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Research

From hemophilia to heart attacks

By Sharon Gray

From discovering the founder mutations for mild hemophilia A in two populations in the province to researching the genomics of human complex diseases including myocardial infarction and stroke, Dr. Yagang Xie is making a significant contribution to genetic research in Newfoundland and Labrador.

Dr. Xie combines clinical research with his duties as director of the Molecular Genetics Laboratory and chief of the Division of Immunology, Cytogenetics and Molecular Genetics for Eastern Health. He is an associate professor in the Discipline of Laboratory Medicine in the Faculty of Medicine.

Dr. Xie’s first research project was a study on mild hemophilia A in one large community in a rural area of Newfoundland and one community in Labrador. In collaboration with other researchers, two founder mutations of the factor VIII gene were identified – one mutation accounts for all Newfoundland patients with mild hemophilia A and the other accounts for all Labrador patients with mild hemophilia A.

“The knowledge of the Newfoundland founder mutation has been successfully translated into clinical service,” said Dr. Xie. “All patients in the Newfoundland population have been tested and population screening has been provided to the local population. The further characterization for the Labrador founder mutation is in process and will be transferred to clinical services in the near future.”

A second project of Dr. Xie’s is on the rare and severe bleeding disorder inherited FXIII deficiency. Newfoundland and Labrador has the highest prevalence of this disorder in Canada. Through a DNA study on patients from different families, Dr. Xie’s research team successfully discovered a Newfoundland specific mutation in the FXIII-A gene which accounts for all of the patients. Clinical service for molecular testing this identified mutation is now in preparation and studies are underway to provide further proof of a founder effect.

Dr. Xie’s genetic research is not limited to bleeding disorders. He is also searching for genetic susceptibility in heredity colon cancers including familial adenomatous polyposis (FAP) and attenuated FAP (AFAP). These two diseases usually present with multiple polyps in the colon and frequently progress to colon cancer. Illness and mortality are reduced when at-risk individuals are followed with a colonoscopy screening program and the colon removed surgically when multiple polyps are identified.

The screening program is most efficient when the family-specific mutation in the APC (adenomatosis polyposis coli) gene is known and genetic testing is offered, so that only mutation-positive individuals require colonoscopy screening.

Dr. Xie said once this project is completed, the molecular diagnosis of these mutations will be set up as a clinical service for people in the province. This will help to provide early disease prevention and genetic counselling for patients with FAP/AFAP and their families.

Other research Dr. Xie is involved in is looking at the genetic predisposition for cardiovascular disease. “Myocardial infarction (MI) is a complex disease resulting from a life-long interplay between genetic and environmental factors,” he explained. “The genetic components of MI are known to be the combined effects of a number of genes, with each playing only a small role. Effects of the complicated gene-gene/allele-allele interaction and variable genetic modifiers in different complex populations cause inconsistent or discordant results in most genetic association studies on MI. Our use of the province’s large genetically homogenous populations and the investigation of gene-gene/allele-allele interaction may help to identify mild genetic risk factors and help pin point their corresponding genetically modifiers.”

Using the Newfoundland and Labrador population, Dr. Xie’s research team has successfully associated a number of genes to MI, and they have also reported two novel gene-gene and allele-allele as strong genetic predisposition to MI.

Some of Dr. Xie’s research findings have been published in important scientific journals such as BLOOD and Thrombosis and Haemotasis, and some of these have been patented. He also has a number of manuscripts in preparation.

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