Study Identifies Genes Linked to Autoimmune Kidney Disease

A pair of genes linked to serum levels of the defective immunoglobulin galactose-deficient IgA1 has been identified during a genome-wide association study (GWAS) and may serve as biomarkers to help diagnose the autoimmune kidney disease IgA nephropathy (IgAN), or Berger's disease.

IgAN occurs when the mutated form of the antibody immunoglobulin A (IgA) causes inflammation of the glomeruli, which impedes the kidneys' ability to filter waste from the blood. The primary molecular defect in individuals with IgAN is abnormal O-glycosylation of IgA antibodies. O-glycosylation is a common type of post-translational modification of proteins; specific abnormalities in the mechanism of O-glycosylation have been implicated in cancer, inflammatory, and blood diseases. However, the molecular basis of abnormal O-glycosylation in these complex disorders is not known.


Investigators at the Columbia University Medical Center used a simple lectin-based ELISA assay, based on a GalNAc-specific lectin from Helix aspersa (HAA), to determine the levels of circulating Gd-IgA1 in sera from 2,633 people of European and East Asian ancestry, populations with high rates of the disease. Results obtained with this assay, revealed that serum levels of Gd-IgA1 represented a normally distributed quantitative trait in healthy populations, but up to two thirds of IgAN patients had levels above the 95th percentile for healthy controls.

The screen identified two genome-wide significant loci in the C1GALT1 and C1GALT1C1 genes. These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. These two loci explained approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Moreover, many healthy family members exhibited very high Gd-IgA1 levels, identifying elevated Gd-IgA1 as a heritable risk factor that preceded the development of IgAN.

"Very little is known about the causes of IgAN, genetic or otherwise, so our discovery represents an important step toward developing better therapies for this disease," said first author Dr. Krzysztof Kiryluk, assistant professor of medicine at Columbia University Medical Center. "Since approximately 50% of variability in Gd-IgA1 levels is due to genetic factors, this means that about 43% of the genetic variability is still unexplained. We started with a relatively small study population, so explaining 7% of variability between individuals with the disease was a good start. As we analyze more patients, we expect that we will find more genetic variants and can begin to piece together how these variants interact with environmental factors to cause disease."

The study was published in the February 10, 2017, online edition of the journal PLOS Genetics.