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Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis.

Nishida N, Ohashi J, Khor SS, Sugiyama M, Tsuchiura T, Sawai H, Hino K, Honda M, Kaneko S, Yatsuhashi H, Yokosuka O, Koike K, Kurosaki M, Izumi N, Korenaga M, Kang JH, Tanaka E, Taketomi A, Eguchi Y, Sakamoto N, Yamamoto K, Tamori A, Sakaida I, Hige S, Itoh Y, Mochida S, Mita E, Takikawa Y, Ide T, Hiasa Y, Kojima H, Yamamoto K, Nakamura M, Saji H, Sasazuki T, Kanto T, Tokunaga K, Mizokami M - Sci Rep (2016)

Bottom Line: Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10(-18)) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles.Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively.The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan.

ABSTRACT
Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10(-18)) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.

No MeSH data available.


Related in: MedlinePlus

Associations of estimated haplotypes of HLA class II genes harboring.(A) DPB1 alleles susceptible to chronic hepatitis B infection, and (B) DPB1 alleles protective against chronic hepatitis B infection. Estimated haplotypes, whose frequencies were over 1% (A) in both of two groups, and (B) in either of two groups (i.e. HBV patients and healthy controls), are depicted with P values and OR. P values were calculated using Pearson’s chi-square test in the presence vs. the absence of each haplotype. HLA alleles that are significantly associated with CHB infection in single point analysis are depicted in bold red (susceptible) and bold blue (protective).
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f1: Associations of estimated haplotypes of HLA class II genes harboring.(A) DPB1 alleles susceptible to chronic hepatitis B infection, and (B) DPB1 alleles protective against chronic hepatitis B infection. Estimated haplotypes, whose frequencies were over 1% (A) in both of two groups, and (B) in either of two groups (i.e. HBV patients and healthy controls), are depicted with P values and OR. P values were calculated using Pearson’s chi-square test in the presence vs. the absence of each haplotype. HLA alleles that are significantly associated with CHB infection in single point analysis are depicted in bold red (susceptible) and bold blue (protective).

Mentions: Haplotype analysis of HLA class II genes showed seven haplotypes that were significantly associated with susceptibility to or protection against CHB infection (Table 1). Figure 1A,B summarize the associations of each allele and estimated haplotypes of HLA class II genes with CHB susceptibility. A variety of haplotypes harboring DPB1*05:01 were observed. Of these, two haplotypes, DRB1*09:01-DQB1*03:03-DPB1*05:01 and DRB1*08:03-DQB1*06:01-DPB1*05:01, showed significant associations, with the same trend of association (i.e. susceptibility to CHB infection). These results imply that association of DPB1*05:01 may have the primary effect on CHB susceptibility, regardless of DRB1 and DQB1 alleles. The same can be said for haplotypes harboring DPB1*02:01 or *04:02, although no significant association with CHB infection was observed in haplotypes harboring DPB1*02:01.


Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis.

Nishida N, Ohashi J, Khor SS, Sugiyama M, Tsuchiura T, Sawai H, Hino K, Honda M, Kaneko S, Yatsuhashi H, Yokosuka O, Koike K, Kurosaki M, Izumi N, Korenaga M, Kang JH, Tanaka E, Taketomi A, Eguchi Y, Sakamoto N, Yamamoto K, Tamori A, Sakaida I, Hige S, Itoh Y, Mochida S, Mita E, Takikawa Y, Ide T, Hiasa Y, Kojima H, Yamamoto K, Nakamura M, Saji H, Sasazuki T, Kanto T, Tokunaga K, Mizokami M - Sci Rep (2016)

Associations of estimated haplotypes of HLA class II genes harboring.(A) DPB1 alleles susceptible to chronic hepatitis B infection, and (B) DPB1 alleles protective against chronic hepatitis B infection. Estimated haplotypes, whose frequencies were over 1% (A) in both of two groups, and (B) in either of two groups (i.e. HBV patients and healthy controls), are depicted with P values and OR. P values were calculated using Pearson’s chi-square test in the presence vs. the absence of each haplotype. HLA alleles that are significantly associated with CHB infection in single point analysis are depicted in bold red (susceptible) and bold blue (protective).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835786&req=5

f1: Associations of estimated haplotypes of HLA class II genes harboring.(A) DPB1 alleles susceptible to chronic hepatitis B infection, and (B) DPB1 alleles protective against chronic hepatitis B infection. Estimated haplotypes, whose frequencies were over 1% (A) in both of two groups, and (B) in either of two groups (i.e. HBV patients and healthy controls), are depicted with P values and OR. P values were calculated using Pearson’s chi-square test in the presence vs. the absence of each haplotype. HLA alleles that are significantly associated with CHB infection in single point analysis are depicted in bold red (susceptible) and bold blue (protective).
Mentions: Haplotype analysis of HLA class II genes showed seven haplotypes that were significantly associated with susceptibility to or protection against CHB infection (Table 1). Figure 1A,B summarize the associations of each allele and estimated haplotypes of HLA class II genes with CHB susceptibility. A variety of haplotypes harboring DPB1*05:01 were observed. Of these, two haplotypes, DRB1*09:01-DQB1*03:03-DPB1*05:01 and DRB1*08:03-DQB1*06:01-DPB1*05:01, showed significant associations, with the same trend of association (i.e. susceptibility to CHB infection). These results imply that association of DPB1*05:01 may have the primary effect on CHB susceptibility, regardless of DRB1 and DQB1 alleles. The same can be said for haplotypes harboring DPB1*02:01 or *04:02, although no significant association with CHB infection was observed in haplotypes harboring DPB1*02:01.

Bottom Line: Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10(-18)) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles.Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively.The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan.

ABSTRACT
Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10(-18)) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.

No MeSH data available.


Related in: MedlinePlus