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. 2012 Jun;205(11):1665-76.
doi: 10.1093/infdis/jis249. Epub 2012 Mar 23.

Sequence analysis of Kaposi sarcoma-associated herpesvirus (KSHV) microRNAs in patients with multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome

Alex Ray  1 , Vickie Marshall, Thomas Uldrick, Robert Leighty, Nazzarena Labo, Kathy Wyvill, Karen Aleman, Mark N Polizzotto, Richard F Little, Robert Yarchoan, Denise Whitby
Affiliations

Sequence analysis of Kaposi sarcoma-associated herpesvirus (KSHV) microRNAs in patients with multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome

Alex Ray et al. J Infect Dis. 2012 Jun.

Abstract

Background: Kaposi sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that yield 25 mature microRNAs. We previously reported phylogenetic analysis of the microRNA-coding region of KSHV from Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD) patients. We observed a high level of conservation for most sequences but also a divergent cluster of 5 KSHV sequences, including 2 from MCD patients.

Methods: KSHV microRNA sequences from 23 MCD patients and 7 patients with a newly described KSHV-associated inflammatory cytokine syndrome (KICS) were examined by amplification, cloning, and sequencing of a 646-bp fragment of K12/T0.7 encoding microRNA-K12-10 and microRNA-K12-12 and a 2.8-kbp fragment containing the remaining 10 pre-microRNAs.

Results: Phylogenetic analysis showed a distinct variant cluster consisting exclusively of MCD and KICS patients in all trees. Pearson χ(2) analysis revealed that 40 single-nucleotide polymorphisms (SNPs) at various loci were significantly associated with MCD and KICS risk. Cluster analysis of these SNPs generated several combinations of 3 SNPs as putative indicators of MCD and KICS risk.

Conclusions: These findings show that MCD and KICS patients frequently have unusual KSHV microRNA sequences and suggest an association between the observed sequence variation and risk of MCD and KICS.

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Figures

Figure 1.
Figure 1.
K1 subtype analysis of Kaposi sarcoma–associated herpesvirus (KSHV)–multicentric Castleman disease (MCD) and KSHV-associated inflammatory cytokine syndrome (KICS) patients. All K1 sequences collected were translated prior to analysis and were analyzed by bootstrap neighbor-joining analysis with relevant sequences from GenBank. In total, 100 bootstrap replicates were conducted to determine the topology of the trees using MEGA (version 4.0.2). KSHV-MCD patients are indicated by a square and KICS patients are indicated by a triangle. AIDS–Kaposi sarcoma cases and controls are unmarked.
Figure 2.
Figure 2.
MicroRNA cluster region phylogenetic tree. MicroRNA cluster region phylogenies were determined using bootstrap neighbor-joining analysis and rooted with outlier patient MCD-07 using MEGA (version 4.0.2). Subtype nomenclature is consistent with previous reports [1, 35]. Kaposi sarcoma–associated herpesvirus (KSHV)–multicentric Castleman disease (MCD) patients are indicated by a square, and KSHV-associated inflammatory cytokine syndrome (KICS) patients are indicated by a triangle. AIDS–Kaposi sarcoma cases and controls are unmarked. Conserved sequences are shown as subtypes A and C and variant sequences are shown as subtypes F and B.
Figure 3.
Figure 3.
T0.7/K12 Phylogenetic tree. Subtype nomenclature for the present trees are consistent with that established for T0.7/K12. Neighbor-joining bootstrap analysis was performed using 100 bootstrap replicates and rooted with outlier patient MCD-07 using MEGA (version 4.0.2). Kaposi sarcoma–associated herpesvirus (KSHV)–multicentric Castleman disease (MCD) patients are indicated by a square, and KSHV-associated inflammatory cytokine syndrome (KICS) patients are indicated by a triangle. AIDS–Kaposi sarcoma cases and controls are unmarked. Conserved sequences are shown as subtypes A and C and variant sequences are shown as subtypes F and B.
Figure 4.
Figure 4.
Summary of significant single-nucleotide polymorphisms in microRNA cluster region. Kaposi sarcoma–associated herpesvirus (KSHV)–multicentric Castleman disease (MCD) and KSHV-associated inflammatory cytokine syndrome (KICS) patients were compared to AIDS–Kaposi sarcoma cases and controls using Pearson χ2 test. Because multiple comparisons were performed, P < .05 was deemed to be a threshold for marginal significance, P < .005 to be approaching significance, and P < .0005 to be significant. P values are listed to the right. The microRNA cluster region is shown to the left as a reference, and locations of KSHV pre-microRNAs are indicated by light gray shading.
Figure 5.
Figure 5.
Summary of significant single-nucleotide polymorphisms (SNPs) in T0.7/K12 region. SNPs identified in the T0.7/K12 region were analyzed in the same manner as those identified in the microRNA cluster region. The P values are listed to the right and the T0.7/K12 region is shown to the left with corresponding microRNAs in light gray shading.
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