Scientists Identify Common Genetic Ground Between Scleroderma and Crohn’s

Changes in four DNA spots influence the risk of developing both scleroderma and Crohn’s disease, researches found.

One of the spots hadn’t previously been associated with either disease.

The variants had opposing effects in susceptibility, “thus highlighting the complex effects that shared associations have on disease outcomes,” the researchers said.

The study, “A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease,” was published in the journal Scientific Reports.

Despite their distinct characteristics, evidence suggests that scleroderma and Crohn’s disease share a common genetic basis. However, no studies have analyzed the genetic overlap.

Genome-wide association studies (GWAS) enable researchers to search all genes in an individual’s cells for small variations. Scientists use the data to pinpoint genes that may contribute to the risk of developing a certain disorder.

Investigators at Instituto de Parasitología y Biomedicina López-Neyra in Granada, Spain, and their collaborators sought to better understand the common genetic background between systemic sclerosis and Crohn’s disease. They did so by combining GWAS data from 5,734 scleroderma patients with that of 4,588 people with Crohn’s disease. For comparison, researchers also analyzed data from 14,568 healthy individuals of European ancestry.

They found that changes in the IL12RB2 and STAT3 genes and another variant close to IRF1/SLC22A5 contribute to the risk of developing both disorders.

The alteration in IL12RB2 had been previously associated with scleroderma, and the mutations in STAT3 and near IRF1/SLC22A5 had been linked with Crohn’s. Such genes participate in one’s immune response, and help control cellular differentiation and function.

Scientists also identified a DNA spot located between the genes ZBTB9 and BAK1 (specifically, at position 6p21.31) that increased the likelihood of having the two disorders. This spot had never been associated with either scleroderma or Crohn’s.

The variants had opposite effects in susceptibility to the diseases. The change at 6p21.31 was associated with protection against scleroderma but higher risk of Crohn’s. In contrast, the alterations in IL12RB2, STAT3, and IRF correlated with greater likelihood of developing scleroderma, but less risk of Crohn’s.

“This could be due to the fact that consequences of genetic variants are influenced by the cell type,” the researchers said.

For example, the variant in a gene copy of IL12RB2 that increased risk for scleroderma was associated with higher protein levels in whole blood, while the variant of the same gene that increased the likelihood for having Crohn’s (more frequent than the one linked with scleroderma) had a similar effect in protein levels, specifically in cells called fibroblasts.

Further analysis revealed that the four variants significantly influenced 29 molecular pathways, the most relevant of which were related to the immune molecules interleukin-12 and type I interferon.

Although the identified gene locations bring together two distinct immune-mediated disorders, the cellular effects highlight the complexity of the molecular mechanisms by which these genetic changes affect disease course, the researchers said.

“These results suggest that predisposition to related diseases may be regulated by different dose balance of genes and genomic elements in relevant biological pathways, as well as how these differences affect a specific cell type,” they said.