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Y chromosome loss links to cancer and Alzheimer’s

dumanski-forsberg-photo-mikael-wallerstedt

Men have a shorter lifespan than women and Uppsala University researchers might have an explanation.

Why do women tend to live longer than men? Why do men have higher cancer risks than women? Research led by Professor Jan Dumanski and Assistant Professor Lars Forsberg, Department of Immunology, Genetics and Pathology, Uppsala University, suggests that loss of chromosome Y (LOY) is a factor. With age, our cells acquire mutations, including chromosome loss. Only men’s cells have Y chromosomes, though, so their absence might explain sex differences in disease risk and lifespan.

“When we get old,” Dumanski says, “our three most common diagnoses are cardiovascular problems, cancer, and neurodegenerative disorders such as Alzheimer’s disease. Loss of chromosome Y appears to be linked to each of these.”

In 2015, studies from the Dumanski and Forsberg groups in Science and Nature Genetics showed that LOY is associated with higher cancer risk and smoking is associated with higher LOY risk. These results might explain why men have higher risks of smoking- and nonsmoking-related cancers than women. In addition, scientists in the Netherlands have evidence that LOY is associated with cardiovascular events. The latest paper from Dumanski, Forsberg and colleagues, in American Journal of Human Genetics, shows that LOY is linked to increased risk of Alzheimer’s disease.

Chromosome Y and immune system function

The Uppsala scientists have access to diverse, longitudinal data and blood samples for several large cohorts of European adults. Genotyping blood from men determines the presence and extent of LOY. Data on individual characteristics including behavior, diagnoses, and deaths is used to find associations between LOY and conditions such as Alzheimer’s disease. LOY is fairly common. It is found in about 16% of men in one of the study cohorts, with higher frequencies in older men.

“We have evidence suggesting that LOY is related to immune system defects,” Dumanski says. Poor immunosurveillance would explain how LOY increases risk of cardiovascular disease, if the immune system doesn’t remove atherosclerotic plaques, and cancer and Alzheimer’s, if the system doesn’t recognize and eliminate abnormal cells. Dumanski, Forsberg and their teams are continuing to test the hypothesis that LOY reduces immune function. They are seeking to expand their studies by exploring funding for a larger, prospectively genotyped cohort.

Since LOY can be assessed from a simple blood sample, in 2014, Dumanski and Forsberg started CRAY Innovation (for Cancer Risk Assessment from loss of Y). Their company seeks commercial and academic partnerships to develop clinical tests to improve disease diagnoses based on the strong links between LOY and increased risk of mortality, cancer, and Alzheimer’s disease.

 

Reference:

Dumanski JP, Lambert J-C, Rasi C, Giedraitis V, Davies H, Grenier-Boley B, Lindgren CM, Campion D, Dufouil C, The European Alzheimer’s Disease Initiative Investigators, Pasquier F, Amouyel P, Lannfelt L, Ingelsson M, Kilander L, Lind L, Forsberg LA. Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease. Am J Hum Genet, 2016; 98: 1–12.

 

Photo showing Jan Dumanski and Lars Forsberg, Photo: Mikael Wallerstedt

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