Study Identifies Rare Genetic Variants Linked with Anti-FHs aHUS

Study Identifies Rare Genetic Variants Linked with Anti-FHs aHUS

Rare genetic variants in complement genes have been associated with atypical hemolytic uremic syndrome (aHUS) linked with anti-factor H autoantibodies (anti-FHs), recent research shows.

Moreover, the study adds evidence that common infections contribute to this type of aHUS in genetically predisposed individuals.

These observations explain why there is a peak in anti-FHs disease onset during school age, researchers say, and support the idea that this aHUS type has a complex origin, likely requiring a combination of genetic and environmental factors.

The study, “Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS” was published in the journal Frontiers in Immunology.

In rare cases (about 10%), aHUS is associated with autoantibodies targeting the complement factor H (anti-FHs).

The reason for the formation of these autoantibodies is largely unknown, but in most cases it is associated with a deficiency in factor H-related 1 (FHR1) caused by deletions on CFHR1 and CFHR3 genes, which are adjacent to the CFH gene that encodes factor H.

In these patients, FHR1 deficiency might also be caused by less frequent mutations involving CFHR1 and CFHR4.

A mutation in one of these genes is usually not enough to cause the disorder, with only about half of those who carry a genetic mutation in a complement gene developing aHUS. In fact, in about 30% to 50% of the patients, no genetic mutation can be identified.

The link between FHR1 deficiency and development of related aHUS also remains unclear, especially because there are many healthy people who lack FHR1 too. For instance, homozygous CFHR3-CFHR1 mutations are found in to 3% to 10% of the healthy European populations.

This suggests that FHR1 deficiency alone is not enough and that other factors — possibly other genetic variants — must add up to trigger the disease.

Addressing this possibility, researchers sought to find the genetic determinants behind anti-FH-associated aHUS by comparing patients with this disease with healthy adults with FHR1 deficiency.

This latter reference group, defined here as “supercontrols,” is more informative than the general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. Hence, they were chosen as a comparative group “to optimize the power to detect differences,” researchers said.

The team evaluated the prevalence of genetic variants at several complement-related genes known to underlie aHUS, including CFH, CD46, CFI, CFB, C3, and THBD.

Of 305 aHUS patients recruited from the International Registry of HUS/TTP, 30 were positive for anti-FHs, most of whom were children (median age 7.7 years). FHR1 deficiency was caused by different combinations of mutations at CFHR1, CFHR3 and CFHR4. After screening a population of 960 healthy adults, researchers identified 48 who also had FHR1 deficiency and were used as “supercontrols.”

Comparing the prevalence of genetic variants between anti-FHs aHUS patients and “supercontrols,” researchers found that some rare genetic variants in CFH, THBD, and C3 were more abundant, some of which had never before been linked with aHUS.

A higher percentage of the patients, 24%, carried alterations at one of these genes, compared to 2.1% among “supercontrols.”

They also looked at specific variations within CFH and CD46 — CFH H3 and CD46GGAAC haplotypes — formerly linked with risk of aHUS, to see if they could be related with susceptibility to anti-FHs. None proved different between patients and supercontrols, but were enriched in aHUS patients without anti-FHs, which “highlights the differences in the genetic basis of the two forms of the disease,” researchers wrote.

In addition, the large majority of the studied patients with anti-FHs had infectious illnesses, most commonly upper respiratory tract and gastrointestinal infections, and developed their disease between ages 4 and 12. These findings agree with other published data and “support a ‘two-hit’ model according to which the autoimmunity toward FH could develop as a result of an infection in subjects with genetic predisposing background,” researchers stated.

Taken together, this study indicated that development of anti-FHs aHUS “is complex and multiple ‘hits’ are required for its clinical manifestation,” researchers said.

“Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic [disease-causing] variants or other risk factors influences disease outcome and response to therapies,” they concluded.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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