Rare Genetic Variants Can Dramatically Increase Risk for Type 2 Diabetes

Man using blood sugar measurement device to monitor type 2 diabetes

Men with rare mutations in a gene that can cause some cells to lose the Y chromosome have a more than 6-fold increased risk for type 2 diabetes, according to researchers based at the University of Cambridge.

The team found that men with mutations in the GIGYF1 gene also had higher fat mass, lower levels of insulin-like growth factor (IGF)-1 and lower handgrip strength, than those without this type of variant.

Further investigation revealed that rare GIGYF1 loss of function variants have a similar impact on type 2 diabetes risk in women. More common variants in the same gene also increase risk, but to a lower extent.

Mosaic loss of the Y chromosome or LOY, where more than 18% of a man’s cells do not contain the Y chromosome, is relatively common. The chance of experiencing this condition increases with age, with up to 20% of men over the age of 80 thought to experience it, and environmental factors such as smoking also increase risk.

There has been some debate about whether specific health problems are associated with LOY. Previous studies have suggested that men with LOY are expected to die an average of 5.5 years sooner than men without the condition and links to some cancers have also been suggested.

In this study, published in the journal Nature Communications, the researchers searched for protein coding genetic variants that increase risk for LOY in 82,277 men enrolled in the UK Biobank.

They found that loss of function genetic variants in two genes CHEK2 and GIGYF1, carried by 543 and 40 men in the study group, respectively, were linked to increased risk for LOY.

CHEK2 loss of function has been linked with LOY in the past. This type of mutation impedes DNA damage sensing and apoptosis and is known in some cancers, it is also known to extend reproductive life in women.

GIGYF1 is less well known and has not previously been linked to complex traits such as diabetes, but is thought to control insulin and cell growth factor signalling.

Men with the GIGYF1 loss of function mutations not only had 6-fold higher risk for LOY than other men, they also had 6.10 times higher risk for type 2 diabetes and 4 kg higher fat mass on average, as well as significantly lower serum IGF1 levels and handgrip strength than non-carriers.

“For complex diseases such as type 2 diabetes, many variants play a role, but often only increasing our risk by a tiny amount. This particular variant, while rare, has a big impact on an individual’s risk,” said lead author John Perry, co-leader of the Early Life Etiology and Mechanisms of Diabetes and Related Metabolic Disorders program at the MRC Epidemiology unit in Cambridge. Many genetic variants have been linked to type 2 diabetes risk in the past, but most have a more modest impact on risk.

The researchers also tested whether GIGYF1 loss of function mutations could impact metabolism more widely in men and women in the UK Biobank. Overall, 64 individuals had these variants. The rate of type 2 diabetes in this group was 30% compared with around 7% in the rest of the UK Biobank cohort, with a similar level of risk to the smaller male cohort for developing the condition in carriers who had not yet developed diabetes.

Common variants in GIGYF1 were also linked to higher blood glucose and HbA1c levels, as well as an increased risk for type 2 diabetes, although this was not as high as the risk linked to carriage of the rarer mutations. This association was confirmed in data from a separate biobank, the Million Veteran Program in the U.S.

“We previously highlighted the potential role of IGF signaling in promoting chromosomal instability and the cellular accumulation of DNA damage and reported that genetically higher IGF-1 levels are related to greater LOY,” write the authors.

“It may therefore appear paradoxical that here we find that loss of function in GIGYF1 (putatively leading to decreased IGF-1 signaling) should be associated with increased rather than decreased LOY. We hypothesize that GIGYF1 might enhance DNA damage response mechanisms to protect DNA integrity in the face of IGF-1-mediated tissue growth and differentiation.”

The researchers now plan to investigate their findings further and research the broader impact of GIGYF1 on human metabolism.

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