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Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1


Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23–1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75–0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.

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Figure 1: Manhattan plot showing directly genotyped SNPs plotted according to chromosomal location (x axis), with –log10 P values (y axis) derived from the 1-degree-of-freedom score test.

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This work was supported by the Wellcome Trust, United Kingdom (grant 088791/A/09/Z and 084368/Z/07/Z), and the Agency for Science, Technology and Research, Singapore.

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Authors and Affiliations



M.L.H. and C.P.S. are the study principal investigators who conceived and obtained funding for the project. C.C.K. organized and supervised the GWAS and replication genotyping pipeline, devised the overall analysis plan and wrote the first draft of the manuscript with input from M.L.H., C.P.S. and S.D. T.N.B.C. is the lead coordinator of clinical samples and phenotypes for both the discovery and replication stages. J.P. and D.E.K.T. performed genotyping and quality checks on all samples. C.C.K., S.D., R.T.H.O. and Y.-Y.T. analyzed the data. H.T.L., S.J.D., B.W., J.F., T.V.T., T.T.G., N.T.N.B., L.T.T., L.B.L., N.M.T., N.T.H.T., M.N.L., N.M.N., N.T.H., N.V.V.C., T.T.T. and A.S. coordinated and contributed patient and database phenotype collections as lead investigators for their respective sample collections. D.E.K.T. and J.P. performed genotyping and DNA quality checks. All authors critically reviewed manuscript revisions and contributed intellectual input to the final submission.

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Correspondence to Martin L Hibberd or Cameron P Simmons.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Tables 1–3 (PDF 2865 kb)

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Khor, C., Chau, T., Pang, J. et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nat Genet 43, 1139–1141 (2011).

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