Diabetes, a disease whose prevalence is continuously growing, can over time lead to serious associated diseases, such as diabetic retinopathy and nephropathy. Associated diseases develop in as many as one-third of patients suffering from diabetes, with diabetes being one of the most common causes of nephropathy globally. However, the causes leading to diabetic nephropathy are so far relatively poorly known. The onset of the disease is particularly affected by good control of diabetes, but genes also play a part in the risk of developing the disease.
In an international genetic study published in the Journal of American Society of Nephrology, genes predisposing to diabetic nephropathy were looked for in blood specimens collected from nearly 20,000 patients with type 1 diabetes. The sample includes more than 4,500 Finnish diabetic patients participating in FinnDiane, a study coordinated by the University of Helsinki and the Folkhälsan Research Center.
A total of 16 genes associated with the risk of developing diabetic nephropathy were found in the study, the rarest of which occur in less than 1% of Finns. The strongest association was found in a gene identified in collagen 4a3, slightly altering the structure of collagen occurring in the glomerular basement membrane. Previously, mutations causing rare renal diseases, such as Alport syndrome, have been found in the same gene.
“This variant associated with diabetic nephropathy occurs in roughly one-fifth of patients, and it reduced the risk of nephropathy by as much as 20%. Patients carrying the variant had a thinner glomerular basement membrane, which is known to grow thicker in patients with nephropathy,” Docent Niina Sandholm explains.
The impact of the variant was minor in patients with good diabetic control, or good long-term glucose levels, and, thus, a very low likelihood of developing nephropathy. The protective effect was at its highest in patients whose blood glucose level was high and whose risk of developing the disease was consequently also higher.
Collagens have a more active role than previously thought
Other genes associated with the risk of diabetic nephropathy were found, among others, in the proximity of COLEC11 and DDR1 genes. Of these, COLEC11 contains both an element resembling collagen and an element that binds with sugars, whereas a protein produced by DDR1 is known to bind with collagens.
“Previously, collagens were thought to be mainly passive structural components, but this study highlights their active role in the onset of nephropathy,” says Professor Per-Henrik Groop.