If cancer, heart disease, and emphysema weren’t bad enough, male smokers may have another thing to worry about: losing their Y chromosomes. Researchers have found that smokers are up to four times more likely to have blood cells with no Y chromosome than nonsmokers. That’s worrisome, they say, because a recent study found an association between Y chromosome loss and a shorter life span, as well as a higher risk of multiple cancers.

There is, however, no direct proof that loss of Y sex chromosomes actually causes disease, cautions Stephen Chanock, a cancer geneticist at the National Cancer Institute in Bethesda, Maryland, who was not involved with the work.

To conduct the study, molecular oncologist Jan Dumanski and statistician Lars Forsberg of Uppsala University in Sweden took advantage of data collected from three ongoing Swedish trials. The long-term studies are looking for associations between behavioral, lifestyle, or other traits and disease. As part of the studies, data and blood are collected periodically. Dumanski and Forsberg compared the DNA in blood cells of smokers to nonsmokers in more than 6000 men. The only factors that correlated with high Y chromosome loss were age and smoking, the team reports online today in Science, with smokers 2.4 to 4.3 times more likely to be missing Y chromosomes in their blood cells than nonsmokers.

“It’s a fascinating observation,” says Charles Swanton, head of translational cancer therapeutics at the London Research Institute. The findings, he says, may explain why men have a slightly increased risk of death from the majority of cancers that, unlike breast or prostate cancer, are not specific to either sex. But the number of cells with abnormal chromosomes increases with age anyway, he notes, so the loss of Y may not be directly contributing to cancer. “It would be important to know the mechanism.”

Chanock agrees. “While the findings are intriguing,” he says, “the associations between Y chromosome loss and shortened life span and disease risk do need to be confirmed in other large [long-term] studies.”

That hasn’t stopped the team from founding a startup, CRAY Innovation (Cancer Risk Assessment from loss of chromosome Y Innovation), to develop a diagnostic test that could assess a man’s risk of cancer based on loss of chromosome Y in blood cells.

Dumanski and his colleagues are also planning follow-up studies to better understand how cellular Y chromosome deficiency might cause poor health. The researchers hypothesize that the Y chromosome loss may be skewed toward a specific population of blood cells that become immune cells known to fight cancer. Unable to function normally, the crippled cells may allow disease and cancer to take hold.

Meanwhile, there is some reassuring news for smokers, Forsberg says. Y chromosome damage caused by smoking appears to be reversible and dose-dependent. Previous smokers were no more likely to have Y chromosome loss than those who have never smoked, he notes, so it’s never too late to quit.