THBD gene mutations don’t predispose people to aHUS: Study
Variants in Spanish patients at similar frequencies to general population
Mutations in the THBD gene — previously suggested to predispose people to atypical hemolytic uremic syndrome (aHUS) — might not make any significant contribution to the disease’s development and its severity, according to a small Spanish study.
The mutations were found in Spanish aHUS patients at similar frequencies to those reported in the general population. And in most patients with THBD mutations, the disease likely developed due to another illness or exposure to drugs, with patients tending to “recover spontaneously with the removal of the putative underlying cause,” the researchers wrote in “On the relevance of thrombomodulin variants in atypical hemolytic uremic syndrome,” which was published in Kidney International.
aHUS is a type of thrombotic microangiopathy (TMA), a group of diseases wherein blood clots form in small blood vessels. This can lead to organ damage, most commonly in the kidneys.
With aHUS, blood clots form due to a malfunction of the complement system, a group of proteins that forms part of the body’s immune defenses. About 50-60% of patients have disease-causing mutations in genes encoding complement proteins that are thought to predispose them to the disease.
Alone, these mutations are usually not enough for aHUS to develop. This requires an event trigger, such as an infection, pregnancy, or certain treatments and recreational drugs.
More than a decade ago, mutations in the THBD gene, which provides instructions to produce a protein called thrombomodulin (TM) that regulates complement function, were reported to predispose to aHUS.
THBD mutations and aHUS
“However, studies confirming the THBD-aHUS association and determining whether the complement-regulatory activities of TM are significant in aHUS are lacking,” wrote researchers in Spain who reviewed the genetic and clinical data of patients enrolled in the Spanish aHUS/C3 glomerulopathy registry. In C3 glomerulopathy, an overactive complement drives kidney damage.
The researchers specifically selected patients who carried THBD mutations that were found at a frequency of less than 1% in the general European, non-Finnish population to avoid common, non-disease-causing mutations.
In total, 27 of the 1,216 patients in the registry had such THBD mutations. Twenty of them carried isolated THBD mutations, while seven also had well-known disease-causing mutations in genes linked to aHUS, including C3, CFI, CFH, CFB, or MCP.
THBD mutations known to affect TM’s activity were classified as “functional.” Those that might impair the protein’s function were deemed “potentially functional” and those not expected to affect the TM’s activity were “likely benign.”
In total, 19 patients carried “functional” or “potentially functional” THBD mutations and 14 of them had available clinical data. All but two of them carried only THBD mutations. The other two had disease-causing mutations in the C3 gene. None of the 14 had a family history of TMA.
Among the 12 patients with isolated THBD mutations — the best group to assess their effect on aHUS — six had a history of chronic kidney disease with a cause other than aHUS. Five had a TMA event in a transplanted kidney.
Five of the 12 received kidney replacement therapy, which involved a kidney transplant in four and hemodialysis in the other.
In nine of these patients, the aHUS-like event was linked to a kidney transplant (five), drugs (three), infections (two), ischemia reperfusion damage (one), and pregnancy (one). Ischemia reperfusion damage denotes damage to a tissue after blood flow is restored after a restricted blood supply.
Most patients had additional diseases at presentation. TMA was confirmed by kidney biopsy in seven of the 12 cases.
Soliris (eculizumab) was administered to four patients, but without definite improvements. Blood abnormalities resolved in the other eight patients after the triggers were removed. Half of them saw full kidney improvement and 35.7% had a partial response.
No disease recurrence was seen in the 12 patients with THBD mutations only, even though four kidney transplants were conducted without preventive Soliris treatment.
The two patients with mutations also in the C3 gene had more severe anemia than those with isolated THBD mutations and showed severe acute kidney failure that required prompt hemodialysis. One of these received Soliris for three days, with excellent blood and kidney responses. In the other patient, blood parameters improved after the removal of the trigger (cocaine), but there was no kidney recovery.
A weak association
The researchers found some “functional” THBD mutations were frequent in certain ethnic groups and weren’t more commonly found among aHUS patients relative to the general European, non-Finnish population. In contrast, disease-causing mutations in aHUS-associated complement genes were significantly more frequent among aHUS patients.
“Our study has identified important weaknesses in the proposed association between THBD variants and the development of aHUS,” the researchers wrote. “We show that the THBD variants found in our [patient group] with aHUS merely reflect their prevalence in the normal population. They noted that “patients carrying THBD variants do not exhibit the prototypical clinical profiles of patients with complement-mediated aHUS and resemble those with secondary HUS.”
“Although our study has limitations due to the small number of patients and its retrospective nature, the data generated do not support a significant contribution of the THBD variants to the development of complement-mediated aHUS,” they wrote.