Researchers Identify Genetic Risk Factor for Stroke in Older Adults

January 21, 2021 - A gene variant found in approximately one in 300 people is a significant genetic risk factor for stroke in older adults, according to a study conducted by researchers at Geisinger.

Cerebral small vessel disease (SVD) causes about a quarter of ischemic strokes globally and is the most common cause of vascular dementia. SVD can manifest as lesions on the brain, which usually appear on brain scans. While SVD is commonly associated with aging and hypertension, a minority of cases are caused by cysteine altering variants in the NOTCH3 gene.

This gene variant appears in approximately one in 300 people, researchers noted. A rare hereditary condition known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – which is caused by a NOTCH3 variant – has been associated with SVD and an increased risk of stroke.

"Stroke is a complex multifactorial condition," said Vida Abedi, PhD, a scientist in the department of molecular and functional genomics at Geisinger and a co-author of the study. "Dissecting its risk factors and identifying ways to improve patient outcomes is a crucial part of improving patient care."

In a study published in Stroke, Geisinger researchers evaluated a set of health records, including imaging and genomic sequencing data, of more than 300 Geisinger patients – 118 of whom exhibited a NOTCH3 variant. Of this group, 12.6 percent had a history of stroke compared with 4.9 percent of those in a control group.

The risk of stroke was significantly higher in those older than 65, and patients showed a higher number of white matter lesions on the brain. Although all 118 patients in the study group had a NOTCH3 genetic variant, the specific variant that causes CADASIL was rarely seen.

Because of the high population frequency of NOTCH3 variants, the number of individuals who may be at higher risk of SVD and stroke as a result of a NOTCH3 variant is significant. The study suggests that most individuals with a NOTCH3 variant will develop NOTCH3-associated SVD after age 65.

"This study represents a novel and powerful approach to studying the genetic basis of neurologic disease," said Ramin Zand, MD, a vascular neurologist and clinician-scientist at Geisinger and co-author of the study. "Geisinger's unique resources, its electronic health records and focus on precision medicine allows us to leverage this data to provide better care for all of our patients."

Researchers are increasingly turning to genetic information to uncover insights about prevalent and deadly diseases. A recent study published in Cancer Research found that a significant number of breast cancer patients have higher levels of the ZMYND8 gene, making it a potential target for immunotherapies and precision medicine treatments.

“The gene ZMYND8 is increased in breast cancer conditions, and higher levels of the gene correlate with poor survival of breast cancer patients,” said Yingfei Wang, PhD, assistant professor of pathology and neurology and corresponding author of the study. “It could be a promising target for antitumor immunotherapy.”

In a separate study, a team from Children’s Hospital of Pennsylvania (CHOP) found that a genetic variable responsible for driving the development of inflammatory bowel disease (IBD) is associated with a genetic pathway that is involved in other immune disorders.

To conduct the study, researchers characterized the single nucleotide polymorphism (SNP) rs1887428, located on the promoter region of the JAK2 gene.

“Using this method, we believe we have added an important tool to our arsenal of SNP-to-gene assignment methods, allowing us to pinpoint disease-driving genetic mutations that have previously been difficult to properly assign risk,” said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP and senior author of the paper.

“This study in particular also provides evidence that drugs targeting JAK2 may provide some benefit for those patients suffering from IBD who carry mutations that upregulate the JAK2 pathway, though such precision-based approaches would need to be validated in clinical studies.”