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Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Crosslin DR, Carrell DS, Burt A, Kim DS, Underwood JG, Hanna DS, Comstock BA, Baldwin E, de Andrade M, Kullo IJ, Tromp G, Kuivaniemi H, Borthwick KM, McCarty CA, Peissig PL, Doheny KF, Pugh E, Kho A, Pacheco J, Hayes MG, Ritchie MD, Verma SS, Armstrong G, Stallings S, Denny JC, Carroll RJ, Crawford DC, Crane PK, Mukherjee S, Bottinger E, Li R, Keating B, Mirel DB, Carlson CS, Harley JB, Larson EB, Jarvik GP - Genes Immun. (2014)

Bottom Line: Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)).Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV.Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Genome Sciences, University of Washington, Seattle, WA, USA.

ABSTRACT
Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

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Related in: MedlinePlus

Regional LD plot using the SNP Annotation and Proxy Search software.25
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fig3: Regional LD plot using the SNP Annotation and Proxy Search software.25

Mentions: The variants driving the association in the European ancestry group and tagging HCP5 were rs116062713 (P=1.04 × 10−7) and rs114864815 (P=6.94 × 10−8) located upstream and at the 5′ untranslated region of HCP5, respectively. In each case, the minor allele frequency ((MAF)=0.08) conferred protection, with hazard ratios (HR)=0.73 (95% confidence interval (CI): 0.64–0.82). In the joint ancestry survival analyses, these variants nearly reached genome-wide significance (P=5.22 × 10−8 and 4.54 × 10−8), with HR~0.72 (95% CI: 0.65–0.82). With logistic regression analyses, both the joint and European ancestry analyses yielded associations in this region, with P~4.00x10−6 and odds ratio (OR)~0.74 (95% CI: ~0.65–0.83). Manhattan plots and corresponding QQ plots are provided (Supplementary Figures S1–S3, respectively). We illustrate the regional linkage disequilibrium (LD) plot using annotated P-values from the Cox regression analysis in the European ancestry sample (Figure 3). LD, with respect to rs114864815, was generated using the same European ancestry sample and is annotated with shades of red. The background recombination rate illustrated in blue was generated from the 1000 Genomes Pilot 1 data. There is a region in high LD with the HCP5 variants upstream of HLA-B that yielded the most significant association results in the European ancestry survival analyses (Figure 3). The most significant single-nucleotide polymorphisms (SNPs) (rs114045064 and rs112660930) reached genome-wide significance (P=5.06 × 10−9 and 5.26 × 10−9), with HR=0.77 (95% CI: 0.71–0.85). These SNPs are tagging a repeated untranslated region region of the retrogene of dihydrofolate reductase (DHFR) gene. With respect to logistic regression analyses, both the joint and European ancestry analyses yielded associations in this region, with P~1.00 × 10−7 and OR~0.80 (95% CI:~0.73–0.87). None of these variants reached genome-wide significance in the African ancestry and Hispanic groups (Table 2).


Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Crosslin DR, Carrell DS, Burt A, Kim DS, Underwood JG, Hanna DS, Comstock BA, Baldwin E, de Andrade M, Kullo IJ, Tromp G, Kuivaniemi H, Borthwick KM, McCarty CA, Peissig PL, Doheny KF, Pugh E, Kho A, Pacheco J, Hayes MG, Ritchie MD, Verma SS, Armstrong G, Stallings S, Denny JC, Carroll RJ, Crawford DC, Crane PK, Mukherjee S, Bottinger E, Li R, Keating B, Mirel DB, Carlson CS, Harley JB, Larson EB, Jarvik GP - Genes Immun. (2014)

Regional LD plot using the SNP Annotation and Proxy Search software.25
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308645&req=5

fig3: Regional LD plot using the SNP Annotation and Proxy Search software.25
Mentions: The variants driving the association in the European ancestry group and tagging HCP5 were rs116062713 (P=1.04 × 10−7) and rs114864815 (P=6.94 × 10−8) located upstream and at the 5′ untranslated region of HCP5, respectively. In each case, the minor allele frequency ((MAF)=0.08) conferred protection, with hazard ratios (HR)=0.73 (95% confidence interval (CI): 0.64–0.82). In the joint ancestry survival analyses, these variants nearly reached genome-wide significance (P=5.22 × 10−8 and 4.54 × 10−8), with HR~0.72 (95% CI: 0.65–0.82). With logistic regression analyses, both the joint and European ancestry analyses yielded associations in this region, with P~4.00x10−6 and odds ratio (OR)~0.74 (95% CI: ~0.65–0.83). Manhattan plots and corresponding QQ plots are provided (Supplementary Figures S1–S3, respectively). We illustrate the regional linkage disequilibrium (LD) plot using annotated P-values from the Cox regression analysis in the European ancestry sample (Figure 3). LD, with respect to rs114864815, was generated using the same European ancestry sample and is annotated with shades of red. The background recombination rate illustrated in blue was generated from the 1000 Genomes Pilot 1 data. There is a region in high LD with the HCP5 variants upstream of HLA-B that yielded the most significant association results in the European ancestry survival analyses (Figure 3). The most significant single-nucleotide polymorphisms (SNPs) (rs114045064 and rs112660930) reached genome-wide significance (P=5.06 × 10−9 and 5.26 × 10−9), with HR=0.77 (95% CI: 0.71–0.85). These SNPs are tagging a repeated untranslated region region of the retrogene of dihydrofolate reductase (DHFR) gene. With respect to logistic regression analyses, both the joint and European ancestry analyses yielded associations in this region, with P~1.00 × 10−7 and OR~0.80 (95% CI:~0.73–0.87). None of these variants reached genome-wide significance in the African ancestry and Hispanic groups (Table 2).

Bottom Line: Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)).Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV.Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Genome Sciences, University of Washington, Seattle, WA, USA.

ABSTRACT
Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Show MeSH
Related in: MedlinePlus