Genetic variants of MICB and PLCE1 and associations with non-severe dengue

Abstract

Background: A recent genome-wide association study (GWAS) identified susceptibility loci for dengue shock syndrome (DSS) at MICB rs3132468 and PLCE1 rs3740360. The aim of this study was to define the extent to which MICB (rs3132468) and PLCE1 (rs3740360) were associated with less severe clinical phenotypes of pediatric and adult dengue.

Methods: 3961 laboratory-confirmed dengue cases and 5968 controls were genotyped at MICB rs3132468 and PLCE1 rs3740360. Per-allele odds ratios (OR) with 95% confidence intervals (CI) were calculated for each patient cohort. Pooled analyses were performed for adults and paediatrics respectively using a fixed effects model.

Results: Pooled analysis of the paediatric and adult cohorts indicated a significant association between MICB rs3132468 and dengue cases without shock (OR = 1.15; 95%CI: 1.07 - 1.24; P = 0.0012). Similarly, pooled analysis of pediatric and adult cohorts indicated a significant association between dengue cases without shock and PLCE1 rs3740360 (OR = 0.92; 95%CI: 0.85 - 0.99; P = 0.018). We also note significant association between both SNPs (OR = 1.48; P = 0.0075 for MICB rs3132468 and OR = 0.75, P = 0.041 for PLCE1 rs3740360) and dengue in infants.

Discussion: This study confirms that the MICB rs3132468 and PLCE1 rs3740360 risk genotypes are not only associated with DSS, but are also associated with less severe clinical phenotypes of dengue, as well as with dengue in infants. These findings have implications for our understanding of dengue pathogenesis.

Figure 1. Genotyping and sample quality control process flowchart.

Figure 2. Forest plot illustrating the association between MICB rs3132468 and susceptibility to dengue.

06DX, DR, FG and MD were cohort studies of children, and 09DX, D001 and FL were cohort studies of adults. The oblongs represent point estimates (referring to the per-allele odds ratio, expressed on the horizontal axis), with the height of the oblongs inversely proportional to the standard error of the point estimates. Horizontal lines indicate the 95% confidence interval for each point estimate. Meta-analysis of children, adults, as well as children and adults with uncomplicated dengue are reflected by blue diamonds. Data from our previously reported GWAS on DSS is reflected by the purple diamond. The width of the diamonds indicates their 95% confidence intervals. Each meta-analysis is accompanied by a test of heterogeneity between the sample collections summarized by it (expressed as P _het).

Figure 3. Forest plot illustrating the association between PLCE1 rs3740360 and susceptibility to dengue.

06DX, DR, FG and MD were cohort studies of children. and 09DX, D001 and FL were cohort studies of adults. The oblongs represent point estimates (referring to the per-allele odds ratio, expressed on the horizontal axis), with the height of the oblongs inversely proportional to the standard error of the point estimates. Horizontal lines indicate the 95% confidence interval for each point estimate. Meta-analysis of children, adults, as well as children and adults with uncomplicated dengue are reflected by blue diamonds. Data from our previously reported GWAS on DSS is reflected by the purple diamond. The width of the diamonds indicates their 95% confidence intervals. Each meta-analysis is accompanied by a test of heterogeneity between the sample collections summarized by it (expressed as P _het).