Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

Einarsdottir, Elisabet; Bevova, Marianna; Zhernakova, Alexandra; Monsuur, Alienke J.; Koskinen, Lotta; Slot, Ruben vanʼt; Mulder, Chris J.; Mearin, M. L.; Korponay-Szabó, Ilma Rita; Kaukinen, Katri; Kurppa, Kalle; Kere, Juha; Mäki, Markku; Wijmenga, Cisca; Saavalainen, Päivi

doi:10.1038/ejhg.2011.2

Cited by 6 publications

(7 citation statements)

References 23 publications

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“…32 Recently, the 6q21-22 region, which contains HACE1, has been confirmed as a celiac disease susceptibility locus (possibly mutated). 33 In our series, loss could not be identified by array comparative genomic hybridization, and loss frequency was observed in only 6% (1/16) of cases by FISH. Therefore, the loss of 6q is not characteristic of EATL cases in Japan and may be useful for exclusion of peripheral T-cell lymphoma, not otherwise specified and Extranodal NK/T lymphoma, nasal type.…”

Section: Discussioncontrasting

confidence: 65%

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

et al. 2015

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Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium-to large-sized cells in 13 cases (65%), small-to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2 + (60%), CD3e + (100%), CD4 + (10%), CD7 + (95%), CD8 + (80%), CD56 + (85%), TIA-1 + (100%), Granzyme B + (25%), T-cell receptor (TCR)β + (10%), TCRγ + (35%), TCRγδ + (50%), and double negative for TCR (six cases, 30%). All cases were EBER − . The genomic profile showed recurrent copy number gains of 1q32. 3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8 + CD56 + phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of αβ-T-cells and γδ-T-cells.

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Section: Discussioncontrasting

confidence: 65%

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

et al. 2015

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“…The most popular genotyping chip, the Affymetrix 6.0 array, contains nearly 1 million SNPs, yet only one-third of these SNPs resides in the coding regions. Even though many GWAS-identified statistically significant SNPs lie in the intron or intergenic regions, [3–5] their biological function remains difficult to explain. Another limitation of genotyping arrays is that, because the SNPs are predetermined on the array, no finding of novel SNPs is possible.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Allele Frequency Estimation Using Pooled Sequencing Data Simulation

Guo¹,

Samuels

Jiang³

et al. 2013

The Scientific World Journal

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Next-generation sequencing (NGS) technology has provided researchers with opportunities to study the genome in unprecedented detail. In particular, NGS is applied to disease association studies. Unlike genotyping chips, NGS is not limited to a fixed set of SNPs. Prices for NGS are now comparable to the SNP chip, although for large studies the cost can be substantial. Pooling techniques are often used to reduce the overall cost of large-scale studies. In this study, we designed a rigorous simulation model to test the practicability of estimating allele frequency from pooled sequencing data. We took crucial factors into consideration, including pool size, overall depth, average depth per sample, pooling variation, and sampling variation. We used real data to demonstrate and measure reference allele preference in DNAseq data and implemented this bias in our simulation model. We found that pooled sequencing data can introduce high levels of relative error rate (defined as error rate divided by targeted allele frequency) and that the error rate is more severe for low minor allele frequency SNPs than for high minor allele frequency SNPs. In order to overcome the error introduced by pooling, we recommend a large pool size and high average depth per sample.

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“…A previous study suggested that rs9391227 in the HACE1 gene was associated with celiac disease involved in the immune system and antigen presentation [51]; while another study revealed that five SNPs (rs17065302, rs11759010, rs6927608, rs4946645 and rs4245525) within HACE1 gene associated with equol-producing phenotype such as blood pressure [23] which may implicate HACE1 in immune responses. However, rs9391227 [51] was not available in both the case-control and family-based samples; while equol-producing phenotype associated five SNPs [23] were not associated with the risk or the AAO of AD in the case-control study and rs6927608 was not associated with the risk and AAO of AD in both samples.…”

Section: Discussionmentioning

confidence: 99%

“…However, rs9391227 [51] was not available in both the case-control and family-based samples; while equol-producing phenotype associated five SNPs [23] were not associated with the risk or the AAO of AD in the case-control study and rs6927608 was not associated with the risk and AAO of AD in both samples. However, rs9391227 had strong LD with three AAO associated SNPs (rs7746856, rs6941988 and rs7770002 with r 2 =1.0, 1.0 and 0.87, respectively) in the case-control study (Figure 5); whereas rs6927608 had weak LD with other SNPs (Figures 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

Bayesian Cox Proportional Hazards Model in Survival Analysis of HACE1 Gene with Age at Onset of Alzheimer's Disease

Wang

Liu

Gong

et al. 2017

Int J Clin Biostat Biom

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Alzheimer’s disease (AD), the most common form of dementia, is a chronic neurodegenerative disease. The HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene is expressed in human brain and may play a role in the pathogenesis of neurodegenerative disorders. Till now, no previous study has reported the association of the HACE1 gene with the risk and age at onset (AAO) of AD; while few studies have checked the proportional hazards assumption in the survival analysis of AAO of AD using Cox proportional hazards model. In this study, we examined the associations of 14 single nucleotide polymorphisms (SNPs) in the HACE1 gene with the risk and the AAO of AD using 791 AD patients and 782 controls. Multiple logistic regression model identified one SNP (rs9499937 with p = 1.8×10−3) to be associated with the risk of AD. For survival analysis of AAO, both classic Cox regression model and Bayesian survival analysis using the Cox proportional hazards model were applied to examine the association of each SNP with the AAO. The hazards ratio (HR) with its 95% confidence interval (CI) was estimated. Survival analysis using the classic Cox regression model showed that 4 SNPs were significantly associated with the AAO (top SNP rs9499937 with HR=1.33, 95%CI=1.13–1.57, p=5.0×10−4). Bayesian Cox regression model showed similar but a slightly stronger associations (top SNP rs9499937 with HR=1.34, 95%CI=1.11–1.55) compared with the classic Cox regression model. Using an independent family-based sample, one SNP rs9486018 was associated with the risk of AD (p=0.0323) and the T-T-G haplotype from rs9786015, rs9486018 and rs4079063 showed associations with both the risk and AAO of AD (p=2.27×10−3 and 0.0487, respectively). The findings of this study provide first evidence that several genetic variants in the HACE1 gene were associated with the risk and AAO of AD.

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Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

Cited by 6 publications

References 23 publications

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

Evaluation of Allele Frequency Estimation Using Pooled Sequencing Data Simulation

Bayesian Cox Proportional Hazards Model in Survival Analysis of HACE1 Gene with Age at Onset of Alzheimer's Disease

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