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Protein Identification for Stroke Progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Authors :
Elmore AR
Adhikari N
Hartley AE
Aparicio HJ
Posner DC
Hemani G
Tilling K
Gaunt TR
Wilson PWF
Casas JP
Gaziano JM
Davey Smith G
Paternoster L
Cho K
Peloso GM
Source :
Stroke [Stroke] 2024 Aug; Vol. 55 (8), pp. 2045-2054. Date of Electronic Publication: 2024 Jul 22.
Publication Year :
2024

Abstract

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.<br />Methods: We performed genome-wide association studies for subsequent major adverse cardiovascular events (MACE; n <subscript>cases</subscript> =51 929; n <subscript>controls</subscript> =39 980) and subsequent arterial ischemic stroke (AIS; n <subscript>cases</subscript> =45 120; n <subscript>controls</subscript> =46 789) after the first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (protein quantitative trait loci) to determine the effect of 1463 plasma protein abundances on subsequent MACE using Mendelian randomization.<br />Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 near gene RNF220 (odds ratio, 0.75 [95% CI, 0.64-0.85]; P =3.69×10 <superscript>-8</superscript> ) with subsequent AIS and rs13294166 near gene LINC01492 (odds ratio, 1.52 [95% CI, 1.37-1.67]; P =3.77×10 <superscript>-8</superscript> ) with subsequent MACE. Using Mendelian randomization, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 ([C-C motif chemokine 27], effect odds ratio, 0.77 [95% CI, 0.66-0.88]; adjusted P =0.05) and TNFRSF14 ([tumor necrosis factor receptor superfamily member 14], effect odds ratio, 1.42 [95% CI, 1.24-1.60]; adjusted P =0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation.<br />Conclusions: We found evidence that 2 proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.<br />Competing Interests: Dr Tilling reports grants from the National Institute for Health and Care Research; grants from Wellcome Trust; and grants from Medical Research Council. Dr Gaunt reports grants from the National Institute for Health and Care Research (UK); grants from Biogen; grants from UK Medical Research Council; and grants from GlaxoSmithKline. Dr Gaziano reports grants from the US Department of Veterans Affairs. Dr Davey Smith reports grants from the Medical Research Council. Dr Peloso reports support from Veterans Health Administration; employment by Boston University; compensation from the American Heart Association for consultant services; and grants from the National Institutes of Health. Dr Hartley started working for Novo Nordisk after contributing to this article. The other authors report no conflicts.

Details

Language :
English
ISSN :
1524-4628
Volume :
55
Issue :
8
Database :
MEDLINE
Journal :
Stroke
Publication Type :
Academic Journal
Accession number :
39038097
Full Text :
https://doi.org/10.1161/STROKEAHA.124.047103