Supplementary Figure 1 a

Transcription

1 Supplementary Figure 1 a b GWAS second stage log 10 observed P log 10 expected P rs3077 (P hetero =0.84) GWAS second stage (BBJ, Japan) First replication (BBJ, Japan) Second replication (RIKEN, Japan) Third replication (Mahidol Uni., Thai) Combined rs (P hetero =0.85) GWAS second stage (BBJ, Japan) First replication (BBJ, Japan) Second replication (RIKEN, Japan) Third replication (Mahidol Uni., Thai) Combined Odds Ratio Supplementary Figure 1. GWAS of chronic hepatitis B. a Q-Q plot with Cochrane-Armitage trend P in the second stage of GWAS. Horizontal and vertical lines represent expected p values under a null distribution and observed p values, respectively. If all the SNPs were not associated with the disease, all plots would lie on the line y=x. Plots circled by red correspond to the significantly associated 11 SNPs. b Meta-analysis of the two SNPs associated with chronic hepatitis B. Forest plots of four cohort studies are shown for each SNP. Each effect size is shown with its confidence interval.

2 Supplementary Figure 2 HLA-DPA1 HLA-DPB1 Supplementary Figure 2. Linkage disequilibrium structure around HLA-DPA1/DPB1 region based on D among 11 significant SNPs (circled by blue) and nucleotide variations on exon 2 of HLA-DPA1/DPB1 genes.

3 Supplementary Table 1. Basal characteristics of cohorts Cohort Source Platform Number of Ethnicity Female Age samples (mean +/- sd) Screening phase First stage case BioBank Japan Illumina HumanHap Japanese 75 (39.9%) / control Osaka Illumina HumanHap Japanese 246 (26.3%) / Second stage case BioBank Japan Affymetrix GeneChip 616 Japanese 238 (38.6%) / control BioBank Japan a Illumina HumanHap Japanese 808 (63.8%) / Replication phase First Replication case BioBank Japan Invader assay 273 Japanese 91 (33.2%) / control BioBank Japan a,b Invader assay 273 Japanese 91 (33.2%) / Second Replication case RIKEN TaqMan Genotyping System 718 Japanese 230 (32.0%) / control BioBank Japan a TaqMan Genotyping System 1280 Japanese 594 (46.8%) / Third Replication case Mahidol Univ. TaqMan Genotyping System 308 Thai 48 (15.6%) /- 7.6 control Mahidol Univ. TaqMan Genotyping System 546 Thai 101 (16.5%) /- 7.6 a The control groups from BioBank Japan consisted of the individuals with diseases other than chronic hepatitis B. b Matched with age, gender and the amount of alcohol consumption.

4 Supplementary Table 2. Significant SNPs of GWAS after Bonferroni's correc SNP Chr Position Nearest gene Alleles Risk allele P value a P value b (1st stage) (2nd stage) rs E+07 HLA-DPA1 A/G G 1.59E E-13 rs E+07 HLA-DPA1 A/G G 1.59E E-13 rs E+07 HLA-DPA1 T/C T 4.45E E-13 rs E+07 HLA-DPB1 A/G G 4.45E E-12 rs E+07 HLA-DPB1 T/C T 2.12E E-10 rs E+07 HLA-DPB1 T/G G 1.55E E-10 rs E+07 HLA-DPB1 A/G G 3.49E E-08 rs E+07 HLA-DPB1 T/C T 3.16E E-08 rs E+07 HLA-DPA1 T/C C 5.05E E-08 rs E+07 HLA-DPB1 A/G A 1.57E E-08 rs E+07 HLA-DPB1 A/G A 2.58E E-08 a Minimum of the Fisher's exact tests for three models: allele frequency model, dominant model, and recessive model. b P value of Cochrane-Armitage trend test.

5 Supplementary Table 3. Association analysis of HLA-DP alleles. DPA1 Case Control P value DPB1 Case Control P value DPA1* E-11 DPB1* (26.8%) (38.3%) (19.5%) (22.4%) DPA1* DPB1* (19.8%) (18.0%) (2.9%) (4.2%) DPA1* E-08 DPB1* (53.1%) (42.7%) (4.6%) (3.4%) DPA1* DPB1* (0.0%) (0.0%) (2.5%) (4.7%) DPB1* E-07 (4.5%) (9.5%) DPB1* E-07 (47.3%) (38.2%) DPB1* (0.2%) (0.4%) DPB1* (12.6%) (12.2%) DPB1* (2.1%) (1.7%) DPB1* (1.4%) (1.4%) DPB1* (0.2%) (0.0%) DPB1* (0.4%) (0.0%) DPB1* (0.2%) (0.0%)

6 Supplementary Table 4. List of tagging SNPs for HLA-DP alleles a SNP SNP allele HLA allele rs T DPA1*0103 rs3077 T DPA1*0103 rs A DPA1*0103 rs G DPA1*0103 rs T DPA1*0103 rs A DPB1*0501 rs A DPB1*0501 rs T DPB1*0501 rs T DPB1*0501 rs ,rs T,T DPB1*0402 rs987870,rs T,C DPB1*0301 rs987870,rs T,T DPB1*0301 rs987870,rs T,C DPB1*0301 rs ,rs A,T DPB1*1301 rs ,rs C,T DPB1*1301 rs987870,rs C,T DPB1*1301 rs ,rs T,G DPB1*1301 rs ,rs T,A DPB1*1301 rs ,rs G,G DPB1*1301 rs ,rs G,A DPB1*1301 rs ,rs G,C DPB1*1301 rs ,rs A,G DPB1*1301 rs ,rs A,A DPB1*1301 rs ,rs A,C DPB1*1301 a Each SNP allele (or combination of alleles) has a nearly one-to-one correspondence to each HLA allele. First stage control samples (Japanese population) were used.

7 Supplementary Table 5. Association analysis of SNP rs which is strongly linked with HLA-DR13 SNP Allele case a control a OR (95%CI) b P value c (1/2) rs A/G ( ) 1.04E-04 a Case and control samples of second stage GWAS. b Odds ratio and its 95% confidence interval of allele A estimated by logistic regression model. c P values of Cochrane-Armitage trend test.

8 Supplementary Table 6. Allele frequencies of rs3077 or rs in 11 different HapMap cohorts a. Population origin Country collected HapMap Population rs3077 A allele b rs A allele b Prevalence of HBsAg(+) % Asian China CHD (D) China CHB (H) % c Japan JPT (J) % d USA GIH (G) % c African Nigeria YRI (Y) % e USA ASW (A) Kenya LWK (L) Kenya MKK (K) % f Central American USA MEX (M) % c European Italy TSI (T) % c USA CEU (C) % c a HapMap 3 database: b A allele act as protective allele to chronic hepatitis B infection. c Custer et al. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 38, S (2004). d Tanaka, J. et al. Sex-and age-specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence in the 3,485,648 first-time blood donors during Intervirology 47, (2004). e Uneke, C.J. et al. Prevalence of hepatitis-b surface antigen among blood donors and human immunodeficiency virus-infected patients in Jos, Nigeria. Mem Inst Oswaldo Cruz 100, (2005). f Okoth, F.A. et al. Seroepidemiological study for HBV markers and anti-delta in Kenya. East Afr Med J 68, (1991). Reported prevalences of HBs antigen positivity in Nigeria or Kenya were not nation-wide survey, so they might be biased according to the region investigated.