Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study

Kun Xiang; Peng Wang; Zhiwei Xu; Yu-Qian Hu; Yi-Sheng He; Yue Chen; Ya-Ting Feng; Kang-Jia Yin; Ji-Xiang Huang; Jie Wang; Zheng-Dong Wu; Xiao-Ke Yang; De-Guang Wang; Dong-Qing Ye; Hai-Feng Pan

doi:10.3389/fimmu.2021.667097

Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study

Front Immunol. 2021 Sep 7:12:667097. doi: 10.3389/fimmu.2021.667097. eCollection 2021.

Authors

Kun Xiang^{1

2}, Peng Wang³, Zhiwei Xu⁴, Yu-Qian Hu^{1

2}, Yi-Sheng He^{1

2}, Yue Chen^{1

2}, Ya-Ting Feng^{1

2}, Kang-Jia Yin^{1

2}, Ji-Xiang Huang^{1

2}, Jie Wang^{1

2}, Zheng-Dong Wu^{1

2}, Xiao-Ke Yang⁵, De-Guang Wang⁶, Dong-Qing Ye^{1

2}, Hai-Feng Pan^{1

2}

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
² Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.
³ Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Medical College, Suzhou, China.
⁴ School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁵ Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁶ Department of Nephrology, Second Affiliated Hospital of Anhui Medical University, Hefei, China.

Abstract

The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10^-8) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10^-5) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

Keywords: Mendelian randomization; autoimmune disease; causality; gut microbiome; systemic lupus erythematosus.

MeSH terms

Bacteria / growth & development*
Dysbiosis
Gastrointestinal Microbiome*
Gene-Environment Interaction*
Genome-Wide Association Study
Humans
Intestines / microbiology*
Lupus Erythematosus, Systemic / diagnosis
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / microbiology*
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide*
Protective Factors
Risk Assessment
Risk Factors