Genome-Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations

Noguchi, Emiko; Sanada, Hiromi; Hirota, Tomomitsu; Ochiai, Kaori; Imoto, Yoshimasa; Sakashita, Masafumi; Kurosaka, Fumitake; Akasawa, Akira; Yoshihara, Shigemi; Kanno, Noriko; Yamada, Yumi; Shimojo, Naoki; Kohno, Yoichi; Suzuki, Yôichi; Kang, Mi Jin; Kwon, Ji Won; Hong, Soo Jong; Inoue, Ken; Goto, Yu Ichi; Yamashita, Fumio; Asada, Takashi; Hara, Hiroshi; Saito, Ikuo; Fujieda, Shigeharu; Hizawa, Nobuyuki; Sakamoto, Terufumi; Masuko, Hironori; Nakamura, Yusuke; Nomura, Ichiro; Tamari, Mayumi; Arinami, Tadao; Yoshida, Teruhiko; Saito, Hirohisa; Matsumoto, Kenji

doi:10.1371/journal.pgen.1002170

Cited by 120 publications

(87 citation statements)

References 37 publications

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“…Recent genome-wide association studies (GWASs) have identified loci that harbor susceptibility genes for many respiratory diseases, including asthma and related phenotypes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Many of the most significant GWAS hits are at loci with unknown function that had not been previously considered biologically plausible candidates for disease pathogenesis.…”

Section: Clinical Relevancementioning

confidence: 99%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis-and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 3 10 24 ). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions.

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Section: Clinical Relevancementioning

confidence: 99%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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“…12 The association of the SNP rs987870, which composes the tag haplotype for DPB1*09:01, with pediatric asthma was also reported. 13 For Chinese Han subjects, the SNP rs2281388 showing absolute LD with DPB1*05:01 and the SNP rs4947296 composing the tag haplotype for C*14:02 were reported to be significantly associated with Graves disease 14 ( Tables 5 and 6). These results suggest that the HLA alleles should be considered as indicators of susceptibility to these diseases, even in cases of nonimmune-related diseases such as coronary artery disease.…”

Section: Identification Of Pairs Of Hla Alleles and Snps In Absolute Ldmentioning

confidence: 99%

“…The GWAS of Japanese pediatric asthma reported a significant association of rs987870, located in the intron of the HLA-DPA1 locus, with this disease. 13 The significant association signals were distributed between the HLA-DPB1, HLA-DPB2, COL11A2 and RXRB loci. The authors reported that HLA-DPA1*02:01, which was in strong LD with rs987870 and the HLA-DPB1*09:01 allele, was also significantly associated with the disease.…”

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confidence: 98%

HLA and SNP haplotype mapping in the Japanese population

2012

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The genes that encode the human leukocyte antigen (HLA) class I and II molecules are highly polymorphic and located in the major histocompatibility complex (MHC) region, where there is a high density of immune-related genes. Numerous studies have identified disease susceptibility in this region; however, interpretation of the results is complicated because of the strong linkage disequilibrium (LD) among HLA alleles and single-nucleotide polymorphisms (SNPs). In this study, we evaluated the correlation between the HLA alleles of 6 loci (HLA-A, C, B, DRB1, DQB1 and DPB1) and 6502 SNPs within 8 Mb of the extended MHC region using 92 Japanese subjects to identify SNP single loci or haplotypes that tag HLA alleles. We found a total of 39 HLA alleles that showed strong LD (r 2 X0.8) with SNPs, including 11 non-synonymous SNPs in non-HLA genes. In addition, we identified several SNP haplotypes in strong LD (r 2 X0.8) with eight HLA alleles, which do not possess tag SNPs. Our detailed list of tag SNPs and haplotypes could be utilized for a better understanding of the results obtained by association studies in the Japanese population and for the characterization of the differences in LD structures between races.

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“…21 The HLA-DPA1/HLA-DPB1 (6p21.3) and SLC30A8 (8q24.11) loci were found in Japanese and East Asian asthma patients of 15 years of age or less. 22 Examination of Caucasian childhood-asthma subjects who require glucocorticoids for asthma control uncovered DENND1B (1q31.3). 16 Replication of this locus was found in both Caucasians and African Americans.…”

Section: Studies On Asthma Susceptibilitymentioning

confidence: 99%

Genome-wide association studies in asthma: progress and pitfalls

March¹,

Sleiman²,

Hákonarson³

2015

AGG

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Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine.

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Genome-Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations

Cited by 120 publications

References 37 publications

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

HLA and SNP haplotype mapping in the Japanese population

Genome-wide association studies in asthma: progress and pitfalls

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