A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population

Hamdi Mbarek, Hidenori Ochi, Yuji Urabe, Vinod Kumar, Michiaki Kubo, Naoya Hosono, Atsushi Takahashi, Yoichiro Kamatani, Daiki Miki, Hiromi Abe, Tatsuhiko Tsunoda, Naoyuki Kamatani, Kazuaki Chayama, Yusuke Nakamura, Koichi Matsuda

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Abstract

Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

Original languageEnglish
Article numberddr301
Pages (from-to)3884-3892
Number of pages9
JournalHuman molecular genetics
Volume20
Issue number19
DOIs
Publication statusPublished - 01-10-2011

Fingerprint

Genome-Wide Association Study
Chronic Hepatitis B
HLA-DP Antigens
HLA-DQ Antigens
Single Nucleotide Polymorphism
Population
Virus Diseases
Hepatitis B virus
Haplotypes
Odds Ratio
Liver Cirrhosis
Hepatocellular Carcinoma
Genome
Antigens
Liver

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mbarek, Hamdi ; Ochi, Hidenori ; Urabe, Yuji ; Kumar, Vinod ; Kubo, Michiaki ; Hosono, Naoya ; Takahashi, Atsushi ; Kamatani, Yoichiro ; Miki, Daiki ; Abe, Hiromi ; Tsunoda, Tatsuhiko ; Kamatani, Naoyuki ; Chayama, Kazuaki ; Nakamura, Yusuke ; Matsuda, Koichi. / A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. In: Human molecular genetics. 2011 ; Vol. 20, No. 19. pp. 3884-3892.
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abstract = "Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.",
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Mbarek, H, Ochi, H, Urabe, Y, Kumar, V, Kubo, M, Hosono, N, Takahashi, A, Kamatani, Y, Miki, D, Abe, H, Tsunoda, T, Kamatani, N, Chayama, K, Nakamura, Y & Matsuda, K 2011, 'A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population', Human molecular genetics, vol. 20, no. 19, ddr301, pp. 3884-3892. https://doi.org/10.1093/hmg/ddr301

A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. / Mbarek, Hamdi; Ochi, Hidenori; Urabe, Yuji; Kumar, Vinod; Kubo, Michiaki; Hosono, Naoya; Takahashi, Atsushi; Kamatani, Yoichiro; Miki, Daiki; Abe, Hiromi; Tsunoda, Tatsuhiko; Kamatani, Naoyuki; Chayama, Kazuaki; Nakamura, Yusuke; Matsuda, Koichi.

In: Human molecular genetics, Vol. 20, No. 19, ddr301, 01.10.2011, p. 3884-3892.

Research output: Contribution to journalArticle

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T1 - A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population

AU - Mbarek, Hamdi

AU - Ochi, Hidenori

AU - Urabe, Yuji

AU - Kumar, Vinod

AU - Kubo, Michiaki

AU - Hosono, Naoya

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Miki, Daiki

AU - Abe, Hiromi

AU - Tsunoda, Tatsuhiko

AU - Kamatani, Naoyuki

AU - Chayama, Kazuaki

AU - Nakamura, Yusuke

AU - Matsuda, Koichi

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N2 - Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

AB - Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

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