IgA Nephropathy (IgAN), also known as Berger’s disease, is the most common form of primary glomerulonephritis worldwide. The disease is characterized by the abnormal buildup of the immune protein immunoglobulin A (IgA) within the glomeruli. This IgA deposition causes inflammation and progressive scarring, which can eventually lead to chronic kidney disease and kidney failure. While the exact cause remains unknown, research consistently points to a complex interplay between an individual’s genetic makeup and environmental factors determining susceptibility.
IgA Nephropathy: Defining the Genetic Link
IgA Nephropathy is not a strictly hereditary disease caused by a single gene mutation. It is classified as a multifactorial or polygenic condition, influenced by multiple genes and external triggers. Over 90% of cases are sporadic, meaning they occur without a clear family history.
Despite the high rate of sporadic cases, familial aggregation confirms a significant genetic component. The disease tends to cluster within families, where multiple members are affected. Studies show that first-degree relatives (parents, siblings, or children) of someone with IgAN have a significantly increased risk, estimated up to 16 times higher than the general population.
A genetic predisposition does not mean the disease is inevitable. Individuals may inherit susceptibility genes but never develop the full clinical disease unless other factors come into play. Genetic factors are estimated to account for 40% to 50% of the overall disease risk.
Specific Genes and Familial Risk Patterns
Genome-wide association studies (GWAS) have identified numerous genetic regions contributing to susceptibility, primarily involving genes related to the immune system and IgA protein processing. The most strongly associated region is the Major Histocompatibility Complex (MHC) on chromosome 6.
The MHC region contains genes, such as HLA-DRB1 and HLA-DQB1, that are central to immune regulation and antigen presentation. Variations in these genes can influence the immune system’s response to foreign substances, potentially leading to the abnormal immune reaction seen in IgAN. Other susceptibility loci have been identified outside the MHC, including those involved in the complement system. For example, a common deletion of the CFHR3 and CFHR1 genes on chromosome 1q32 has been found to be protective against IgAN.
Galactose-Deficient IgA1 (Gd-IgA1)
A key genetic factor is the production of galactose-deficient IgA1 (Gd-IgA1). IgA1 normally has sugar molecules attached to its hinge region, but in IgAN patients, this glycosylation process is faulty. This defective glycosylation is considered a heritable trait and is observed in about 75% of patients. Variations in genes like C1GALT1 can increase the risk of producing the abnormal IgA protein that forms damaging immune complexes in the kidney.
Environmental and Secondary Triggers
Environmental and acquired factors play a significant role in triggering or exacerbating IgAN. The disease process often begins with an immune response at mucosal surfaces, such as the respiratory or gastrointestinal tracts. Infections in these areas frequently precede episodes of visible blood in the urine, suggesting that the body’s response to infection activates the IgAN pathway.
Secondary forms of IgA nephropathy can arise due to other systemic conditions that affect the immune system or mucosal surfaces. These acquired conditions include:
- Certain liver diseases, such as cirrhosis.
- Chronic infections like Hepatitis B or C.
- Inflammatory bowel disease (IBD).
- Celiac disease, an autoimmune reaction to gluten.
Addressing these underlying health issues can help manage the associated kidney disease.
Implications for Family Screening and Genetic Counseling
Monitoring is recommended for first-degree relatives of individuals diagnosed with IgAN due to the established familial risk. Surveillance tools are simple and non-invasive, focusing on detecting early signs of kidney damage. Annual check-ups should include monitoring blood pressure and performing a urinalysis to screen for persistent microscopic hematuria and proteinuria.
For families with a strong history, genetic counseling provides a comprehensive risk assessment. A counselor explains the polygenic nature of IgAN, the likelihood of inheritance, and the concept of incomplete penetrance. There is no single predictive genetic test available, as the disease involves many genes and environmental interactions. Counseling focuses on proactive monitoring and lifestyle modifications.