Researchers have identified two genes that contribute to a disease called glomerulonephritis, or acute kidney inflammation.
Their study, “GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway”, appeared in the journal PLOS Genetics.
IgA nephropathy is an autoimmune kidney disease that is the most common cause of glomerulonephritis. Research has shown that abnormal O-glycosylation in IgA1 — a subtype of the antibody IgA which comprises about 85 percent of total IgA concentration in serum —is a factor in the disease. When a sugar molecule (galactose) fails to attach itself to an oxygen atom in a protein, this creates an abnormal IgA1 hat triggers an autoimmune response, ultimately damaging the kidneys’ filtering structures.
Previous work from the same research team at New York’s Columbia University and the University of Alabama-Birmingham (UAB) School of Medicine showed that up to two-thirds of IgA nephropathy patients have high IgA1 levels. In addition, elevated serum galactose-deficient IgA1 levels show high heritability; galactose-deficient-IgA1 was also shown to be a risk factor preceding the development of IgA nephropathy.
“Very little is known about the causes of IgA nephropathy, genetic or otherwise, so our discovery represents an important step toward developing better therapies for this disease,” Krzysztof Kiryluk, MD, the study’s lead author and an assistant professor of medicine at Columbia University Medical Center, said in a press release.
Using a high-throughput blood test, the research team performed a genome-wide association study of 2,633 subjects of European and East Asian ancestry for defective O-glycosylation of serum IgA1.
Researchers showed that serum levels of galactose-deficient IgA1 remain stable over four years, which means that environmental factors have little effect on O-glycosylation of IgA1. Furthermore, IgA1 levels were higher in patients with IgA nephropathy compared to controls. In addition, serum galactose-deficient IgA levels were positively correlated with age and total IgA levels.
The scientists also discovered that naturally occurring DNA changes in two genes – C1GALT1 and C1GALT1C1 – were significantly associated with levels of galactose-deficient IgA1.
The two genes encode key proteins in O-glycosylation of IgA1 molecules. The C1GALT1 gene encodes the enzyme responsible for the addition of galactose to O-glycans, whereas C1GALT1C1 encodes a protein that acts as a chaperone for the enzyme during its synthesis.
Scientists confirmed the role of both genes during in vitro experiments of C1GALT1 and C1GALT1C1, as reduced levels of each of the two genes increased production of galactose-deficient IgA1 secreted by the cells.
Together, changes in these two genes explain about 7 percent of galactose-deficient variability on IgA1 in Europeans, and 2 percent in East Asians.
The results provide new genetic clues to understanding IgA nephropathy and have relevance for other diseases with similar underlying molecular defects, such as inflammatory bowel disease, certain types of blood diseases and cancer.
Roughly half the patients with IgA nephropathy have progressive disease and may develop kidney failure. Although medication can slow glomerulonephritis, there is currently no cure. The incidence rate for glomerulonephritis is believed to vary between 0.2 and 2.5 cases per 100,000 inhabitants per year.
The Columbia-UAB team is now performing a larger association study with 10,000 patients.
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