Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt
Authors: Vincent Pedergnana, Mohamed Abdel‐Hamid, Julien Guergnon, Ioannis Theodorou, Arnaud Fontanet, Laurent Abel, Aurélie Cobat
Journal: Hepatology (2015)

This work was supported by grants from the EC FP7 Coordinated Actions–The SPHINX Consortium and the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (grant nos.: ANRS 12107, 12122, and 12210). The Laboratory of Human Genetics of Infectious Diseases is supported by the French National Research Agency (ANR) under the “Investments for the Future” program (grant no.: ANR‐10‐IAHU‐01). Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: Hoffmann et al.1 recently reported in Hepatology the association of two nonsynonymous single‐nucleotide 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.2 Egypt has the highest prevalence of HCV infection worldwide, with a seroprevalence ranging from 10% in children to 45% in adults. We recently refined the definition of the IL28B region associated with SC in Egypt in a sample of 261 individuals, 130 with SC and 131 with chronic infection.3 Here, we genotyped the two MDA5 SNPs in the same Egyptian sample.3 We replicated the association of the T allele of rs3747517 (H843) with SC (odds ratio [OR] of SC for T/T vs. T/C [or T/C vs. C/C] = 1.44; 95% confidence interval [CI]: 1.0‐2.13; Pone‐sided = 0.03; Fig. 1A). A more significant association with SC was obtained with the C allele of rs1990760 (A946; OR for C/C vs. T/C = 1.69; 95% CI: 1.18‐2.44; Pone‐sided = 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; r2 = 0.33). Thus, the rare H843/T946 haplotype identified as the strongest predictor of SC1 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 = 1.69; 95% CI: 1.18‐2.44; P = 0.005; Fig. 1B). LD analysis of MDA5 (162,262,079‐162,323,703 bps) in the European populations of the public database of the 1000 Genomes Project (http://www.1000genomes.org) identified six additional SNPs with a minor allele frequency above 5%, only one of which, rs13023380, was in strong LD (r2 > 0.5) with rs1990760 (r2 = 0.66; D’=1). Genotyping of rs13023380 revealed a consistent pattern of LD in Egypt (r2 = 0.76; D’=0.97). Univariate analysis showed a slightly more significant association of SC with allele G of rs13023380 (OR for GG vs. AG = 1.88; 95% CI: 1.30‐2.78; P = 0.001). Haplotype analysis for rs1990760‐rs13023380 showed that haplotypes carrying the G allele of rs13023380 (TG or CG) were the strongest predictors of SC (OR = 1.87; 95% CI: 1.28‐2.76; P = 0.001; Fig. 1B). Therefore, in this population, the signal is supported by the nonsynonymous SNP, rs1990760, and/or the intronic SNP, rs13023380. However, the effects of rs1990760 and rs13023380 could not be distinguished statistically, owing to strong LD (the TG haplotype is rare). Interestingly, rs13023380 is located in a transcription factor‐binding site (http://www.ensembl.org), and further studies are required to investigate its functional role. Overall, our results extend the association of MDA5 variants with SC to an Egyptian population mostly infected by HCV genotype 4.Figure 1: MDA5 SNPs are associated with the SC of HCV using an additive genetic model. The rate of SC observed in Egyptian subjects is shown by genotype: (A) for the three MDA5 SNPs, rs3747517 (white), rs1990760 (light gray), and rs13023380 (dark gray); (B) for haplotypes consisting of the two SNPs, rs3747517‐rs1990760 (white and light gray), and the two SNPS, rs1990760‐rs13023380 (dark gray). For rs3747517‐rs1990760 haplotype analyses, taking the CT haplotype as the reference (and TC and CC as alternatives because the TT haplotype was not observed, in white) revealed a significant association with SC, whereas no such association was observed when the CC haplotype was used as the reference (with CT and CC as alternatives, in light gray). Thus, the association of rs3747517‐rs1990760 with SC is supported by the T allele of rs1990760, rather than by the C allele of rs3747517. The amino acid changes are indicated in boxes, where appropriate (A), with the frequencies of the first allele (A) or haplotype (B), in bold italics, shown in brackets for subjects with SC (n = 130) and subjects with chronic infection (n = 131).