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DNA tweak no good for diabetics

Increased protein production could harm eyes, kidneys

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4:06pm, May 5, 2008
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A little tweak to a diabetic’s DNA could tip the balance toward blindness and kidney failure, a new study shows.

Natural variation in just a single base pair — letters of the genetic alphabet – raises levels of erythropoietin, a protein that stimulates red blood cell production and the growth of blood vessels. Bumping up erythropoietin, EPO for short, about doubles the risk that diabetics will develop diabetic retinopathy and end-stage kidney disease, a study published online and in the May 13 Proceedings of the National Academy of Sciences shows.

Controlling erythropoietin levels or blocking its activity could help diabetics stave off complications or halt the progression of diseases already attacking eyes and kidneys. The research also sounds a cautionary note for diabetics who undergo kidney dialysis. Erythropoietin is often prescribed to dialysis patients to pump up red blood cell counts, but the new research suggests that EPO should be used with caution to avoid harming the eyes and kidneys.

Kang Zhang, an ophthalmologist and geneticist at the University of Utah School of Medicine in Salt Lake City and his colleagues set out to solve a mystery that doctors who treat diabetics know well.

“We all see patients with their blood sugar completely under control, but they have complications right and left,” Zhang says. “Then there are other people whose blood sugar is all out of whack, and yet, they never get into trouble.”

Diabetic retinopathy results from an excess of blood vessels invading the retina. The blood vessels can lead to tears in the eye tissue or detachment of the retina in the most severe form of the disease, known as proliferative diabetic retinopathy. Nearly every diabetic will develop some degree of retinopathy over time, but only about half progress to the severe form.

Still, the eye disease is the leading cause of new cases of blindness in working adults in the United States and is responsible for about 10 percent of blindness overall.

Eye experts have known for years that a protein called VEGF is involved in stimulating the unwanted blood vessel growth. Experimental therapies to block the protein seem promising, but the treatment is not yet approved for widespread use in the United States.

Zhang and his team chose 10 genes involved in blood vessel growth and looked for natural variations — called single nucleotide polymorphisms or SNPs — in the DNA sequence of the genes linked to greater risk of developing diabetes complications.

The researchers found a change at a particular spot in a stretch of DNA called a promoter that controls whether the erythropoietin gene is switched on or off. Some people have the DNA base guanine (G). Others have thymine (T). The T creates a molecular landing-pad for a protein called AP1, which is a powerful molecule that turns genes on. AP1 can’t land on promoters that have G instead of T. About half of people in the general population have the T form.

Non-diabetics who had the T variant in both copies of the erythropoietin gene (one inherited from their mother, one from the father) made 7.5 times more erythropoietin in their eyes than non-diabetics who inherited two copies of the G form.

Diabetics who had two copies of the risky T variant also had double the risk of developing eye and kidney complications compared with diabetics with a different form. The result could mean that diabetics should get genetic testing, called genotyping, to determine which form they have, Zhang says. People who have the risky variant could then be given treatments to block EPO in the eye and kidney.

But other eye experts say that controlling blood sugar could make a bigger difference in avoiding complications from diabetes.

“I don’t think we’re at the point that we’re going to start genotyping people,” says Emily Chew, deputy director of epidemiology and clinical research at the National Eye Institute. “If half the people have this, what’s the point?”

Chew called the study “very exciting,” but she cautioned that erythropoietin may have complicated interactions with blood sugar and other proteins.

Zhang agrees that blocking EPO throughout the body is probably not a good idea.

“EPO is a hugely important factor to maintain our red blood cell production, so you don’t want to make people anemic,” he says.

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