Genetic Clues of an Autoimmune Kidney Disease

IgA
nephropathy (IgAN), also known as Berger's disease, is an autoimmune kidney disease
and a common cause of kidney failure. IgAN occurs when an antibody called immunoglobulin A (IgA) collects
in the kidneys, causing inflammation of the glomeruli, the kidneys'
filtering structures. Over time, the inflammation can hinder the
kidneys' ability to filter waste from the blood.

About half of patients
with IgAN have progressive disease and eventually develop kidney
failure. There is no cure for IgAN, but medications, along with blood
pressure control, can slow disease progression.

Researchers have uncovered new genetic clues to understanding IgAN. The findings are relevant to IgAN
as well as other diseases with similar underlying molecular defects,
such as inflammatory bowel disease and certain types of blood disease
and cancer.

‘New genetic clues to understanding IgA nephropathy have been uncovered by researchers.’

"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 lead author
Krzysztof Kiryluk, the Herbert Irving assistant professor of
medicine at Columba University Medical Center (CUMC).

The study, conducted by researchers at CUMC and the University of
Alabama at Birmingham (UAB) School of Medicine, was published last month
in PLOS Genetics.

The key molecular defect in people with IgAN is abnormal
O-glycosylation of IgA antibodies. O-glycosylation - in which a sugar
molecule attaches to an oxygen atom in the amino acid residue of a
protein - plays a role in various physiologic processes. Studies of
families have shown that problems in the O-glycosylation of IgA are
common in people with IgAN and are largely genetic in origin, although
the exact genes involved were unknown.

To identify genes linked to O-glycosylation problems in IgAN, Dr.
Kiryluk and colleagues performed genome-wide association study (GWAS) of
2,633 people of European and East Asian ancestry, populations with high
rates of the disease. All of the participants were analyzed for blood
levels of galactose-deficient IgA1 (Gd-IgA1), a marker for IgAN, using a
new high-throughput blood test developed by lead investigator of the
study Jan Novak, associate professor of microbiology at UAB. A GWAS
study of this kind had never been done before, because there was no way
to efficiently measure the biomarker in such a large volume of
patients.

The researchers found that variations in two genes, C1GALT1 and
C1GALT1C1, were significantly more common in people with high levels of
the Gd-IgA1 marker. "The genes are found on different chromosomes, but
they make proteins that interact to form an enzyme critical for the
proper glycosylation of IgA molecules," said Dr. Kiryluk.

To confirm that C1GALT1 and C1GALT1C1 are involved in
O-glycosylation, the researchers knocked down the two genes in cells in
from IgAN patients and controls. Knocking down the genes increased
production of the Gd-IgA1 marker in cells from both groups.

Variations in both genes, combined, accounted for about 7% of
the overall variability in blood levels of Gd-IgA1 in the study
population. "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," said Dr. Kiryluk. "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." A GWAS study of
some 10,000 patients is now underway.

Bacterial infection of urinary bladder can cause pain and burning sensation while passing urine. Abnormal Vesico-ureteric reflex, due to which the urine goes back to the kidneys from the bladder is also known to cause infection.

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