Polymorphisms in melanoma differentiation‐associated gene 5 link protein function to clearance of hepatitis C virus

Abstract

Among patients newly infected with hepatitis C virus (HCV), only 20–30 % clear the infection spontaneously. In the remaining 70 %, the infection persists causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. RIG-I-like helicases such as MDA-5 are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analysed 14 non-synonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients that spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We find that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (OR: 16.23 (95 % CI: 3.67 – 71.87); p = 1.1 × 10−6). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. Conclusion These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection.

Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt

“…1A). A more significant association with SC was obtained with the C allele of rs1990760 (A946; OR for C/C vs. T/C 5 1.69; 95% CI: 1.18-2.44; P one-sided 5 0.005), consistent with the trend shown in Table 2 of Hoffman et al (1) Multivariate analysis confirmed that the effect of rs1990760 was independent of the IL28B SNP rs12979860. Linkage disequilibrium (LD) analysis on our cohort revealed that rs3747517 and rs1990760 were in strong LD (D'=1; r 2 5 0.33).…”

“…Linkage disequilibrium (LD) analysis on our cohort revealed that rs3747517 and rs1990760 were in strong LD (D'=1; r 2 5 0.33). Thus, the rare H843/T946 haplotype identified as the strongest predictor of SC (1) was not observed in this Egyptian population. Our haplotype analysis for rs3747517-rs1990760 showed that SC was the most strongly associated with haplotypes carrying allele C (TC or CC) of rs1990760 (OR 5 1.69; 95% CI: 1.18-2.44; P 5 0.005; Fig.…”

“…Hoffmann et al (1) recently reported in HEPATOLOGY the association of two nonsynonymous singlenucleotide polymorphisms (SNPs) of melanoma differentiation-associated gene 5 (MDA5), rs3747517 (R843H), and rs1990760 (T946A), with the spontaneous clearance (SC) of hepatitis C virus (HCV) infection in Europeans. MDA5 recognizes HCV and plays an important role in initiating host innate immune response during HCV infection.…”

“…Overall, our results extend the association of MDA5 variants with SC to an Egyptian population mostly infected by HCV genotype 4. In a recent article in HEPATOLOGY, Hoffmann et al (1) used two different European-ancestry cohorts to identify a haplotype in the melanoma differentiationassociated gene 5 (mda5) that is associated with a 16-fold increased likelihood for spontaneous hepatitis C virus (HCV) clearance. In this haplotype, H843/ T946, the single-nucleotide polymorphism (SNP) rs3747517 encoding the H843 variant was also associated with spontaneous HCV clearance, whereas the SNP (rs1990760) encoding T946 was not.…”

MDA5—filament, dynamics and disease

“…Multiple Genome Wide Association (GWA) studies have shown that MDA5 is not only involved in antiviral immunity [31], but also in pathogenesis of several immune disorders, such as type 1 diabetes [32, 33], systemic lupus erythematosus [34, 35], multiple sclerosis [36] and rheumatoid arthritis [37]. Single nucleotide polymorphisms (SNPs) in the MDA5 gene ( IFIH1 ), such as T946A, R843H, E627X and I923V, were shown to be complete or partial loss-of-function mutations and to be associated with protection from these diseases [17, 31, 38, 39].…”