Inflammatory biomarkers and risk of ischemic stroke and subtypes: A 2-sample Mendelian randomization study

ABSTRACT

Objective: Chronic inflammation is considered as playing an important role in the pathophysiology of atherosclerosis, but the exact contributing inflammatory pathway on stroke is not clear. We aimed to examine the causal association of inflammatory biomarkers, such as interleukin-1 receptor antagonist (IL-1Ra), soluble interleukin-6 receptor (sIL-6R) and C-reactive protein (CRP), with the risk of ischemic stroke and its subtypes.

Methods: Two-sample mendelian randomization analyses were performed using IL-1Ra, sIL-6R and CRP related genetic variants as instrumental variables. Summary-level data on ischemic stroke and its subtypes were obtained from the largest GWAS meta-analysis on stroke to date – the Multiancestry Genome-wide Association Study of Stroke (MEGASTROKE) consortium. Associations of IL-1Ra with stroke or its subtypes were estimated using inverse-variance weighted (IVW) method with SNPs rs6743376 and rs1542176 as instruments. Wald ratio method with SNP rs2228145 as the instrument was used for sIL-6R and IVW, MR-Egger, simple and weighted median approaches with 4- or 18-SNPs instruments were used for CRP.

Results: Genetically elevated ln(IL-1Ra), ln(sIL-6R) and ln(CRP) levels were not causally associated with ischemic stroke (OR = 1.00, 95% CI: 0.97–1.04, p = 0.80; OR = 0.93, 95% CI: 0.87–0.99, p = 0.03; OR = 1.01, 95% CI: 0.94–1.09, p = 0.78). No significant association was observed between ln(IL-1Ra), ln(sIL-6R) and ln(CRP) level and ischemic stroke subtypes.

Conclusions: Our study did not find convincing evidence to support that inflammatory biomarkers like IL-1Ra, sIL-6R and CRP are causally associated with the risk of ischemic stroke or its subtypes.

KEYWORDS:

• IL-1Ra
• CRP
• Inflammation
• Mendelian randomization
• Stroke

Acknowledgments

Data on stroke have been contributed by MEGASTROKE investigators and have been downloaded from http://megastroke.org. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. The MEGASTROKE consortium represents a large-scale international collaboration launched by the International Stroke Genetics Consortium, and releases the summary statistics from the 2018 meta-analysis of GWAS data in stroke and stroke subtypes. Participants were drawn from 29 studies with genome-wide genotypes imputed to 1000 Genomes Project (1000G) phase 1v3 or similar. The MEGASTROKE consortium tested ~8 million SNPs and indels with minor-allele frequency ≥0.01 in up to 67,162 stroke cases and 454,450 controls for association with stroke. Analyses were performed for any stroke (n = 67,162); any ischemic stroke regardless of subtype (n = 60,341); and ischemic stroke subtypes (large-artery atherosclerosis, n = 6,688; small-artery occlusion, n = 11,710; cardioembolism, n = 9,006). The MEGASTROKE consortium involved participants of European (40,585 cases; 406,111 controls), East Asian (17,369; 28,195), African (5,541; 15,154), South Asian (2,437; 6,707), mixed Asian (365; 333), and Latin American (865; 692) ancestry. The present study involved European participants only (40,585 cases; 406,111 controls).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study is supported by grants from the National Natural Science Foundation of China [81971091], Beijing Hospitals Authority Youth Programme [QML20190501], Ministry of Science and Technology of the People’s Republic of China [2016YFC0901002, 2016YFC0901001, 2017YFC1310901, 2017YFC1310902, 2017YFC1307905, 2018YFC1311700 and 2018YFC1311706], Beijing Municipal Administration of Hospitals [SML20150502], Beijing Municipal Science & Technology Commission [D171100003017002, D151100002015003] and National Science and Technology Major Project [2017ZX09304018].

Notes on contributors

Jinxi Lin

Jinxi Lin is a researcher in China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital. She is also a neurologistwith more than 17 years experiences in stroke research. She got the PhD degree on neurology in March 2002. She has several publications in research of cerebrovascular disease.

Yilong Wang

Yilong Wang is a neurologist in Beijing Tiantan Hospital, advisor of PhD and MD of Capital Medical University. He is also a clinical researcher with more than 15 years experiences in stroke clinical research. He has several publications in clinical research of ischemic stroke and cerebral small vessel diseases. He also provides continuing education lectures regarding clinical research and stroke.

Yongjun Wang

Yongjun Wang is a neurologist in Beijing Tiantan Hospital, advisor of PhD and MD of Capital Medical University. He is the vice director of China Stroke Association. He has several publications in clinical research of ischemic stroke and transit ischemic attack, especially the antiplatelet therapy of minor stroke and transit ischemic attack. Chief editor of Stroke & Vascular Neurology and Chinese Stroke Journal. He also provides continuing education lectures regarding neurology and stroke.

Yuesong Pan

Yuesong Pan is a researcher in China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital. He is a clinical epidemiologist with more than 10 years experiences in stroke clinical research. He got the PhD degree on clinical epidemiology and biostatistics in July 2018. He has several publications in clinical research of stroke. He has also presented numerous oral presentations or posters at national and international stroke conferences. He also provides continuing education lectures regarding clinical research method and biostatistics.