Association between genetic variants in the <i>BLK</i> region and KD in a combined analysis of Taiwanese and Korean populations.

a<p>SNP positions are derived from NCBI human genome reference sequence Build 36.3.</p>b<p>622 KD cases and 1,107 controls.</p>c<p>261 KD cases and 550 controls.</p>d<p>186 KD cases and 600 controls.</p>e<p>288 KD cases and 498 controls.</p>f<p>Meta-analyses with the Cochran<i>–</i>Mantel–Haenszel method.</p>g<p>These statistical values are for the allelic model. Chr, chromosome; Case RAF, risk allele frequency in KD cases; Control RAF, risk allele frequency in controls; OR, odds ratio; 95%CI, 95% confidence interval.</p

Analysis of the correlation of genotypes of rs2736340 in <i>BLK</i> region with expression levels in transformed B cells.

<p>Geno, genotypes; Freq, frequency; SD, standard deviation; CHB, 45 Han Chinese in Beijing; JEP, 44 Japanese in Tokyo; CEU_parents; CEU_children; YRI_parents; YRI_children; All populations, 270 individuals from 4 populations (CEU: 90 (30 trios) Utah residents with ancestry from northern and western Europe; CHB: 45 unrelated Han Chinese in Beijing; JPT: 45 unrelated Japanese in Tokyo; YRI: 90 (30 trios) Yoruba in Ibadan, Nigeria). All unrelated, 210 unrelated individuals, including 60 Yoruba (YRI) and 60 CEPH (CEU) parents, and 90 unrelated Chinese (CHB) and Japanese (JPT) samples.</p

B cell population in peripheral blood mononuclear cells (PBMC) and <i>BLK</i> expression in peripheral blood leukocytes (PBLs) induced at the acute stage of KD.

<p>(A) PBMCs were stained with anti-CD19 or anti-CD3 monoclonal antibodies, and the percentage of CD19⁺ B cells and CD3⁺ T cells in samples taken from a patient at acute and convalescent stages of KD and from a healthy control were determined by multicolor flow cytometry. (B) Levels of <i>BLK</i> expression were determined by real-time RT-PCR, and levels in KD patients were compared to those in fever controls. Values are expressed as mean ± standard error (SE). RNA was harvested from PBLs from KD patients at different stages of disease development or from age-matched fever controls. KD1, <i>n</i> = 20, before IVIG treatment (within 24 h before IVIG treatment); KD2, <i>n</i> = 12, after IVIG treatment (3–7 days after IVIG treatment); and KD3, <i>n</i> = 10, convalescence stage (3 weeks after IVIG treatment). FC, <i>n</i> = 19, fever controls.</p

Meta-analysis of association of rs2736340 with KD.

a<p>These statistical values are for the allelic model.</p>b<p>Meta-analyses with the Cochran–Mantel–Haenszel method. Case RAF, risk allele frequency in KD cases; Control RAF, risk allele frequency in controls; OR, odds ratio; 95% CI, 95% confidence interval.</p>c<p>T is the risk allele, and also the minor allele in European descent.</p

Per-cohort analysis of <i>BLK</i> rs2736340.

<p>Boxes indicate the odds ratio for each cohort, and horizontal lines denote the 95% confidence interval for the corresponding odds ratio. Diamonds represent summary odds ratios for the respective meta-analyses. Solid vertical line indicates an odds ratio of 1.0, and dashed vertical line denotes the odds ratio obtained from meta-analysis of all samples.</p

Genotypes of rs2736340 are associated with BLK expression and down stream signaling of B cell receptor in B cell lines established from KD patients and in B cells purified from the acute stage of KD patients.

<p>(A) BLK expression was detected by real-time RT-PCR, and expression from patients with T/T or T/C genotypes was compared to that from patients with C/C genotypes. Values are mean ± SE (C/C, <i>n</i> = 4; T/T, <i>n</i> = 5; and T/C, <i>n</i> = 5). (B) BLK expression and ERK1/2 expression and activation were detected by Western blot. BLK, antibody against BLK; ERK1/2, antibody against p44/p42 ERK1/2; p- ERK1/2, antibody against phospho-p44/p42 ERK1/2; GAPDH, antibody against GAPDH.</p

Single-nucleotide polymorphisms (SNPs) analyzed and linkage disequilibrium (LD) pattern of the GRIN3A gene used in this study.

<p>Genomic location of the SNPs present on chromosome 9q31.1. Linkage disequilibrium (LD) blocks in the GRIN3A gene estimated using HAPLOVIEW software [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081384#B43" target="_blank">43</a>]. Pairwise D′ values (%) are indicated in squares; red indicates linkage disequilibrium (D′ = 1, logarithm of odds (LOD) ≥ 2).</p

T2D prediction, glycemic genetic score.

<p>Forest plot of association between glycemic genetic score with incident T2D over a decade-long follow-up period, by ancestry. MESA (European and Asian ancestry) and the <i>G6PD</i> variant (rs1050828) in ARIC (European and African American) were not included in the discovery GWAS analysis. Effect estimates were combined in a fixed effects meta-analysis. Overall effect estimate: 1.05, 95% CI 1.04–1.06, <i>p</i> = 2.5 × 10⁻²⁹. ARIC, Atherosclerosis Risk in Communities Study; ES, Effect Size; FHS, Framingham Heart Study; GWAS, genome-wide association study; G6PD, glucose-6-phosphate dehydrogenase; I-Squared, Higgin's I-squared statistic, a measure of heterogeneity; MESA, Multiethnic Study of Atherosclerosis; SCHS, Singapore Chinese Health Study; T2D, type 2 diabetes.</p

Manhattan plot of HbA1c associated variants.

<p>Manhattan plot of the transethnic meta-analysis results in MANTRA. The dashed grey line indicates log₁₀BF = 6. Grey and green points denote known/novel loci, respectively. The lead HbA1c-associated variants identified through the ancestry-specific/transethnic analyses are circled in purple (the <i>G6PD</i> variant was not included in the MANTRA analysis, but the locus on the X-chromosome is indicated in the figure). Lines joining the plot & SNP number denote known loci (black), novel loci (green), and loci with a secondary distinct signal (red). MANTRA, Meta-Analysis of Transethnic Association.</p

Table of HbA1c associated variants.

<p>Table with results and classification of the 60 HbA1c-associated variants. SNP number corresponds to number in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002383#pmed.1002383.g001" target="_blank">Fig 1</a>.</p