Genetic link between obesity and diabetes

NZ scientists untangle the genetic link between obesity and diabetes

Auckland researchers have made a major leap in our understanding of the genetic basis for obesity and type 2 diabetes, and why these two conditions so often go hand in hand.

In New Zealand, almost a third (30.7 percent) of adults live with obesity, which is a major risk factor for type 2 diabetes and other disorders.

“The fact that obesity and diabetes so often affect the same people suggests similar genes are contributing to the development of both the disorders,” says study lead Dr Justin O’Sullivan, a molecular biologist from the Liggins Institute at the University of Auckland.

“But until now, scientists have struggled to untangle the genetic links between the two conditions, which are both on the rise in populations around the world.”

In a study published in the international journal Frontiers in Genetics, Dr O’Sullivan’s team have shown how genetic changes that fall in the so-called “junk DNA” and are linked to diabetes and obesity can act together to alter how genes behave.

“The techniques we developed in this study provide medical researchers with new information and a different viewpoint from which to look at the genetics behind obesity and diabetes, which could ultimately help us better treat and even prevent them,” says Dr O’Sullivan.

The researchers focussed on SNPs, pronounced “snips”, which stands for single nucleotide polymorphisms. They’re regions of the DNA that commonly vary between individuals and that have been linked to a disease. Some fall inside genes, but most fall outside them, in segments once believed to be little more than inactive spacers between genes.

The theory is that SNPs outside genes are brought into contact with, and influence the working of, far-off genes through the way DNA is tightly coiled inside the cell nucleus. DNA, the long molecules inside our cells containing our entire genetic blueprint, are around two metres long, but packed into a cell nucleus only 100th of a millimetre across.

“SNPs offer a key to unlock the riddles of many diseases and disorders that can be passed from parent to child, but do not seem to pass directly through the genes,” says Dr O’Sullivan.

SNPs that predispose people to obesity are different from the ones linked to diabetes. But using their new technique, the Auckland team have revealed for the first time that there are many instances where a SNP for obesity and a SNP for diabetes are both in contact with, and change the functioning of, the same gene.

“We can’t tell from this study if the SNPs themselves are causing the disorders through changing the way the genes work, or if it is something nearby on that same DNA segment,” says Tayaza Fadason, a PhD student at the Institute in the research team.

“But it is clear that these SNPs we have identified are markers of DNA segments that are somehow altering the functioning of the genes they come into contact with.”

Says Dr O’Sullivan: “The other remarkable finding was that many of the regulatory SNP-gene connections we pinpointed affect body tissues not usually thought of as driving obesity or type 2 diabetes – breast tissue, brain tissue from the cerebellum, skin and blood, the fat that sits just beneath the skin. On the other hand, while visceral fat has a big contribution to diabetes, we found few SNP-gene connections in that tissue.

“This means researchers need to broaden their hunt for genetic drivers of obesity and diabetes beyond the usual suspects.”

It also lends weight to a new way of thinking about DNA and the human genome that is gaining traction among geneticists, which recognises that there’s more to genetics than the sequence of genes, he says. “We also need to understand the other forms of information in DNA – including how it’s folded - which affect how genes are read and used.”

The research team also included Cameron Ekblad and William Schierding from the Liggins Institute, and John Ingram from The New Zealand Institute of Plant and Food Research.

The team is currently looking at SNP-gene connections’ role in type 1 diabetes, muscle wasting and the relationships between other medical disorders.

KEY POINTS
Many people with obesity also develop type 2 diabetes, but until now, the genetic link between these two conditions has been unclear
Using new techniques, researchers from the Liggins Institute and New Zealand Institute of Plant and Food Research have identified pieces of the DNA, called SNPs, that change the activity of far-off genes through being brought into contact with them because of how DNA is tightly coiled into the cell nucleus
These regulatory SNP-gene connections suggest that a far wider range of tissues may play a role in obesity and diabetes than the “usual suspects” that scientists currently focus on

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