| Title: | Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis |
| Journal: | Journal of the American Heart Association |
| Published: | 20 Dec 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34927447/ |
| DOI: | https://doi.org/10.1161/jaha.121.023277 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/JAHA.121.023277 |
Publication 10877
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Abstract
Background Although trials suggest that anti-inflammatory approaches targeting interleukin (IL)-6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL-6 signaling could reduce risk additively to low-density lipoprotein cholesterol (LDL-C) lowering. Here, we assess interactions in associations of genetic downregulation of IL-6 signaling and LDL-C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL-6 signaling downregulation and LDL-C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL-6 signaling, lower LDL-C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL-6 and LDL-C scores above the median, individuals with LDL-C scores lower than the median but IL-6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93-0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93-0.98) was estimated for individuals with genetic IL-6 scores below the median but LDL-C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90-0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; P for multiplicative interaction=0.51). Genetic IL-6 score below the median was associated with lower cardiovascular disease risk across measured LDL-C strata (<100 or ≥100 mg/dL). Conclusions Genetically downregulated IL-6 signaling and genetically lowered LDL-C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL-6 inhibition and LDL-C lowering treatments for cardiovascular prevention.</p>
4 Authors
- Marios K Georgakis
- Rainer Malik
- Stephen Burgess
- Martin Dichgans
1 Application
| Application ID | Title |
|---|---|
| 2532 | UK Biobank Stroke Study (UKBiSS): developing an in-depth understanding of the determinants of stroke and its subtypes |
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