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GWAS in Diabetes Patients Uncovers Risk Loci for Kidney Disease

NEW YORK – Researchers led by a team at Massachusetts General Hospital have linked 16 novel gene loci to diabetic kidney disease.

Diabetes is the leading cause of kidney disease, and according to the US National Institute of Diabetes and Digestive and Kidney Diseases, about a quarter of adults with diabetes also have kidney disease. While poor blood sugar control is associated with the development of complications from diabetes, some people with diabetes develop kidney disease even when they have had good control of their blood sugar levels, while others don't develop the condition despite poor blood sugar control.

The researchers, thus, sought to uncover genetic variants that might predispose people to diabetic kidney disease. As they reported yesterday in the Journal of the American Society of Nephrology, they found 16 diabetic kidney disease (DKD)-associated loci, including a protective one in the collagen gene COL4A3, by studying a cohort of nearly 20,000 people with type 1 diabetes.

"This study represents a substantial advance in the genetics of DKD, where previous studies had yielded few robust associations," said senior author Jose Florez, chief of the endocrine division and diabetes unit at MGH and a professor at Harvard Medical School, in a statement. "The 16 DKD-associated regions provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment."

To encompass the full range of diabetic kidney disease in their analysis, he and his colleagues relied on 10 different definitions of the disease, based on factors such as albuminuria and estimated glomerular filtration rates. They conducted a genome-wide association study for each of those 10 phenotypes in their cohort of 19,406 patients of European ancestry with type 1 diabetes.

From this, they homed in on 16 novel independent loci that reached genome-wide significance, but four SNPs reached their stricter study-wide threshold.

The strongest signal they uncovered was at rs55703767, a common missense mutation within the COL4A3 gene. That gene encodes a key structural component of the glomerular basement membrane, and mutations in COL4A3 have been connected to heritable nephropathies like Alport syndrome. The protein it encodes binds a number of molecules like integrins and heparin.

In this study, the rs55703767 variant was protective against diabetic nephropathy, any albuminuria, the combined CKD-DN phenotype, and macroalbuminuria, the researchers noted.

The variant affects an amino acid within a triple helical domain structure, potentially changing the conformation of the collagen complex. Given its protective nature, it might provide added tensile strength or flexibility to the glomerular basement membrane, the researchers hypothesized. In a separate cohort from the Renin-Angiotensin System Study, they found that individuals with this COL4A3 variant have thinner glomerular basement membrane walls.

As high blood sugar levels contribute to diabetic complications, the researchers stratified their associate analysis by HbA1c levels in the Finnish Diabetic Nephropathy Study. In that cohort, they found that the COL4A3 variant was nominally significant, but only in individuals with HbA1c levels greater than 7.5 percent but lower than 9.3 percent. This suggested to them that the environmental effect of HbA1c might overpower any genetic effect of the COL4A3 variant.

Two of the other genome-wide significant signals also fell near collagen protein-related genes, such as COLEC11 and DDR1, an innate immune factor and a collagen receptor, respectively.

Additionally, the three other loci that reached study-wide significance are near the TAMM41, BMP7, and HAND2 genes. BMP7, the researchers noted, is needed for renal morphogenesis.

They added that their findings improve the understanding of the pathogenesis of diabetic kidney disease and may help in the development of molecularly targeted treatments.

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