Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension

ABSTRACT

Background

A recent Mendelian randomization (MR) did not support an effect of the lead interleukin-6 receptor (IL-6 R) variant on risk of pulmonary arterial hypertension (PAH). Thus, we used two sets of genetic instrumental variants (IVs) and publicly available PAH genome-wide association studies (GWAS) to reassess the genetic causal link between IL-6 signaling and PAH.

Methods

Six independent IL-6 signaling and 34 independent soluble IL-6 receptor (sIL-6 R) genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study.

Results

We found that as IL-6 signaling genetically increased, the risk of PAH reduced using IVW (odds ratio [OR] = 0.023, 95% confidence interval [CI]: 0.0013–0.393; p = .0093) and weighted median (OR = 0.033, 95% CI: 0.0024–0.467; p = .0116). Otherwise, as sIL-6 R genetically increased, the risk of PAH increased using IVW (OR = 1.34, 95% CI: 1.16–1.56; p = .0001), weighted median (OR = 1.36, 95% CI: 1.10–1.68; p = .005), MR-Egger (OR = 1.43, 95% CI: 1.05–1.94; p = .03), and weighted mode (OR = 1.35, 95% CI for OR: 1.12–1.63; p = .0035).

Conclusion

Our analysis suggested the causal link between genetically increased sIL-6 R and increased risk of PAH and between genetically increased IL-6 signaling and reduced risk of PAH. Thus, higher sIL-6 R levels may be a risk factor for patients with PAH, whereas higher IL-6 signaling may be a protective factor for patients with PAH.

KEYWORDS:

• IL-6
• sIL-6R
• PAH
• Genome-wide association study
• Mendelian randomization

Abbreviations

PAH: pulmonary arterial hypertension; IL-6: interleukin-6; sIL-6R: soluble IL-6 receptor; GWAS: Genome-wide association study; MR: Mendelian randomization; SNP: Single nucleotide polymorphism; IVW: Inverse variance weighted.

Acknowledgments

We thank ieu open gwas project (https://gwas.mrcieu.ac.uk/datasets/) for providing summary results data for these analyses.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

RW conceived and initiated the project. SZ and GZ analyzed the data and wrote the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript, and approved the final version of the manuscript. All authors read and approved the final manuscript.

Data availablity statement

The summary statistics of pulmonary arterial hypertension (PAH) GWAS (GWAS ID: finn-b-I9_HYPTENSPUL) is available on ieu open gwas project at https://gwas.mrcieu.ac.uk/datasets/. The MR analysis code can be found at https://mrcieu.github.io/TwoSampleMR/articles/index.html.

Ethics statement

The study was reviewed and approved by the Ethics Committee of Beijing Institute of Brain Disorders in Capital Medical University.

Additional information

Funding

This study was supported by grants from R&D Program of Beijing Municipal Education Commission [Grant no: KZ202210025035]; National Natural Science Foundation of China [Grant no: 82071758 and 32270933].