A gene variant is a permanent change in the DNA sequence of a gene. These alterations can affect how a gene functions, and while many are harmless, some are linked to health conditions. One such alteration is the Y402H variant, a specific change within the Complement Factor H (CFH) gene. Variants of the CFH gene, including Y402H, are associated with an increased risk for developing certain medical issues.
The Role of the Complement Factor H Gene
The Complement Factor H (CFH) gene provides instructions for creating a protein that regulates the complement system, a part of the innate immune system. The complement system is a network of proteins that helps antibodies destroy foreign invaders like bacteria and viruses. It acts as a rapid-response alarm, identifying pathogens for removal and triggering inflammation to clear infections.
This system must be tightly controlled to prevent it from damaging the body’s healthy tissues. The CFH protein acts as a brake, distinguishing the body’s cells from foreign ones. It binds to the surfaces of host cells and deactivates a complement protein called C3b. This action shuts down the complement cascade on healthy cells, ensuring the immune weapon is aimed only at legitimate threats.
Without effective regulation from proteins like CFH, the complement system can remain in a state of constant, low-level activation. This unchecked activity leads to chronic inflammation and cellular injury in various parts of the body. Proper CFH gene function is necessary for maintaining the balance between immune defense and self-preservation.
How the Y402H Variant Affects Gene Function
The Y402H designation describes a common single-point mutation in the CFH gene, known as a single nucleotide polymorphism (SNP). This mutation involves the change of a single DNA building block. The change results in a different amino acid being placed in the final protein. At position 402 of the CFH protein, the amino acid Tyrosine (Y) is replaced by Histidine (H), giving the variant its name: Y402H.
This substitution has functional consequences for the resulting protein. The version of the CFH protein with Histidine at position 402 is less effective at its regulatory job. The change occurs in a region of the protein responsible for binding to cell surfaces to protect the body’s tissues. With Histidine present, the protein’s ability to bind to these surfaces and deactivate the complement system is weakened.
As a result, the brake on the complement system becomes less reliable in certain tissues. This impairment does not shut down the protein’s function entirely but makes it less efficient. This inefficiency leads to a state of chronic, low-grade inflammation, which is the primary mechanism through which the Y402H variant contributes to disease risk.
Connection to Age-Related Macular Degeneration
The Y402H variant is most strongly linked to an increased risk of developing age-related macular degeneration (AMD). AMD is a progressive eye disease affecting the macula, the part of the retina responsible for sharp, central vision. The disease can lead to a loss of central vision, making activities like reading and driving difficult, while peripheral vision remains intact.
The connection between Y402H and AMD lies in the chronic inflammation this variant promotes within the eye. The weakened CFH protein is less capable of protecting retinal cells from complement system attack. This sustained inflammation is a driving force behind the formation of drusen, which are small, yellow deposits under the retina. While some drusen are a normal part of aging, large and numerous drusen are a hallmark of AMD.
The risk from the Y402H variant depends on the number of copies a person inherits. An individual with one copy of the variant has an approximately 2.5 to 3-fold increased risk of developing AMD. For those who inherit two copies, the risk increases by as much as three to six times. Y402H is a risk factor, not a diagnosis, as many with the variant will not develop AMD. Other factors like age, smoking, and diet also play a role.
The variant is associated with both major forms of advanced AMD: geographic atrophy (the “dry” form) and choroidal neovascularization (the “wet” form). The frequency of this variant is significantly higher in individuals with AMD compared to control populations. This genetic predisposition helps explain why AMD can run in families.
Other Associated Health Conditions
While Y402H is most linked with AMD, other variants in the CFH gene are associated with different, rarer health conditions. The most notable is atypical hemolytic uremic syndrome (aHUS), a disease causing blood clots in small blood vessels, often leading to kidney failure. The CFH mutations that cause aHUS are rare and have a more severe impact on the protein’s function than the common Y402H variant.
The Y402H variant itself has been investigated for links to other conditions, such as a rare kidney disease called C3 glomerulopathy, but these associations are not as strong as the one with AMD. For most people who carry the Y402H variant, the primary health implication remains the increased risk for age-related macular degeneration.
Genetic Testing and Managing Risk
A person can discover they have the Y402H variant through genetic tests. Direct-to-consumer testing companies often include this SNP in their health reports. A doctor may also order clinical genetic testing if there is a strong family history of AMD or if signs of the disease are present. This information is useful for understanding personal risk.
Knowing you carry the Y402H variant allows you to take proactive steps to protect your vision. The primary action is to schedule regular, comprehensive eye exams with an ophthalmologist. These exams can detect the earliest signs of AMD, such as drusen formation, long before vision loss occurs. Early detection is important for managing the disease’s progression.
Lifestyle modifications are beneficial in mitigating genetic risk. Quitting smoking is important, as it is a major environmental risk factor for AMD. Maintaining a healthy weight and adopting a diet rich in leafy green vegetables and omega-3 fatty acids also supports retinal health. These choices can help counteract the inflammatory predisposition associated with the Y402H variant.
For individuals with an AMD diagnosis, specific nutritional supplements may be recommended. The Age-Related Eye Disease Studies (AREDS/AREDS2) established a formulation of vitamins and minerals shown to slow the disease’s progression. It is important to consult with an eye care professional before starting these supplements, as they are for managing existing disease, not for prevention in the general population.