Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis‐associated Pulmonary Arterial Hypertension

Abstract

Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc.

The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection

“…Our finding of a genetic association of CX3CR1 with liver fibrosis is supported by other studies that correlated this gene with fibroproliferative disorders such as age-related macular degeneration [27], systemic sclerosis [28] and fibrostenosing Crohn's disease [26]. Interestingly in these diseases, carriage of the 249I and/or 280M alleles was associated with a more pronounced disease phenotype, whereas in coronary heart disease the 280M allele seems to be protective [22,23].…”

“…Specifically, the 249I and the 280M alleles result in fewer receptor binding sites and decreased ligand affinity [23,24]. These SNPs have already been shown to be associated with the progression of extrahepatic inflammatory [24,25] and fibrotic diseases [26][27][28], and might therefore also be relevant to liver fibrosis due to HCV.…”

A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis

“…In particular, predicting PAH appears to be very critical for increasing the survival rate in SSc. In this scenario, our results add the UPAR gene to an emerging pool of vasculopathy risk factors, including the KCNA5 , TNFAIP3 , IL23R , SDF‐1 / CXCL12 , ENG , NOS2 , and CX3CR1 genes, that could be used in the future as powerful indicators of the development of SSc‐related PAH (4, 25–31). Moreover, future gene–gene interaction investigations will contribute to a better understanding of the genetic predisposition to SSc‐related vasculopathy.…”

“…That study has identified CD247 as a new susceptibility locus for SSc and has also confirmed the role of different autoimmunity‐associated gene regions, such as HLA class II , and genes, such as IRF5 and STAT4 , as SSc genetic risk factors (33). To the best of our knowledge, the UPAR gene and other genes that have been previously associated with SSc vascular phenotypes, but not with SSc per se, were not highlighted in that genome‐wide association study (25–31, 33). Therefore, large genome‐wide association studies with precise vascular phenotyping will be required in order to firmly establish the role of those genes as SSc‐related vasculopathy risk factors.…”

Rôle de la fractalkine/CX3CL1 et de son récepteur CX3CR1 dans les pathologies allergiques

“…Un rôle pour la chimiokine CX3CL1 et son récepteur CX3CR1 a été suspecté dans le contexte de nombreuses maladies inflammatoires au cours desquelles l'expression de CX3CL1 est élevée comme le psoriasis [21,49] ( §), la bronchopneumopathie obstructive [22], l'hypertension [23] et la fibrose pulmonaire [24]. Il a été par ailleurs proposé que CX3CR1 participait à la pathogenèse de ces affections en favorisant la transmigration des monocytes et/ou des lymphocytes exprimant le récepteur.…”