.06-1.36，P=0.013）。IVW分析显示，DM（OR=0.98，95%CI：0.96-0.99，P=0.026）与PM（OR=0.98，95%CI：0.97-0.99，P=0.002）分别与雌激素受体（estrogen receptor, ER）阳性乳腺癌的发病风险轻度降低相关，而MSCTD与ER阴性乳腺癌的发病风险升高相关（OR=1.85，95%CI：1.27-2.44，P=0.039）。SLE、SS、SSc及OA与BC（包括ER阳性乳腺癌及ER阴性乳腺癌）均无因果关联。而在东亚人群中，IVW分析显示，RA（OR=0.94，95%CI：0.89-0.99，P=0.0096）与SLE（OR=0.95，95%CI：0.92-0.99，P=0.0058）与BC的发病风险降低相关。
研究结论：本研究表明，欧洲人群与东亚人群中，MSCTD患者与BC的因果关联存在显著差异：欧洲人群中的RA患者与AS患者BC发病风险升高，MSCTD患者ER阴性乳腺癌发病风险升高；而东亚人群中的RA患者与SLE患者BC发病风险降低。