Additional file 1: of ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population

Fig. S1 Atorvastatin concentration-dependent cytotoxicity on HepaRG cells. Fig. S2 Expression levels of ABCB1 protein in Flp-In-293 cells stably expressing ABCB1 proteins encoded by 2677G wild-type, 2677 T and 2677A alleles. Fig. S3 Cell viability curve for IC50 determination in Flp-In-293 cells stably expressing ABCB1 proteins encoded by 2677G wild-type, 2677 T and 2677A alleles. Table S1 Distribution of disease status in 30 AILI and 414 non-AILI patients registered in BioBank Japan. Table S2 Frequency of rs2032582 in 30 AILI and 414 non-AILI patients. Table S3 Association of HLA-A alleles with atorvastatin-induced liver injury. Table S4 Association of HLA-B alleles with atorvastatin-induced liver injury. Table S5 Association of HLA-C alleles with atorvastatin-induced liver injury. (DOCX 147 kb

Haplotypes with Copy Number and Single Nucleotide Polymorphisms in <em>CYP2A6</em> Locus Are Associated with Smoking Quantity in a Japanese Population

<div><p>Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers ( = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; ) in the 19q13 region, encompassing the <em>CYP2A6</em> locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; ) located 30 kb downstream of the CYP2A6 gene. Imputation of the <em>CYP2A6</em> locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA -test ). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.</p> </div

Frequency and relative effect size of haplotype between rs11878604 (SNP) and rs8102683 (CNP).

¶<p>Haplotypes consisting of alleles at rs11878604 [T/C] and haplotypic copy numbers at rs8102683 [0/1/2].</p>*<p>Haplotype frequencies and relative effect sizes are jointly evaluated using a haplotype-specific linear regression model as described previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044507#pone.0044507-Stram1" target="_blank">[27]</a>. All model parameters were estimated using a standard EM (expectation-maximization) algorithm <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044507#pone.0044507-McLachlan1" target="_blank">[28]</a>.</p>†<p>Variance explained by these six haplotypes and its significance was assessed in the standard ANOVA (analysis of variance) framework.</p

Manhattan plot showing the significance of association for all CNPs and SNPs in the genome-wide CPD analysis.

<p>The SNPs consist of both Illumina 610K chip and imputed HapMap SNPs. All CNPs and SNPs are plotted on the axis according to their positions on each chromosome against association with CPD on the axis (-value). SNPs and CNPs with -values are highlighted in green. A dark gray line shows the genome-wide significance level after Bonferroni's correction with a total of 2,312,503 SNPs and 4,256 CNPs.</p

Association of the haplotype between rs11878604 (SNP) and rs8102683 (CNP) for three dieseases.

<p>Association of the haplotype between rs11878604 (SNP) and rs8102683 (CNP) for three dieseases.</p

Signal plots before conditioning (a), after conditioning on rs8102683 (b) and after conditioning on rs8102683 and rs11878604 (c).

<p>SNPs and CNPs are plotted on the axis according to their positions on chromosome 19 (NCBI Build 37; hg19) against association with CPD on the left axis (-value). SNPs from the 1000 genomes imputation (phase I; 2011-11-23) are indicated with circles, SNPs genotyped on the Illumina 610K chip are indicated with triangles and CNPs genotyped with PlatinumCNV using the raw signal intensity data from the chip are indicated with diamonds. SNPs in the commonly deleted region (shown by the gray shaded area) are imputed as tri-allelic SNPs with deletions (see Materials and Methods for details). All SNP associations are assessed using allele dosages (the number difference between the A and B alleles; see Materials and Methods), and the CNP associations are assessed using the posterior mean copy number dosage <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044507#pone.0044507-Kumasaka1" target="_blank">[8]</a>. Recombination rates (cM/Mb) across the region are shown by the purple line plotted against the right axis. The most significant variant of the SNP or CNP for each panel is pink, and the surrounding SNPs and CNPs are color-coded to reflect the strength of LD with the top variant according to the Pearson's values.</p

Additional file 1: Table S1. of Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

Top fifteen SNPs in the GWAS of ATDILI. Table S2. Top fifteen SNPs in the replication study of ATDILI. Table S3. Top SNPs in the GWAS of the pattern of ATDILI. Table S4. Top SNPs for GWAS of ATDILI in genes related to autoimmune diseases, oxidative stress, pharmacokinetic, and HLA region. (PDF 57 kb

Schematic representation of the genomic organization according to the human genome hg18 at chromosome 11q14.3 with the positions of CNVs called in the region and reported CNVs in the vicinity found in the Database of Genomic Variants, accessed by July 2015.

<p>Blue bars represent gains identified by other studies that were deposited in the database while red bars represent losses. Brown bars depict CNVs with both losses and gains documented.</p

-Log₁₀ of one-tailed empirical p-values from pathway enrichment analysis implemented using PLINK v.1.07 <i>cnv-enrichment-test</i>.

<p>-Log₁₀ of one-tailed empirical p-values from pathway enrichment analysis implemented using PLINK v.1.07 <i>cnv-enrichment-test</i>.</p

Schematic representation of the genomic organization according to the human genome hg18 at chromosome 6p21.3 with the positions of CNVs called in the region and reported CNVs in the vicinity found in the Database of Genomic Variants, accessed by July 2015.

<p>Blue bars represent gains identified by other studies that were deposited in the database while red bars represent losses. Brown bars depict CNVs with both losses and gains documented.</p