Related Experiment Video
Updated: Aug 8, 2025
Author Spotlight: Exploring the Role of Inflammation in the Co-occurrence of Primary Sjogren's Syndrome and Lung Adenocarcinoma
Published on: September 20, 2024
Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension
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.
Insights
This study found that increased interleukin-6 signaling genetically reduces pulmonary arterial hypertension (PAH) risk, while increased soluble IL-6 receptor (sIL-6R) genetically increases PAH risk. These findings suggest IL-6 signaling is protective, and sIL-6R is a risk factor for PAH.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Immunology
Background:
- Previous Mendelian randomization (MR) studies did not establish a link between the interleukin-6 receptor (IL-6R) variant and pulmonary arterial hypertension (PAH) risk.
- Reassessing the genetic causal relationship between IL-6 signaling and PAH is crucial.
Purpose of the Study:
- To investigate the causal effect of IL-6 signaling and soluble IL-6 receptor (sIL-6R) on PAH risk using a two-sample MR design.
- To clarify the distinct roles of IL-6 signaling and sIL-6R in PAH pathogenesis.
Main Methods:
- Utilized two sets of genetic instrumental variables (IVs) for IL-6 signaling and sIL-6R.
- Employed publicly available genome-wide association studies (GWAS) data for PAH, including 162,962 European individuals.
- Performed a two-sample MR study to analyze the associations.
Main Results:
- Increased IL-6 signaling was genetically associated with a reduced risk of PAH (OR=0.023, p=0.0093).
- Increased sIL-6R was genetically associated with an increased risk of PAH (OR=1.34, p=0.0001).
- Consistent results were observed across multiple MR analysis methods (IVW, weighted median, MR-Egger).
Conclusions:
- Genetically elevated sIL-6R is a risk factor for increased PAH risk.
- Genetically elevated IL-6 signaling is a protective factor against PAH.
- Findings suggest distinct and opposing roles for IL-6 signaling and sIL-6R in PAH development.
More Related Videos
Related Concept Videos
01:20The JAK-STAT Signaling Pathway
01:30Pulmonary Hypertension: Classification and Pathogenesis
There are various classifications for PH, each relating to different underlying causes and also...
01:11Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...