Genetic variants in cytokine genes linked to CAD in new study

Cytokine dysregulation in immune system may increase risk of developing CAD

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Certain variations in genes that encode cytokines — signaling molecules involved in immune responses — may predispose people toward the development of cold agglutinin disease (CAD), a new study suggests.

The study, “Cytokine polymorphisms in patients with autoimmune hemolytic anemia,” was published in Frontiers in Immunology.

CAD is a type of autoimmune hemolytic anemia (AIHA), a group of diseases wherein the immune system mistakenly attacks and destroys red blood cells. In CAD, self-reactive antibodies called cold agglutinins attack these cells at cold temperatures.

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Abnormalities in cytokine signaling seen in autoimmune diseases

Cytokines are signaling molecules that immune cells use to communicate with each other and coordinate inflammatory responses. Abnormalities in cytokine signaling have been previously described in autoimmune diseases like AIHA, but whether these are a cause or result of CAD remains unclear.

“There is growing interest in the possible role of the genetic background in the regulation of immune effectors and cytokines in several autoimmune diseases, including outcome and response to biological drugs,” the researchers wrote.

Variations in the genes that provide instructions to make cytokines can affect the levels and activity of these signaling molecules, but whether such variations affect the likelihood of developing AIHA isn’t known.

In this study, scientists in Italy collected genetic data from 123 people with AIHA, including 46 (28 women and 18 men) with CAD and 77 with warm AIHA, who were diagnosed at their center. In warm AIHA, as the name suggests, immune attacks against red blood cells occur at warm temperatures.

The researchers determined rates of single-nucleotide variations in five cytokine genes among patients, then compared these rates against the general population. Nucleotides are the building blocks of DNA.

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Differences detected for 2 cytokine genes

Notable differences were detected for two cytokine genes: those encoding tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta).

At a particular spot in the TNF-alpha gene, most people have a nucleotide called guanine, abbreviated G. However, some people have an alanine nucleotide, abbreviated A, instead.

As everyone inherits two copies of the TNF-alpha gene — one from each biological parent — it’s possible to have three combinations or genotypes of this particular DNA section (GG, GA, or AA). However, given the A variant is rare, most people have either GG or GA.

The researchers found the GG genotype was less frequent among AIHA patients relative to the general population (64% vs. 77%-84%). This difference was more pronounced in the group of warm AIHA patients (58%), as CAD patients showed a nearly normal frequency of that genotype (74%).

In turn, the rare A variant, and GA and AA genotypes were more common among people with AIHA.

Similarly, AIHA patients also had significantly lower rates of a particular variant in the TGF-beta gene, referred to as the GG genotype (74% for CAD and 77% for AIHA vs. 87% in healthy people).

Activity of the TGF-beta and IL-10 genes was higher in patients with more severe anemia. Also, genotypes associated with greater TNF-alpha and TGF-beta activity were more frequent in AIHA patients — particularly those with CAD — who received several prior treatments.

“It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease,” the researchers wrote.

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TNF-alpha blood levels found lower in AIHA than in controls

For example, the A variant in the TNF-alpha gene has been linked with higher levels of TNF-alpha, a cytokine known to promote inflammation. As such, it might be expected that TNF-alpha levels would be high in AIHA patients.

“Surprisingly, [TNF-alpha blood] levels were found to be lower in AIHA than in controls,” the researchers wrote.

One possible explanation is that, in AIHA patients, more TNF-alpha is getting used up as part of ongoing inflammation, so circulating levels might appear low even though activity of the signaling molecule is actually high, the team noted.

“Overall, the results pinpoint the complexity of the cytokine network,” the scientists concluded, highlighting a need for further investigation into how cytokine dysregulation may contribute to CAD.