Variants in two genes involved in the body’s immune response and inflammation were associated with age-of-onset of symptoms in Portuguese families with familial amyloid polyneuropathy (FAP), due to the common Val30Met mutation, a study shows.
The study, “C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients,” was published in the journal Annals of Clinical and Translational Neurology.
Familial amyloid polyneuropathy (FAP) is a rare, inherited disease caused by the abnormal deposits of protein in organs and tissues, mainly in the nerves, heart, kidneys, and eyes. These abnormal deposits build up slowly, and cause damage to the affected organs, leading to symptoms of the disease.
The condition is caused by mutations in the TTR gene, which directs the production of transthyretin, a protein that transports vitamin A (retinol), and a hormone called thyroxine, throughout the body. FAP is inherited in an autosomal dominant pattern, meaning that only one copy of the mutated TTR gene is needed to cause the disease. That means that children who get the abnormal gene from only one parent can still get the disease. However, not all people with a mutation will develop the disease.
Signs and symptoms start in adulthood, getting worse over time, and depend on where the amyloid protein accumulates. The symptoms include peripheral neuropathy — a loss of nerve function in the periphery of the body, including the feet, legs, hands, and arms — and autonomic neuropathy, when the nerves that control involuntary bodily functions, such as blood pressure, temperature control, and digestion, are damaged.
FAP is most common in certain populations of Portugal, Sweden, and Japan. The most common TTR gene mutation, known as Val30Met, occurs in about 1 in 583 people in some parts of Portugal, compared with about 1 in 100,000 people in the U.S. FAP was first identified in 1952 in several families in Portugal.
Age of symptoms onset varies widely, even within the same family, and can range from age 20 through 80. As a result, some people with the disease may never experience any symptoms, but may still pass the defective gene to their children.
Variation in age at onset is a hallmark of FAP due to Val30Met, “showing that this variant alone cannot explain it,” the researchers said.
Several studies in animal models, and in different human populations, suggest that variations in genes other than TTR may act as genetic modifiers, and influence the age at which the first symptoms emerge.
More recently, common variants of the C1QA gene, which codes for parts of C1q, were associated with earlier onset forms of FAP. Meanwhile, variants of the C1QC gene, which also codes for parts of C1q, were linked to a later onset form of FAP. These results suggest that C1q genes can affect functional pathways in the course of the disease.
In the light of this data, researchers from i3S, at University of Porto, in Portugal, sought to investigate if the C1QA and C1QC variants may act as genetic modifiers of age of onset in Portuguese families with a history of FAP due to Val30Met mutations.
To search for variants, DNA samples from 267 patients from 117 families were sequenced. These families came not only from the high‐penetrance (and early‐onset) regions, but also from the low‐penetrance (and late‐onset) areas of Portugal.
Computational analysis to assess genetic alterations and gene-gene interactions revealed five variants — two in C1QA and three in C1QC gene — that were associated with age at onset variability.
Two variants for C1QA gene — GA genotype of rs201693493 and CT genotype of rs149050968 — were significantly associated with later onset of symptoms, corresponding to a mean increase ofn 16 and 10 years, respectively. Computer predictions estimated that GA genotype of rs201693493 was involved in altering splicing of C1QA gene, a process that alters the final protein coded by the gene.
For C1QC, researchers found three significant variants. The first two — GA genotype of rs2935537 and GA genotype of rs201241346 — were associated with earlier onset of symptoms, with a decrease in mean age at onset of seven and 11 years, respectively. The third — GA genotype of rs200952686 — was associated with later‐onset, increasing it by a mean of 32 years.
No significant gene interactions were seen between C1QA and C1QC.
“Importantly, we conclude that C1QA was associated with later AO [age at onset] and C1QC may have a double role: some variants may confer earlier and other later AO, depending on the associated pathophysiological [disease-causing] mechanisms,” the investigators said.
Researchers add that this data confirms the role of complement C1Q genes in variability of age of onset, and reinforces the involvement of this immune pathway in modifying patient outcomes. Consistent with prior studies demonstrating the activation of inflammatory markers in different patient tissues, this study supports the idea that inflammation could play a role in symptoms onset.
The investigators noted that they cannot exclude that other genes and variations, not identified by their study, may also contribute to the variations in age of onset.