Polymorphisms involving gain or loss of CpG sites are significantly enriched in trait-associated SNPs

Zhou, Dan; Li, Zhenli; Yu, Dan; Wan, Ledong; Zhu, Yimin; Lai, Maode; Zhang, Dandan

doi:10.18632/oncotarget.5650

Cited by 30 publications

(24 citation statements)

References 36 publications

(34 reference statements)

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“…Numerous studies focus on differentially methylated regions in complex diseases. The role of DNA methylation in cancer etiology and progression is well established 13 , 35 . Our EMSA results indicate that while allele G of rs4693608 is susceptible to DNA methylation, allele A may escape this modification.…”

Section: Discussionmentioning

confidence: 99%

Identification of strong intron enhancer in the heparanase gene: effect of functional rs4693608 variant on HPSE enhancer activity in hematological and solid malignancies

et al. 2018

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Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of heparan sulfate (HS) proteoglycans and releases HS-bound cytokines, chemokines, and bioactive growth-promoting factors. Heparanase plays an important role in the nucleus as part of an active chromatin complex. Our previous studies revealed that rs4693608 correlates with heparanase levels and increased risk of acute and extensive chronic graft vs. host disease (GVHD). Discrepancy between recipient and donor in this SNP significantly affected the risk of acute GVHD. In the present study, we analyzed the HPSE gene region, including rs4693608, and demonstrated that this region exhibits SNPs-dependent enhancer activity. Analysis of nuclear proteins from normal leukocytes revealed their binding to DNA probe of both alleles with higher affinity to allele G. All malignant cell lines and leukemia samples disclosed a shift of the main bands in comparison to normal leukocytes. At least five additional shifted bands were bound to allele A while allele G probe was bound to only one main DNA/protein complex. Additional SNPs rs4693083, rs4693084, and rs4693609 were found in strong linkage disequilibrium (LD) with rs11099592 (exon 7). Only rs4693084 affected protein binding to DNA in cell lines and leukemia samples. As a result of the short distance between rs4693608 and rs4693084, both SNPs may be included in a common DNA/protein complex. DNA pull-down assay revealed that heparanase is involved in self-regulation by negative feedback in rs4693608-dependent manner. During carcinogenesis, heparanase self-regulation is discontinued and the helicase-like transcription factor begins to regulate this enhancer region. Altogether, our study elucidates conceivable mechanism(s) by which rs4693608 SNP regulates HPSE gene expression and the associated disease outcome.

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Section: Discussionmentioning

confidence: 99%

Identification of strong intron enhancer in the heparanase gene: effect of functional rs4693608 variant on HPSE enhancer activity in hematological and solid malignancies

et al. 2018

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“…A considerable proportion of the best-CADD5 meQTL-SNPs represents deleterious coding SNPs that also create/abolish CpG sites. SNPs affecting CpG sites account for up to 20% of common SNPs in human genome 39 , 40 , 53 , and were found to be significantly enriched in eQTLs and in trait-associated SNPs 53 . The potentially methylation-sensitive hippocampal QTL-SNPs might exert meaningful susceptibility effects of trait-associated SNPs.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus

et al. 2017

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Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of singlenucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal cismeQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cisacting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.

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“…In our study, we observed that the variant allele of rs9660710 is an eQTL for miR-429 expression and significantly increase the miR-429 expression in normal tissues. Moreover, rs9660710 is a CpG site related SNP (cgSNP) [36] and meQTL for miR-429 expression. Consequently, we speculated that rs9660710 may disrupt transcription factor response elements or DNA methylation to promote the expression of miR-429, respectively.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in regulatory regions of microRNAs are associated with lung cancer risk

et al. 2016

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Genetic variants in regulatory regions of some miRNAs might be associated with lung cancer risk and survival. We performed a case-control study including 1341 non-small cell lung cancer (NSCLC) cases and 1982 controls to evaluate the associations of 7 potentially functional polymorphisms in several differently expressed miRNAs with NSCLC risk. Each SNP was also tested for the association with overall survival of 1001 NSCLC patients. We identified that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a were significantly associated with NSCLC risk [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.06–1.30, P = 0.002; OR = 0.88, 95% CI = 0.80–0.98, P = 0.017; respectively]. However, no significant association between variants and NSCLC death risk was observed in survival analysis. Functional annotation showed that both rs9660710 and rs763354 were located in regulatory elements in lung cancer cells. Compared to normal tissues, miR-200a-3p, miR-200a-5p, miR-200b-3p, miR-200b-5p and miR-429 were significantly increased in The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) tumors, whereas miR-30a-3p and miR-30a-5p were significantly decreased in tumors (all P < 0.05). Furthermore, we observed that rs9660710 is an expression quantitative trait locus (eQTL) or methylation eQTL for miR-429 expression in TCGA normal tissues. Our results indicated that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a might modify the susceptibility to NSCLC.

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Polymorphisms involving gain or loss of CpG sites are significantly enriched in trait-associated SNPs

Cited by 30 publications

References 36 publications

Identification of strong intron enhancer in the heparanase gene: effect of functional rs4693608 variant on HPSE enhancer activity in hematological and solid malignancies

Identification of strong intron enhancer in the heparanase gene: effect of functional rs4693608 variant on HPSE enhancer activity in hematological and solid malignancies

Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus

Genetic variants in regulatory regions of microRNAs are associated with lung cancer risk

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