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1.  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.
doi:10.1186/s13073-014-0077-3
PMCID: PMC4254433  PMID: 25473436
2.  Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multiethnic Population 
Diabetes Care  2013;36(9):2836-2842.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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).
CONCLUSIONS
T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
doi:10.2337/dc12-2553
PMCID: PMC3747911  PMID: 23603917
3.  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.
doi:10.1038/ng.2416
PMCID: PMC3483423  PMID: 23001124
4.  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.
Background
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).
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001106.
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
doi:10.1371/journal.pmed.1001106
PMCID: PMC3191151  PMID: 22022235
5.  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.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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).
RESULTS
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).
CONCLUSIONS
Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.
doi:10.2337/dc10-0452
PMCID: PMC2945168  PMID: 20628086
6.  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.
doi:10.1038/ejhg.2009.157
PMCID: PMC2824775  PMID: 19844255
HDL-C; family study; complex traits; coronary heart disease; gene identification
7.  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.
doi:10.1038/ejhg.2009.157
PMCID: PMC2824775  PMID: 19844255
high-density lipoprotein cholesterol; family study; complex traits; coronary heart disease; gene identification
8.  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.
doi:10.1371/journal.pone.0003583
PMCID: PMC2571995  PMID: 18974833

Results 1-8 (8)