Is IgA Nephropathy Genetic? Explaining the Scientific Link

IgA nephropathy, or Berger’s disease, is a condition caused by the buildup of the antibody immunoglobulin A (IgA) in the kidneys. This accumulation leads to inflammation and damage that can impair the kidneys’ ability to filter waste from the blood. While the disease’s progression varies, it is a significant cause of kidney problems worldwide. Scientific investigation increasingly points to a strong connection between an individual’s genetic makeup and the development of IgA nephropathy.

Understanding IgA Nephropathy

IgA nephropathy occurs when an abnormal form of the IgA protein gets trapped in the glomeruli—the tiny filtering units within the kidneys. While normal IgA antibodies help protect the body’s mucous membranes from infections, the IgA molecules in this disease are structurally different. This causes them to clump together and form deposits that the body cannot clear effectively.

These deposits trigger an inflammatory response that can damage the glomeruli over time. This damage can lead to blood and protein leaking into the urine, known respectively as hematuria and proteinuria. For many, the first sign is visible blood in the urine, often following a respiratory or gastrointestinal infection. The course of the disease is highly variable; some experience slow progression over decades, while others face significant kidney damage and eventually kidney failure.

The production of this abnormal IgA involves a specific type called IgA1, which has a “hinge” region where sugar molecules attach via glycosylation. In IgA nephropathy, this process is faulty, resulting in galactose-deficient IgA1 (Gd-IgA1). The body then identifies these Gd-IgA1 molecules as foreign and produces antibodies to attack them, forming immune complexes that lodge in the kidneys and cause harm.

The Genetic Link to IgA Nephropathy

Scientific evidence indicates that genetic factors significantly contribute to an individual’s risk of developing IgA nephropathy. One of the earliest lines of evidence is familial aggregation, where the disease appears more frequently in certain families than expected by chance. Studies have documented cases where multiple family members across different generations are affected, suggesting an inherited predisposition.

Further support comes from studies showing marked differences in the prevalence of IgA nephropathy among various ethnic groups. The condition is most common in people of East Asian descent and common in those of European ancestry, but it is much less frequent in individuals of African descent. These geographic and ethnic variations suggest that genetic differences between populations play a role in susceptibility.

IgA nephropathy is a complex, or polygenic, disease. This means it is not caused by a mutation in a single gene but by the combined effects of variations in multiple genes, each contributing a small amount to the overall risk. This polygenic nature explains why not everyone with a family history of the disease will develop it, as inheriting a specific combination of risk variants only increases susceptibility.

Key Genes and Genetic Mechanisms Implicated

Genome-wide association studies (GWAS) have pinpointed several specific genetic regions, or loci, associated with an increased risk for IgA nephropathy. These studies scan the entire genome of many individuals to find genetic variations that are more common in people with the disease. This approach has identified over 30 risk loci, and many of these implicated genes are connected to the immune system, particularly the production and regulation of IgA.

A central mechanism is the abnormal glycosylation of the IgA1 antibody. Research has identified genetic variants in genes that code for glycosyltransferases, the enzymes responsible for attaching sugar molecules to proteins. For instance, variations in genes like C1GALT1 and ST6GALNAC2 have been linked to the production of galactose-deficient IgA1. These genetic alterations may make the enzymes less efficient, leading to the creation of the abnormal IgA1 molecules.

Other identified genes highlight the broader immune response. Loci within the Major Histocompatibility Complex (MHC) on chromosome 6 have shown strong associations, suggesting how the body recognizes its own proteins may be altered. Genes related to the complement system, which helps clear immune complexes, have also been implicated. Variations in these genes may impair the body’s ability to remove IgA deposits from the kidneys. Genes involved in maintaining the intestinal mucosal barrier have also been identified, pointing to a connection between gut health and kidney disease.

Inheritance Patterns and Familial Risk

Because IgA nephropathy is a polygenic condition, it does not follow the straightforward inheritance patterns seen in single-gene disorders. While some families with a strong history of the disease appear to show a pattern similar to autosomal dominant inheritance, this is not the norm. The complex interplay of multiple genes makes predicting its inheritance much more challenging.

First-degree relatives—parents, siblings, and children—of an individual with IgA nephropathy have a higher risk of developing the condition compared to the general population. However, this increased risk is one of susceptibility, not certainty. Having the associated genetic variants does not guarantee that a person will get the disease; it only means they are more predisposed.

This phenomenon is known as incomplete penetrance, where not everyone who has the genetic predisposition for a disease actually develops it. It is believed that environmental factors or other triggers are required for the disease to manifest in a genetically susceptible person. These triggers could include common infections, which are known to sometimes precede the initial discovery of blood in the urine.

Genetic Testing and Its Role

In clinical practice, genetic testing is not routinely used to diagnose IgA nephropathy or to screen asymptomatic family members. A definitive diagnosis relies on a kidney biopsy, which allows doctors to see the characteristic IgA deposits in the glomeruli. While research has identified numerous gene variants, none are predictive enough on their own for diagnostic purposes.

The primary limitation of genetic testing is its polygenic nature. Since dozens of genes each contribute a small amount to the overall risk, testing for a single gene or a small panel cannot accurately predict whether someone will develop the condition. A person could carry several known risk variants and remain healthy, while another with fewer might develop the disease due to other genetic or environmental factors.

Although not used for diagnosis, genetic research continues to provide valuable insights into the mechanisms of IgA nephropathy. Understanding the specific pathways affected by these genetic variants helps scientists identify potential targets for new therapies. In the future, a comprehensive genetic risk score might help identify individuals at high risk who could benefit from closer monitoring, but this application remains in the research phase.