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. 2012 Jun;20(6):690-5.
doi: 10.1038/ejhg.2011.260. Epub 2012 Jan 18.

A major locus on chromosome 3p22 conferring predisposition to human herpesvirus 8 infection

Vincent Pedergnana  1 , Antoine Gessain, Patricia Tortevoye, Minji Byun, Delphine Bacq-Daian, Anne Boland, Jean-Laurent Casanova, Laurent Abel, Sabine Plancoulaine
Affiliations

A major locus on chromosome 3p22 conferring predisposition to human herpesvirus 8 infection

Vincent Pedergnana et al. Eur J Hum Genet. 2012 Jun.

Abstract

Infection with human herpesvirus 8 (HHV-8), the etiological agent of Kaposi's sarcoma, has been shown to display strong familial aggregation, in countries in which HHV-8 infection is endemic. We investigated 40 large families (608 subjects aged one to 88 years) living in an isolated area of Cameroon in which HHV-8 is highly endemic. We performed a two-step genetic analysis for HHV-8 infection status (HHV-8+/HHV-8- determined by immunofluorescence) consisting of an initial segregation analysis followed by a model-based genome-wide linkage analysis. Overall HHV-8 seroprevalence was 60%, increasing with age. Segregation analysis provided strong evidence for a recessive major gene conferring predisposition to HHV-8 infection. This gene is predicted to have a major effect during childhood, with almost all homozygous predisposed subjects (∼7% of the population) becoming infected by the age of 10. Linkage analysis was carried out on the 15 most informative families, corresponding to 205 genotyped subjects. A single region on chromosome 3p22 was significantly linked to HHV-8 infection (LOD score=3.83, P=2.0 × 10(-5)). This study provides the first evidence that HHV-8 infection in children in endemic areas has a strong genetic basis involving at least one recessive major locus on chromosome 3p22.

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Figures

Figure 1
Figure 1
HHV-8 seroprevalence rates in 608 Bantu subjects from an isolated village in the Ntem Valley, South Cameroon, as a function of age, classified into three classes (1–9, 10–39 and >39 years old). Antibodies directed against lytic HHV-8 antigens were detected in immunofluorescence assays with the KS-1 cell line. Bars indicate the 95% confidence intervals for seroprevalence rates.
Figure 2
Figure 2
Characteristics of the recessive major gene conferring predisposition to HHV-8 infection, as predicted by the segregation analysis model. (a) Penetrance (ie, probability of being HHV-8 seropositive) for children under the age of 15 years, as a function of age, genotype for the detected major gene (DD, two upper lines; Dd or dd, two lower lines) and HHV-8 status of preceding siblings. D is the recessive allele conferring predisposition to HHV-8 infection. Dashed lines and solid lines correspond to children without and with at least one HHV-8-seropositive sibling, respectively. (b) Variation with age of the probability of carrying either a predisposing genotype (DD, dashed line) or a non-predisposing genotype (Dd or dd, plain line), for HHV-8+ subjects.
Figure 3
Figure 3
Genome-wide linkage analysis in 15 Cameroonian families with at least one HHV-8+ child under the age of 10 years. (a) Multipoint LOD scores (y axis) are plotted along the 22 autosomes (lower x axis: chromosome numbers, upper x axis: physical distances in megabases). (b) Expanded view of the region with the highest LOD score on chromosome 3p22. Genes with known functions and microRNA sequences located within the 95% confidence interval of the peak are indicated, and those involved in antiviral response and immunity are underlined.
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