Multi-omic analysis of stroke recurrence in African Americans from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial

Abstract

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2–3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.

Lipidomic signature of stroke recurrence after transient ischemic attack

“…Recent studies analyzing different bio uids (serum and urine) from a metabolomic approach have demonstrated, comparing stroke patients with healthy controls, the presence of speci c metabolic pro les ascribed to changes in fatty acids, amino acids, choline metabolism, phospholipids, sphingolipids, and folate one-carbon cycle [34][35][36][37][38] . These few works collectively reveal the complexity of analyzing and discern metabolic events associated with stroke and the identi cation of unambiguous biomarkers.…”

Genetic plasma biomarkers associated with ischemic stroke

“…A metabolomic-epigenetics study investigated the stroke recurrence in an African American population [49]. Thus, the alkaline ceramidase 2 (ACER2) locus encoding ACER2, sphingosine, and sphinganine were associated with five common variants and one different variant [rs10757056 (sphingosine only), rs10118089, rs7020745, rs10125228, rs10757058, and rs10118371].…”

“…Thus, the alkaline ceramidase 2 (ACER2) locus encoding ACER2, sphingosine, and sphinganine were associated with five common variants and one different variant [rs10757056 (sphingosine only), rs10118089, rs7020745, rs10125228, rs10757058, and rs10118371]. The most significant association included leukotriene B4 and rs7025659-SPTLC1 (P = 6.12e-07; post-hoc comparison between TG to GG genotypes, P = 3.00E-07) [49]. Further, individuals with IS and high leukotriene B4 levels were linked to less successful functional recovery [50].…”