How Genetics and Heritability Play a Role in IgA Nephropathy, a Type of Kidney Disease

Immunoglobulin A nephropathy (IgA nephropathy, or IgAN), also called Berger’s disease, is a type of kidney disease. It develops when an antibody called immunoglobulin A builds up in your kidneys. This can damage the small filters, called glomeruliinside your kidneys and lead to kidney failure over time.

Most cases of IgAN are not hereditary. But Inherited genetics may play an important role in IgAN. You may not develop the disease unless you inherit several risk genes and also experience environmental triggers that affect how those genes work.

Most people diagnosed with IgA nephropathy have sporadic cases, meaning the disease develops without a clear family history. However, about 10% of cases are familial, meaning they can be hereditary. This is probably due to hereditary genetic factors.

However, IgA nephropathy does not have a single-gene inheritance pattern. It is polygenicmeaning that multiple genetic regions contribute to the development of the disease. This may explain why IgAN appears different in different people, with some people developing severe kidney damage while others develop mild disease.

Large-scale genome-wide association studies have identified 30 different regions in chromosomes this may increase the risk of IgAN. These include genetic mutations and gene variants such as:

• IGAN1, a chromosomal region associated with susceptibility to IgAN
• SPRY2which can affect critical immune pathways
• COL4A3 And COL4A5which can weaken the kidney filters

Epigenetic factors also play a role. These are behavioral and environmental factors, such as illness, smoking, stress, etc., that “turn on” or “turn off” the expression or activity of a gene. Risk genes do not necessarily lead to IgAN, unless or until you encounter one of these factors.

Studies suggest that the heritability of IgA nephropathy can range from 40 to 50%, meaning that inherited genetics influence approximately half of the risk.

Additionally, heritability follows an autosomal dominant inheritance pattern with incomplete penetrance.

Autosomal dominance This means that inheriting just one copy of the risk gene variant from either parent is enough to increase the risk of developing IgA nephropathy.

However, incomplete penetrance means that not everyone who inherits the risk gene variant develops the disease. This may be because environmental factors also play a role.

Besides genetic variants, a few other factors can also increase risk. You may be more likely to develop IgAN if you:

• Are men
• are between 10 and 40 years old
• Have Pacific Islander, Asian, or White European ancestry
• have other health problems such as celiac disease, hepatitis, inflammatory bowel disease, or human immunodeficiency virus (HIV)
• Smoke

Although most cases of IgA nephropathy are not hereditary, about 10% of cases may be familial, meaning the disease can be passed to your child if you carry IgAN or carry risk genes. However, due to incomplete penetrance, not all children who inherit risk gene variants develop the disease.

Genetic counseling may be helpful for families with a history of IgA nephropathy or if you are concerned about the risk to your child.

A genetic counselor can ask you questions about your family history, review your medical records and tests, and help clarify the chances of passing risky variants to children. They may also recommend genetic testing if you or your child are at risk for IgA nephropathy.

There is no single, definitive test for this disease because it likely develops due to a complex interaction of genetic and environmental factors. Counselors may recommend a combination of tests to determine the risk of developing IgAN. These tests may involve taking a sample of your blood, saliva, or cells taken from the inside of your cheek.

If you decide to get tested, a genetic counselor can help you interpret your results and decide what it means for your family, family planning, and next steps.