What genetic connections are there in the pathogenesis of stroke between different descent groups?

What genetic connections are there in the pathogenesis of stroke between different descent groups?

In a recent study published in Nature Researchers identified genetic links to stroke pathogenesis.

Lernen: Die Schlaganfallgenetik beeinflusst die Entwicklung von Arzneimitteln und die Risikovorhersage bei allen Abstammungslinien. Bildquelle: sfam_photo/Shutterstock

Stroke accounts for approximately 12% of deaths worldwide and is the second leading cause of death. Stroke is mainly caused by cerebral ischemia and, less commonly, by intracerebral hemorrhage (ICH). The main etiologic subtypes of cerebral ischemia are cardioembolic stroke (CES), large artery atherosclerotic stroke (LAS), and small vessel stroke (SVS).

The frequency of stroke subtypes varies by ancestry, with the prevalence of ICH and SVS being increased in Africans and Asians compared to Europeans. Stroke-associated genetic loci have been identified primarily in individuals of European ancestry. The most comprehensive genome-wide association study (GWAS) meta-analysis (MEGASTROKE) to date has identified 32 stroke risk loci.

The study and results

In the present study, researchers examined genetic associations with stroke pathogenesis. The fixed-effect inverse variance-weighted (IVW) GWAS meta-analysis included 29 population-based cohorts with 110,182 stroke patients and 1,503,898 controls. The study population included individuals of the following ancestry: European, East Asian, African American, South Asian, and Hispanic.

Analyzes were performed for each ischemic stroke (AIS) regardless of subtype, ischemic stroke subtype (ICH, SVS, CES, LAS), and each stroke (AS). In IVW meta-analyses, more than 7.5 million single nucleotide polymorphisms (SNPs) were tested for associations with stroke. The researchers identified stroke-associated variants at 60 loci with genome-wide significance, including 33 new loci.

Most associations for these loci were with AS (48, 22 new) and AIS (48, 18 new). AIS subtypes were not available for some cohorts. Nevertheless, genome-wide significance was achieved for seven loci for SVS, eight for CES, and four for LAS. In cross-lineage meta-analyses, genome-wide significance was achieved for 53 loci. Thirty-five loci were genome-wide significant in Europeans, six in East Asians, two in African Americans, and one in South Asians.

Three new genome-wide significant loci were identified for AS in a secondary cross-ancestry GWAS using multi-ancestry genetic association meta-regression (MR-MEGA). In addition, secondary multi-trait analyzes of GWAS (MTAG) were performed in Europeans and East Asians to improve the statistical power of AIS subtypes by including stroke subtype-correlated features.

In Europeans, the authors identified 11 additional loci associated with LAS, five with SVS and three with CES. A total of 89 (including 61 new) loci were identified as stroke risk loci in primary (IVW) and secondary (MTAG and MR-MEGA) analyses.

Pathway analysis of the versatile gene-based association study 2 (VEGAS2) showed significant enrichment of stroke risk loci in pathways involved in 1) the negative regulation of coagulation, 2) the carboxylation of amino-terminal glutamate residues to activate coagulation-related proteins, and 3) the pathways mediated by the Angiopoietin receptor Tie2-mediated signaling is involved.

Next, a three-pronged approach to genomically guided drug discovery for stroke prevention/treatment was implemented. First, the authors observed significant enrichment of genomes for repositioning drugs (GREP) for stroke-associated genes in drug target genes for hematopoietic organs and blood.

Second, using Trans-Phar to assess negative correlations between genetically determined and compound-regulated gene expression profiles, the authors observed negative correlations of GR.32191 (thromboxane A2 receptor antagonist) for CES and BRD.A22514244 (drug target unknown) for SVS. Third, they found causal associations between nine plasma proteins and stroke risk using Protein Quantitative Trait Loci (pQTL).

In addition, the team examined whether a genetic risk score (GRS) based on risk loci from cross-ancestry IVW meta-analyses of AS could identify individuals at increased risk of AIS by accounting for clinical risk factors in five clinical trials across the spectrum of cardiometabolic diseases. The primary analysis included 51,288 Europeans; Of these, 960 developed AIS over a period of three years. Higher GIGASTROKE-GRS was associated with increased risk of AIS in Europeans. This connection was more robust than that of previous MEGASTROKE GRS.

Conclusions

The GWAS meta-analyses of more than 1.6 million participants from five different ancestries identified 89 stroke risk locations and stroke subtypes. Sixty loci were identified by primary IVW analyzes and 29 by secondary MTAG and MR-MEGA analyses. There was significant susceptibility to stroke across all lineages. The confidence level for these loci was medium/high for 87% of the primary risk loci and 60% of the secondary loci.

Using data from five clinical trials in patients with cardiometabolic diseases, the authors showed that cross-lineage GRS predicted ischemic stroke independent of clinical risk factors. Although the trials primarily involved Europeans, consistent results were found among smaller East Asian participants. These results have provided critical insights into the pathogenesis of stroke that can serve as a basis for future research, developed tools to predict genetic risk across the lineage, and identified potential drug targets for intervention.

Reference:

• Mishra, A., Malik, R., Hachiya, T. et al. (2022). Die Schlaganfallgenetik beeinflusst die Entwicklung von Arzneimitteln und die Risikovorhersage bei allen Abstammungslinien. Natur. doi: https://doi.org/10.1038/s41586-022-05165-3 https://www.nature.com/articles/s41586-022-05165-3

.