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

Chiea Chuen Khor, Tran Nguyen Bich Chau, Junxiong Pang, Sonia Davila, Hoang Truong Long, Rick T H Ong, Sarah J Dunstan, Bridget Wills, Jeremy Farrar, Ta Van Tram, Tran Thi Gan, Nguyen Thi Nguyet Binh, Le Trung Tri, Le Bich Lien, Nguyen Minh Tuan, Nguyen Thi Hong Tham, Mai Ngoc Lanh, Nguyen Minh Nguyet, Nguyen Trong Hieu, Nguyen Van N Vinh Chau, Tran Thi Thuy, Dennis E K Tan, Anavaj Sakuntabhai, Yik-Ying Teo, Martin L Hibberd, Cameron P Simmons, Chiea Chuen Khor, Tran Nguyen Bich Chau, Junxiong Pang, Sonia Davila, Hoang Truong Long, Rick T H Ong, Sarah J Dunstan, Bridget Wills, Jeremy Farrar, Ta Van Tram, Tran Thi Gan, Nguyen Thi Nguyet Binh, Le Trung Tri, Le Bich Lien, Nguyen Minh Tuan, Nguyen Thi Hong Tham, Mai Ngoc Lanh, Nguyen Minh Nguyet, Nguyen Trong Hieu, Nguyen Van N Vinh Chau, Tran Thi Thuy, Dennis E K Tan, Anavaj Sakuntabhai, Yik-Ying Teo, Martin L Hibberd, Cameron P Simmons

Abstract

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, P(meta) = 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, P(meta) = 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.

Figures

Figure 1
Figure 1
Manhattan plot showing directly genotyped SNPs plotted according to chromosomal location (X-axis, with −Log10P-values (Y-axis) derived from the trend test. The lower horizontal dotted line indicates the threshold for bringing SNPs forward to the replication stage (P < 10−4). SNPs surpassing P < 10−8 (upper horizontal dotted line) on combined analysis of both GWAS and replication data are reflected by red dots, and gene names are given for these loci. SNPs in MICB and PLCE1 have significant associations.

References

    1. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1998;11:480–496.
    1. Anders KL, et al. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg. 84:127–134.
    1. Thai KT, et al. Seroprevalence of dengue antibodies, annual incidence and risk factors among children in southern Vietnam. Trop Med Int Health. 2005;10:379–386.
    1. Loke H, et al. Susceptibility to dengue hemorrhagic fever in vietnam: evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes. Am J Trop Med Hyg. 2002;67:102–106.
    1. Loke H, et al. Strong HLA class I--restricted T cell responses in dengue hemorrhagic fever: a double-edged sword? J Infect Dis. 2001;184:1369–1373.
    1. Stephens HA, et al. HLA-A and -B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais. Tissue Antigens. 2002;60:309–318.
    1. Sakuntabhai A, et al. A variant in the CD209 promoter is associated with severity of dengue disease. Nat Genet. 2005;37:507–513.
    1. Vejbaesya S, et al. TNF and LTA gene, allele, and extended HLA haplotype associations with severe dengue virus infection in ethnic Thais. J Infect Dis. 2009;199:1442–1448.
    1. Steinle A, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics. 2001;53:279–287.
    1. Gonzalez S, Lopez-Soto A, Suarez-Alvarez B, Lopez-Vazquez A, Lopez-Larrea C. NKG2D ligands: key targets of the immune response. Trends Immunol. 2008;29:397–403.
    1. Garrity D, Call ME, Feng J, Wucherpfennig KW. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc Natl Acad Sci U S A. 2005;102:7641–7646.
    1. Hoang LT, et al. The early whole-blood transcriptional signature of dengue virus and features associated with progression to dengue shock syndrome in Vietnamese children and young adults. J Virol. 84:12982–12994.
    1. Libraty DH, et al. Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis. 2002;185:1213–1221.
    1. Vaughn DW, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis. 2000;181:2–9.
    1. Kumar V, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet
    1. Hinkes B, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38:1397–1405.
    1. Chau TN, et al. Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants. J Infect Dis. 2009;200:1893–1900. doi:10.1086/648407.
    1. Tien NT, et al. A prospective cohort study of dengue infection in schoolchildren in Long Xuyen, Viet Nam. Trans R Soc Trop Med Hyg. 2010;104:592–600. doi:S0035-9203(10)00132-X [pii] 10.1016/j.trstmh.2010.06.003.
    1. Balmaseda A, et al. Trends in patterns of dengue transmission over 4 years in a pediatric cohort study in Nicaragua. J Infect Dis. 2010;201:5–14. doi:10.1086/648592.
    1. Porter KR, et al. Epidemiology of dengue and dengue hemorrhagic fever in a cohort of adults living in Bandung, West Java, Indonesia. Am J Trop Med Hyg. 2005;72:60–66. doi:72/1/60 [pii]
    1. Endy TP, et al. Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol. 2002;156:40–51.
    1. Mammen MP, et al. Spatial and temporal clustering of dengue virus transmission in Thai villages. PLoS Med. 2008;5:e205. doi:08-PLME-RA-0417 [pii] 10.1371/journal.pmed.0050205.
    1. Endy TP, et al. Determinants of inapparent and symptomatic dengue infection in a prospective study of primary school children in Kamphaeng Phet, Thailand. PLoS Negl Trop Dis. 2011;5:e975. doi:10.1371/journal.pntd.0000975.
    1. Mells GF, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet
    1. Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.
    1. Price AL, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909.
    1. Purdue MP, et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. 43:60–65.
    1. Thomas G, et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) Nat Genet. 2009;41:579–584.
    1. Lettre G, Lange C, Hirschhorn JN. Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet Epidemiol. 2007;31:358–362.
    1. McGovern DP, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 42:332–337.
    1. Asano K, et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet. 2009;41:1325–1329.
    1. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner