Limits...
Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus.

Pedergnana V, Abdel-Hamid M, Guergnon J, Mohsen A, Le Fouler L, Theodorou I, Mohamed MK, Fontanet A, Plancoulaine S, Abel L - PLoS ONE (2012)

Bottom Line: The most associated SNPs were rs12979860 (P = 1.6 × 10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 × 10(-7)).Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases.HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.

ABSTRACT
Spontaneous clearance of hepatitis C virus (HCV) occurs in ~30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6 × 10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 × 10(-7)). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.

Show MeSH

Related in: MedlinePlus

Haplotype frequencies estimated from the Egyptian population, as a function of HCV status.Haplotype frequencies are given for each of the two groups: individuals with persistent infection (“Chronic infection”) and individuals who cleared the infection (“Spontaneous clearance”). As defined in the text, the protective haplotypes (1 and 2) favour HCV clearance, whereas the “at risk” haplotypes (3 to 7) confer a predisposition to chronic HCV infection. The more frequent protective haplotype (haplotype 1) could be defined as the reference protective haplotype, while the more frequent “at risk” haplotype (haplotype 3), which is composed of the exact opposite alleles for all SNPs of haplotype 1, could be defined as the reference “at risk” haplotype. The dashed-line circles show discrepancies within the two protective haplotypes, i.e. between haplotype 2 and the reference protective haplotype 1. The dashed-line squares show discrepancies within the “at risk” haplotypes, i.e. between haplotypes 4–7 and the reference “at risk” haplotype 3. Only two SNPs identified by the solid-line rectangle (rs8103142 and rs12979860) shows have the same allele for the two protective haplotypes and the alternative allele in all the five at risk haplotypes.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3375300&req=5

pone-0038578-g002: Haplotype frequencies estimated from the Egyptian population, as a function of HCV status.Haplotype frequencies are given for each of the two groups: individuals with persistent infection (“Chronic infection”) and individuals who cleared the infection (“Spontaneous clearance”). As defined in the text, the protective haplotypes (1 and 2) favour HCV clearance, whereas the “at risk” haplotypes (3 to 7) confer a predisposition to chronic HCV infection. The more frequent protective haplotype (haplotype 1) could be defined as the reference protective haplotype, while the more frequent “at risk” haplotype (haplotype 3), which is composed of the exact opposite alleles for all SNPs of haplotype 1, could be defined as the reference “at risk” haplotype. The dashed-line circles show discrepancies within the two protective haplotypes, i.e. between haplotype 2 and the reference protective haplotype 1. The dashed-line squares show discrepancies within the “at risk” haplotypes, i.e. between haplotypes 4–7 and the reference “at risk” haplotype 3. Only two SNPs identified by the solid-line rectangle (rs8103142 and rs12979860) shows have the same allele for the two protective haplotypes and the alternative allele in all the five at risk haplotypes.

Mentions: Finally, we estimated haplotype frequencies derived from the six polymorphic SNPs in this population. The objective of this haplotype analysis was not to test formally for differences in haplotype frequencies between subjects with clearance and those with chronic infection, but to further refine our univariate results by providing the general haplotype structure of this Egyptian sample. Seven haplotypes had an estimated frequency >0.02 in the whole sample. Based on differences in haplotype frequencies between subjects with spontaneous clearance and those with chronic infection, these seven haplotypes could be classified into two protective (favouring clearance) haplotypes (one of which was much more common than the other) and five “at risk” haplotypes (conferring a predisposition to chronic infection) (Figure 2). The two protective haplotypes differed only in terms of the allele of SNP rs4803217. In comparisons with the alleles present in the two protective haplotypes, only two SNPs presented the alternative allele in all five at risk haplotypes, discrepancies being observed for the others. The two SNPs with consistently different alleles between the protective and at risk haplotypes were rs12979860 and rs8103142, the non-synonymous SNP. This observation is consistent with the univariate association results and supports the view that the core of the association is dependent on these two SNPs, the effect of which are indistinguishable in this sample.


Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus.

Pedergnana V, Abdel-Hamid M, Guergnon J, Mohsen A, Le Fouler L, Theodorou I, Mohamed MK, Fontanet A, Plancoulaine S, Abel L - PLoS ONE (2012)

Haplotype frequencies estimated from the Egyptian population, as a function of HCV status.Haplotype frequencies are given for each of the two groups: individuals with persistent infection (“Chronic infection”) and individuals who cleared the infection (“Spontaneous clearance”). As defined in the text, the protective haplotypes (1 and 2) favour HCV clearance, whereas the “at risk” haplotypes (3 to 7) confer a predisposition to chronic HCV infection. The more frequent protective haplotype (haplotype 1) could be defined as the reference protective haplotype, while the more frequent “at risk” haplotype (haplotype 3), which is composed of the exact opposite alleles for all SNPs of haplotype 1, could be defined as the reference “at risk” haplotype. The dashed-line circles show discrepancies within the two protective haplotypes, i.e. between haplotype 2 and the reference protective haplotype 1. The dashed-line squares show discrepancies within the “at risk” haplotypes, i.e. between haplotypes 4–7 and the reference “at risk” haplotype 3. Only two SNPs identified by the solid-line rectangle (rs8103142 and rs12979860) shows have the same allele for the two protective haplotypes and the alternative allele in all the five at risk haplotypes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375300&req=5

pone-0038578-g002: Haplotype frequencies estimated from the Egyptian population, as a function of HCV status.Haplotype frequencies are given for each of the two groups: individuals with persistent infection (“Chronic infection”) and individuals who cleared the infection (“Spontaneous clearance”). As defined in the text, the protective haplotypes (1 and 2) favour HCV clearance, whereas the “at risk” haplotypes (3 to 7) confer a predisposition to chronic HCV infection. The more frequent protective haplotype (haplotype 1) could be defined as the reference protective haplotype, while the more frequent “at risk” haplotype (haplotype 3), which is composed of the exact opposite alleles for all SNPs of haplotype 1, could be defined as the reference “at risk” haplotype. The dashed-line circles show discrepancies within the two protective haplotypes, i.e. between haplotype 2 and the reference protective haplotype 1. The dashed-line squares show discrepancies within the “at risk” haplotypes, i.e. between haplotypes 4–7 and the reference “at risk” haplotype 3. Only two SNPs identified by the solid-line rectangle (rs8103142 and rs12979860) shows have the same allele for the two protective haplotypes and the alternative allele in all the five at risk haplotypes.
Mentions: Finally, we estimated haplotype frequencies derived from the six polymorphic SNPs in this population. The objective of this haplotype analysis was not to test formally for differences in haplotype frequencies between subjects with clearance and those with chronic infection, but to further refine our univariate results by providing the general haplotype structure of this Egyptian sample. Seven haplotypes had an estimated frequency >0.02 in the whole sample. Based on differences in haplotype frequencies between subjects with spontaneous clearance and those with chronic infection, these seven haplotypes could be classified into two protective (favouring clearance) haplotypes (one of which was much more common than the other) and five “at risk” haplotypes (conferring a predisposition to chronic infection) (Figure 2). The two protective haplotypes differed only in terms of the allele of SNP rs4803217. In comparisons with the alleles present in the two protective haplotypes, only two SNPs presented the alternative allele in all five at risk haplotypes, discrepancies being observed for the others. The two SNPs with consistently different alleles between the protective and at risk haplotypes were rs12979860 and rs8103142, the non-synonymous SNP. This observation is consistent with the univariate association results and supports the view that the core of the association is dependent on these two SNPs, the effect of which are indistinguishable in this sample.

Bottom Line: The most associated SNPs were rs12979860 (P = 1.6 × 10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 × 10(-7)).Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases.HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.

ABSTRACT
Spontaneous clearance of hepatitis C virus (HCV) occurs in ~30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6 × 10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 × 10(-7)). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ∼20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.

Show MeSH
Related in: MedlinePlus