People who experience an arterial ischemic stroke (AIS) or transient ischemic stroke (TIA) are at an increased risk of suffering a second stroke or other major adverse cardiovascular event (MACE), making it critically important to identify risk factors and treatments to prevent these subsequent occurrences.
A research team headed by scientists at the Boston University School of Public Health (BUSPH), the National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre (Bristol BRC), and Veteran’s Affairs Boston Healthcare System (VA Boston), have now identified two proteins, CCL27 and TNFRSF14, that are associated with subsequent MACE, but not with initial stroke. These proteins are known to activate inflammation, which plays a key role in the development of strokes and many chronic conditions and diseases. The findings suggest that inflammation is a contributing factor to MACE outcomes among people after they have their first stroke.
The collective findings could unveil new pathways for treating patients after they experience their first stroke, the investigators suggested. “While previous studies have found associations between inflammation and incident AIS/MACE, our study found that these causal proteins may also have a role in subsequent MACE, which could lead to potential novel drug targets,” said Nimish Adhikari, a PhD student in biostatistics at BUSPH and VA Boston.
Adhikari, and Andrew Elmore, senior research associate in health data science at NIHR Bristol BRC, are co-lead authors of the team’s published paper in Stroke, which is titled “Protein Identification for Stroke Progression via Mendelian Randomization in Million Veteran Program and UK Biobank.” In their paper the team concluded, “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.”
Stroke remains a significant public health concern worldwide, the authors noted. Arterial ischemic stroke (AIS) accounts for about 85% of all stroke cases, and is caused by occlusion of cerebral blood vessels.
For their newly reported study, the team turned to genetic information and medical history data from two large biobanks, the VA’s Million Veteran Program and UK Biobank. They conducted ancestry-specific genome-wide association studies (GWAS) to find associations between DNA and incident and subsequent AIS and MACE. “In this study, we perform GWAS of subsequent AIS and MACE after incident AIS in the Million Veteran Program (MVP) and UK Biobank (UKB) stratified by ancestry and meta-analyzed across ancestries … We then use our subsequent events GWAS to perform MR for plasma protein abundances using protein quantitative trait loci (pQTLs) from UKB Pharma Proteomics Project.”
GWAS are typically performed to determine whether individuals have had a medical event for the first time, but applying this method to subsequent MACE events could shed novel insights about stroke progression, information that would be valuable for therapeutic drug identification, the researchers say.
In total, the researchers examined 93,422 individuals who had an incident stroke, among which 51,929 had subsequent MACE and 45,120 had subsequent AIS. In population specific analyses, they observed two significant genetic variants: rs76472767, near gene RNF220 on chromosome 1 in the African ancestry GWAS for subsequent MACE, and rs13294166, near gene LINC01492 on chromosome 9 in the same ancestry GWAS for subsequent AIS.
“There were no genome-wide significant associations in the multiancestry meta-analysis for subsequent AIS or MACE events,” the team commented in their paper, “but we did observe 2 genome-wide significant (P<5 x 10−8) genetic variants in specific ancestry analyses: rs76472767 near gene RNF220 on chromosome 1 in the African ancestry GWAS for subsequent MACE … and rs13294166 near gene LINC01492 on chromosome 9 in the African ancestry GWAS for subsequent AIS … ”
Elmore further explained, “We used that data to find if there were certain molecules that were associated with either incident or subsequent states. From that, we were able to identify a link between certain molecules that play a part in inflammation and these stroke and MACE outcomes.” The team expanded, “We also performed MR to identify putative causal proteins for risk of subsequent MACE in patients with stroke. We observed putatively causal evidence for 2 novel proteins (CCL27 and TNFRS14) associated with subsequent MACE risk in pQTL, suggesting that inflammation is a contributing factor to subsequent MACE outcomes after incident stroke AIS.” These proteins were not found to be associated with incident AIS, the team further commented.
While the prevalence of stroke has declined worldwide over the last three decades, it is still the second-leading cause of death and third-leading cause of disability across the globe, and it remains a significant public health issue. Stroke also continues to disproportionately affect populations among racial, ethnic, socioeconomic, and geographical lines, furthering health inequities in both high- and low-income countries. Identifying novel drug targets for new therapeutic interventions that thwart stroke progression could save millions of people from experiencing stroke-related disability and mortality. It’s unknown if targeting other modifiable risk factors for stroke could also offer pathways for effective treatment after someone experiences their first stroke. “We are looking forward to extending this research to other cardiometabolic outcomes beyond stroke,” says co-senior and corresponding author Gina Peloso, PhD, associate professor of biostatistics at BUSPH.
