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1.  ABC: a tool to identify SNVs causing allele-specific transcription factor binding from ChIP-Seq experiments 
Bioinformatics  2015;31(18):3057-3059.
Motivation: Detection of allelic imbalances in ChIP-Seq reads is a powerful approach to identify functional non-coding single nucleotide variants (SNVs), either polymorphisms or mutations, which modulate the affinity of transcription factors for chromatin. We present ABC, a computational tool that identifies allele-specific binding of transcription factors from aligned ChIP-Seq reads at heterozygous SNVs. ABC controls for potential false positives resulting from biases introduced by the use of short sequencing reads in ChIP-Seq and can efficiently process a large number of heterozygous SNVs.
Results: ABC successfully identifies previously characterized functional SNVs, such as the rs4784227 breast cancer risk associated SNP that modulates the affinity of FOXA1 for the chromatin.
Availability and implementation: The code is open-source under an Artistic-2.0 license and versioned on GitHub ( ABC is written in PERL and can be run on any platform with both PERL (≥5.18.1) and R (≥3.1.1) installed. The script requires the PERL Statistics::R module.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4668780  PMID: 25995231
2.  Pre-neoplastic epigenetic disruption of transcriptional enhancers in chronic inflammation 
Oncotarget  2016;7(13):15772-15786.
Chronic periodontitis (CP) is a chronic inflammatory disease independently associated with higher incidence of oral cavity squamous cell carcinoma (OSCC). However, the molecular mechanism responsible for this increased incidence is unknown. Here we profiled the DNA methylome of CP patients and healthy controls and compared to a large set of OSCC samples from TCGA. We observed a significant overlap between the altered DNA methylation patterns in CP and in OSCC, suggesting an emergence of a pre-neoplastic epigenome in CP. Remarkably, the hypermethylated CpGs in CP were significantly enriched for enhancer elements. This aberrant enhancer methylation is functional and able to disrupt enhancer activity by preventing the binding of chromatin looping factors. This study provides new insights on the molecular mechanisms linking chronic inflammation and tumor predisposition, highlighting the role of epigenetic disruption of transcriptional enhancers.
PMCID: PMC4941276  PMID: 26908456
DNA methylation; enhancers; chronic periodontitis; oral cavity squamous cell carcinoma
3.  Physical activity and genetic predisposition to obesity in a multiethnic longitudinal study 
Scientific Reports  2016;6:18672.
Physical activity (PA) has been shown to reduce the impact of FTO variation and obesity genetic risk scores (GRS) on BMI. We examined this interaction using a quantitative measure of PA and two adiposity indexes in a longitudinal multi-ethnic study. We analyzed the impact of PA on the association between 14 obesity predisposing variants (analyzed independently and as a GRS) and baseline/follow-up obesity measures in the multi-ethnic prospective cohort EpiDREAM (17423 participants from six ethnic groups). PA was analyzed using basic (low-moderate-high) and quantitative measures (metabolic equivalents (METS)), while BMI and the body adiposity index (BAI) were used to measure obesity. Increased PA was associated with decreased BMI/BAI at baseline/follow-up. FTO rs1421085, CDKAL1 rs2206734, TNNl3K rs1514176, GIPR rs11671664 and the GRS were associated with obesity measures at baseline and/or follow-up. Risk alleles of three SNPs displayed nominal associations with increased (NTRK2 rs1211166, BDNF rs1401635) or decreased (NPC1 rs1805081) basic PA score independently of BMI/BAI. Both basic and quantitative PA measures attenuated the association between FTO rs1421085 risk allele and BMI/BAI at baseline and follow-up. Our results show that physical activity can blunt the genetic effect of FTO rs1421085 on adiposity by 36–75% in a longitudinal multi-ethnic cohort.
PMCID: PMC4698633  PMID: 26727462
4.  ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters 
Nature communications  2015;2:6186.
Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here by integrating chromatin interaction maps with the large collection of transcription factor binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.
PMCID: PMC4431651  PMID: 25645053
Chromatin interaction; chromatin loops; chromatin conformation capture; ZNF143; CTCF; Cohesin; transcription; gene expression; single nucleotide polymorphism (SNP); genetic variant; allele-specific binding; allele-specific chromatin loop; ENCODE; nucleosome; histone modification
5.  Laying a solid foundation for Manhattan ‘Setting the functional basis for the post-GWAS era’ 
Trends in genetics : TIG  2014;30(4):140-149.
Genome-wide association studies (GWAS) have identified more than 8,900 genetic variants, mainly single nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translational rate and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of the genome has contributed to post-GWAS studies by facilitating the identification of the functional targets of risk-associated loci. Many non-coding genetic variants within risk-associated loci alter gene expression by modulating the activity of cis-regulatory elements. Here, we review these recent findings and discuss their implication for the post-GWAS era and relate their importance to the interpretation of disease-associated mutations identified through whole-genome sequencing.
PMCID: PMC4026049  PMID: 24661571
gwas; genetic risk variant; causal variant; missing heritability; functional genomic; noncoding
6.  Enhancer alterations in cancer: a source for a cell identity crisis 
Genome Medicine  2014;6(9):77.
Enhancers are selectively utilized to orchestrate gene expression programs that first govern pluripotency and then proceed to highly specialized programs required for the process of cellular differentiation. Whereas gene-proximal promoters are typically active across numerous cell types, distal enhancer activation is cell-type-specific and central to cell fate determination, thereby accounting for cell identity. Recent studies have highlighted the diversity of enhancer usage, cataloguing millions of such elements in the human genome. The disruption of enhancer activity, through genetic or epigenetic alterations, can impact cell-type-specific functions, resulting in a wide range of pathologies. In cancer, these alterations can promote a ‘cell identity crisis’, in which enhancers associated with oncogenes and multipotentiality are activated, while those promoting cell fate commitment are inactivated. Overall, these alterations favor an undifferentiated cellular phenotype. Here, we review the current knowledge regarding the role of enhancers in normal cell function, and discuss how genetic and epigenetic changes in enhancer elements potentiate oncogenesis. In addition, we discuss how understanding the mechanisms regulating enhancer activity can inform therapeutic opportunities in cancer cells and highlight key challenges that remain in understanding enhancer biology as it relates to oncology.
PMCID: PMC4254433  PMID: 25473436
7.  Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multiethnic Population 
Diabetes Care  2013;36(9):2836-2842.
To determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos and if they can add to the prediction of incident T2DM in a high-risk population.
In the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up.
Nine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM, with an odds ratio of 1.08 (95% CI 1.05–1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691–0.725) and increased only marginally to 0.714 (0.698–0.731) with the addition of the gene score (P for C statistic change = 0.0052).
T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
PMCID: PMC3747911  PMID: 23603917
8.  Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression 
Nature genetics  2012;44(11):1191-1198.
Genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with human traits and diseases. But because the vast majority of these SNPs are located in the noncoding regions of the genome their risk promoting mechanisms are elusive. Employing a new methodology combining cistromics, epigenomics and genotype imputation we annotate the noncoding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results demonstrate that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of H3K4me1 in a cancer and cell-type-specific manner. Furthermore, the majority of these risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, which results in allele-specific gene expression, exemplified by the effect of the rs4784227 SNP on the TOX3 gene found within the 16q12.1 risk locus.
PMCID: PMC3483423  PMID: 23001124
9.  The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study 
PLoS Medicine  2011;8(10):e1001106.
Ron Do and colleagues find that a prudent diet high in raw vegetables may modify the increased genetic risk of cardiovascular disease conferred by the chromosome 9p21 SNP.
One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.
Methods and Findings
We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10−8≤p≤5.21×10−7). A significant interaction (p = 4.0×10−4) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10−7), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10−3) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10−4, and HR = 1.35, p = 4.1×10−3, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10−9) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).
The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular diseases (CVDs)—diseases that affect the heart and/or the blood vessels—are a leading cause of illness and death worldwide. In the United States, for example, the leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction, or MI); the third leading cause of death in the US is stroke, a CVD in which the brain's blood supply is interrupted. Environmental factors such as diet, physical activity, and smoking alter a person's risk of developing CVD. In addition, certain genetic variants (alterations in the DNA that forms the body's blueprint; DNA is packed into structures called chromosomes) alter the risk of developing CVD and are passed from parent to child. Thus, in CVD, as in most common diseases, both genetics and the environment play a role.
Why Was This Study Done?
Recent studies have identified several genetic variants that are associated with an increased risk of developing CVD. One of the most robust of these genetic associations is a cluster of single nucleotide polymorphisms (SNPs, differences in a single DNA building block) in a chromosomal region (locus) called 9p21. So far, this association has been mainly studied in European populations. Moreover, the interaction of this locus with environmental factors has not been extensively studied. A better understanding of how 9p21 variants affect CVD risk in people of different ethnicities and of the interaction between this locus and environmental factors could allow the development of targeted strategies for the prevention of CVD. In this study, the researchers investigate the association of 9p21 risk variants with CVD in people of different ethnicities and test for an interaction between this locus and environmental factors.
What Did the Researchers Do and Find?
The researchers assessed four 9p21 SNPs in people enrolled in the INTERHEART study, a global retrospective case-control study that investigated potential MI risk factors by comparing people who had had an acute non-fatal MI with similar people without heart disease. All four SNP risk variants increased the risk of MI by about a fifth. However, the effect of the SNPs on MI was influenced by the “prudent” diet pattern score of the INTERHEART participants, a score that includes fresh fruit and vegetable intake as recorded in food frequency questionnaires. That is, the risk of MI in people carrying SNP risk variants was influenced by their diet. The strongest interaction was seen with an SNP called rs2383206, but although rs2383206 carriers who ate a diet poor in fruits and vegetables had a higher risk of MI than people with a similar diet who did not carry this SNP, rs2383206 carriers and non-carriers who ate a fruit- and vegetable-rich diet had a comparable MI risk. Overall, the combination of the least “prudent” diet and two copies of the risk variant (human cells contain two complete sets of chromosomes) was associated with a two-fold increase in risk for MI in the INTERHEART study. Additionally, data collected in the FINRISK study, which characterized healthy individuals living in Finland at baseline and then followed them to see whether they developed CVD, revealed a similar interaction between diet and 9p21 SNPs.
What Do These Findings Mean?
These findings suggest that the risk of CVD conferred by chromosome 9p21 SNPs may be influenced by diet in multiple ethnic groups. Importantly, they suggest that the deleterious effect of 9p21 SNPs on CVD might be mitigated by consuming a diet rich in fresh fruits and vegetables. The accuracy of these findings may be affected by recall bias in the INTERHEART study (that is, some people may not have remembered their diet accurately) and by the small number of CVD cases in the FINRISK study. Nevertheless, these findings suggest that gene–environment interactions are important drivers of CVD, and they raise the possibility that a sound diet can mediate the effects of 9p21 SNPs.
Additional Information
Please access these websites via the online version of this summary at
The American Heart Association provides information about many types of cardiovascular disease for patients, caregivers, and professionals and tips on keeping the heart healthy
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The US Centers for Disease Control and Prevention has a simple fact sheet on gene-environment interactions; the US National Institute of Environmental Health Sciences provides links to other information on gene-environment interactions
More information is available on the INTERHEART study and on the FINRISK study
PMCID: PMC3191151  PMID: 22022235
10.  Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study 
Diabetes Care  2010;33(10):2250-2253.
Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure—outcomes that may have a genetic etiology.
We genotyped 4,197 participants of the multiethnic DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965).
One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47–2.42]; P = 5.32 × 10−7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10−4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10−3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05).
Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.
PMCID: PMC2945168  PMID: 20628086
11.  Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects 
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay–Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.
PMCID: PMC2824775  PMID: 19844255
HDL-C; family study; complex traits; coronary heart disease; gene identification
12.  Fine Mapping and Association Studies of a High-Density Lipoprotein Cholesterol Linkage Region on Chromosome 16 in French-Canadian Subjects 
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multi-generational families and a study of 61 families from the Saguenay–Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49 respectively. Variance components linkage methods identified a LOD score of 2.61, at 98 cM near the marker D16S515 in the Quebec-wide families and a LOD score of 2.96 at 86 cM, near the marker D16S2624 in the SLSJ families. In the Quebec-wide sample, four families demonstrated segregation over a 25.5 cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6, segregated in four families and with additional families we observed a p value of 0.015 for this variant. However, an association study of this SNP in unrelated Quebec-wide samples was not significant. We also identified a SNP (rs11646677) in the same region, which was significantly associated with low HDL-C (p=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells demonstrated a significant difference in expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French Canadian studies.
PMCID: PMC2824775  PMID: 19844255
high-density lipoprotein cholesterol; family study; complex traits; coronary heart disease; gene identification
13.  Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies 
PLoS ONE  2008;3(10):e3583.
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a “cosmopolitan” tagging approach to capture the genetic diversity across ∼2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.
PMCID: PMC2571995  PMID: 18974833

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