Trans-ethnic Mendelian randomization study of systemic lupus erythematosus and common female hormone-dependent malignancies

Tingting Zhu; Yantao Ding; Xiaoli Xu; Liyin Zhang; Xuejun Zhang; Yong Cui; Lu Liu

doi:10.1097/CM9.0000000000002555

Trans-ethnic Mendelian randomization study of systemic lupus erythematosus and common female hormone-dependent malignancies

Chin Med J (Engl). 2023 Nov 5;136(21):2609-2620. doi: 10.1097/CM9.0000000000002555.

Authors

Tingting Zhu^{1

2

3

4}, Yantao Ding^{1

2

3}, Xiaoli Xu^{1

2

3}, Liyin Zhang⁵, Xuejun Zhang^{1

2

3}, Yong Cui⁶, Lu Liu^{1

2

3}

Affiliations

¹ Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
² Institute of Dermatology, Anhui Medical University, Hefei, Anhui 230022, China.
³ Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui 230022, China.
⁴ Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
⁵ Department of Dermatology, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214001, China.
⁶ Department of Dermatology, China-Japan Friendship Hospital, Beijing 100029, China.

Abstract

Background: Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis.

Methods: We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results.

Results: We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P = 0.002). The statistical powers of positive MR results were all >0.9.

Conclusion: This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.

MeSH terms

Breast Neoplasms*
Carcinoma, Endometrioid*
Endometrial Neoplasms*
Female
Genome-Wide Association Study
Humans
Lupus Erythematosus, Systemic* / genetics
Mendelian Randomization Analysis
Neoplasms, Hormone-Dependent*
Polymorphism, Single Nucleotide
Reproducibility of Results