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Abstract：
BACKGROUND: Previous studies have implicated rheumatoid arthritis as an independent risk factor for bone density loss. However, whether there is a causal relationship between rheumatic diseases and bone mineral density (BMD) and fractures is still controversial. We employed a bidirectional Mendelian analysis to explore the causal relationship between rheumatic diseases and BMD or fractures.
METHODS: The rheumatic diseases instrumental variables (IVs) were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. Analyses were performed for the three rheumatic diseases: ankylosing spondylitis (AS) (n = 22,647 cases, 99,962 single nucleotide polymorphisms [SNPs]), rheumatoid arthritis (RA) (n = 58,284 cases, 13,108,512 SNPs), and systemic lupus erythematosus (SLE) (n = 14,267 cases, 7,071,163 SNPs). Two-sample Mendelian randomization (MR) analyses were carried out by using R language TwoSampleMR version 0.5.7. The inverse-variance weighted (IVW), MR-Egger, and weighted median methods were used to analyze the causal relationship between rheumatic diseases and BMD or fracture.
RESULTS: The MR results revealed that there was absence of evidence for causal effect of AS on BMD or fracture. However, there is a positive causal relationship of RA with fracture of femur (95% CI = 1.0001 to 1.077, p = 0.046), and RA and fracture of forearm (95% CI = 1.015 to 1.064, p = 0.001). SLE had positive causal links for fracture of forearm (95% CI = 1.004 to 1.051, p = 0.020). Additionally, increasing in heel bone mineral density (Heel-BMD) and total bone mineral density (Total-BMD) can lead to a reduced risk of AS without heterogeneity or pleiotropic effects. The results were stable and reliable. There was absence of evidence for causal effect of fracture on RA (95% CI = 0.929 to 1.106, p = 0.759), and fracture on SLE (95% CI = 0.793 to 1.589, p = 0.516).
CONCLUSIONS: RA and SLE are risk factors for fractures. On the other hand, BMD increasing can reduce risk of AS. Our results indicate that rheumatic diseases may lead to an increased risk of fractures, while increased BMD may lead to a reduced risk of rheumatic diseases. These findings provide insight into the risk of BMD and AS, identifying a potential predictor of AS risk as a reduction in BMD.
METHODS: The rheumatic diseases instrumental variables (IVs) were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. Analyses were performed for the three rheumatic diseases: ankylosing spondylitis (AS) (n = 22,647 cases, 99,962 single nucleotide polymorphisms [SNPs]), rheumatoid arthritis (RA) (n = 58,284 cases, 13,108,512 SNPs), and systemic lupus erythematosus (SLE) (n = 14,267 cases, 7,071,163 SNPs). Two-sample Mendelian randomization (MR) analyses were carried out by using R language TwoSampleMR version 0.5.7. The inverse-variance weighted (IVW), MR-Egger, and weighted median methods were used to analyze the causal relationship between rheumatic diseases and BMD or fracture.
RESULTS: The MR results revealed that there was absence of evidence for causal effect of AS on BMD or fracture. However, there is a positive causal relationship of RA with fracture of femur (95% CI = 1.0001 to 1.077, p = 0.046), and RA and fracture of forearm (95% CI = 1.015 to 1.064, p = 0.001). SLE had positive causal links for fracture of forearm (95% CI = 1.004 to 1.051, p = 0.020). Additionally, increasing in heel bone mineral density (Heel-BMD) and total bone mineral density (Total-BMD) can lead to a reduced risk of AS without heterogeneity or pleiotropic effects. The results were stable and reliable. There was absence of evidence for causal effect of fracture on RA (95% CI = 0.929 to 1.106, p = 0.759), and fracture on SLE (95% CI = 0.793 to 1.589, p = 0.516).
CONCLUSIONS: RA and SLE are risk factors for fractures. On the other hand, BMD increasing can reduce risk of AS. Our results indicate that rheumatic diseases may lead to an increased risk of fractures, while increased BMD may lead to a reduced risk of rheumatic diseases. These findings provide insight into the risk of BMD and AS, identifying a potential predictor of AS risk as a reduction in BMD.
摘要：
背景：先前的研究表明类风湿性关节炎是骨密度丢失的独立危险因素。然而,风湿性疾病与骨矿物质密度（BMD）和骨折之间是否存在因果关系仍存在争议。我们采用双向孟德尔分析来探索风湿性疾病与BMD或骨折之间的因果关系。
方法：风湿性疾病工具变量（IVs）来自欧洲血统的大型全基因组关联研究（GWAS）荟萃分析数据集。分析了三种风湿性疾病：强直性脊柱炎（AS）（n=22,647例，99,962个单核苷酸多态性[SNP]），类风湿性关节炎（RA）（n=58,284例，13,108,512SNP)，系统性红斑狼疮（SLE）（n=14,267例，7,071,163个SNP）。通过使用R语言TwoSampleMR版本0.5.7进行两个样本孟德尔随机化（MR）分析。逆方差加权(IVW)，MR-Egger,采用加权中位数法分析风湿性疾病与BMD或骨折的因果关系。
结果：MR结果显示，没有证据表明AS对BMD或骨折有因果关系。然而,RA与股骨骨折呈正相关(95%CI=1.0001~1.077,p=0.046),RA和前臂骨折（95％CI=1.015至1.064，p=0.001）。SLE与前臂骨折有正的因果关系(95%CI=1.004~1.051,p=0.020)。此外,足跟骨矿物质密度（Heel-BMD）和总骨密度（Total-BMD）的增加可导致AS风险降低，而没有异质性或多效性作用。结果稳定可靠。没有证据表明骨折对RA的因果关系（95％CI=0.929至1.106，p=0.759），SLE骨折（95%CI=0.793～1.589，p=0.516）。
结论：RA和SLE是骨折的危险因素。另一方面,增加BMD可以降低AS的风险。我们的结果表明，风湿性疾病可能导致骨折的风险增加，而增加的BMD可能导致风湿性疾病的风险降低。这些发现提供了对BMD和AS风险的见解，将AS风险的潜在预测因子确定为BMD的降低。
方法：风湿性疾病工具变量（IVs）来自欧洲血统的大型全基因组关联研究（GWAS）荟萃分析数据集。分析了三种风湿性疾病：强直性脊柱炎（AS）（n=22,647例，99,962个单核苷酸多态性[SNP]），类风湿性关节炎（RA）（n=58,284例，13,108,512SNP)，系统性红斑狼疮（SLE）（n=14,267例，7,071,163个SNP）。通过使用R语言TwoSampleMR版本0.5.7进行两个样本孟德尔随机化（MR）分析。逆方差加权(IVW)，MR-Egger,采用加权中位数法分析风湿性疾病与BMD或骨折的因果关系。
结果：MR结果显示，没有证据表明AS对BMD或骨折有因果关系。然而,RA与股骨骨折呈正相关(95%CI=1.0001~1.077,p=0.046),RA和前臂骨折（95％CI=1.015至1.064，p=0.001）。SLE与前臂骨折有正的因果关系(95%CI=1.004~1.051,p=0.020)。此外,足跟骨矿物质密度（Heel-BMD）和总骨密度（Total-BMD）的增加可导致AS风险降低，而没有异质性或多效性作用。结果稳定可靠。没有证据表明骨折对RA的因果关系（95％CI=0.929至1.106，p=0.759），SLE骨折（95%CI=0.793～1.589，p=0.516）。
结论：RA和SLE是骨折的危险因素。另一方面,增加BMD可以降低AS的风险。我们的结果表明，风湿性疾病可能导致骨折的风险增加，而增加的BMD可能导致风湿性疾病的风险降低。这些发现提供了对BMD和AS风险的见解，将AS风险的潜在预测因子确定为BMD的降低。
