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1.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
2.  To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies 
PMCID: PMC4961927  PMID: 23963160
3.  Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference 
Obesity (Silver Spring, Md.)  2015;23(7):1493-1501.
To conduct an epigenome-wide analysis of DNA methylation and obesity traits.
Design and Methods
We quantified DNA methylation in CD4+ T-cells using the Illumina Infinium Human Methylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled methylation at individual cytosine-phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure.
We found epigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n=2,377) and the Atherosclerosis Risk in Communities study (n=2,105). Top findings were in CPT1A (meta-analysis P= 3.5×10−37 for BMI and P=2.2×10−16 for WC), PHGDH (meta-analysis P= 4.7×10−15 for BMI and 2.2×10−8 for WC), CD38 (meta-analysis P= 3.7×10−11 for BMI and 6.1×10−13 for WC) and long intergenic non-coding RNA 00263 (meta-analysis P= 1.2×10−13 for BMI and 5.8×10−10 for WC), regions with biologically plausible relationships to adiposity.
This large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications.
PMCID: PMC4482015  PMID: 26110892
body mass index; waist circumference; obesity; epigenetics; genomics; CpG methylation
4.  Genetics, Ancestry, and Hypertension: Implications for Targeted Antihypertensive Therapies 
Hypertension is the most common chronic condition seen by physicians in ambulatory care and a condition for which life-long medications are commonly prescribed. There is evidence for genetic factors influencing blood pressure variation in populations and response to medications. This review summarizes recent genetic discoveries that surround blood pressure, hypertension, and antihypertensive drug response from genome-wide association studies, while highlighting ancestry-specific findings and any potential implication for drug therapy targets. Genome-wide association studies have identified several novel loci for inter-individual variation of blood pressure and hypertension risk in the general population. Evidence from pharmacogenetic studies suggests that genes influence the blood pressure response to antihypertensive drugs, although results are somewhat inconsistent across studies. There is still much work that remains to be done to identify genes both for efficacy and adverse events of antihypertensive medications.
PMCID: PMC4886553  PMID: 24903233
Genetics; Hypertension; Genome-wide association studies; Ancestry; Pharmacogenetics
5.  Heritable DNA Methylation in CD4+ Cells among Complex Families Displays Genetic and Non-Genetic Effects 
PLoS ONE  2016;11(10):e0165488.
DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H2) value threshold of 0.4, we identified 20,575 highly heritable CpGs among the 174,445 most variable autosomal CpGs (SD > 0.02). Tests for associations of heritable CpGs with genotype at 2,145,360 SNPs using 717 of 975 individuals showed that ~74% were cis-meQTLs (< 1 Mb away from the CpG), 6% of CpGs exhibited trans-meQTL associations (>1 Mb away from the CpG or located on a different chromosome), and 20% of CpGs showed no strong significant associations with genotype (based on a p-value threshold of 1e-7). Genes proximal to the genotype independent heritable CpGs were enriched for functional terms related to regulation of T cell activation. These CpGs were also among those that distinguished T cells from other blood cell lineages. Compared to genes proximal to meQTL-associated heritable CpGs, genotype independent heritable CpGs were moderately enriched in the same genomic regions that escape erasure during primordial germ cell development and could carry potential for generational transmission.
PMCID: PMC5085095  PMID: 27792787
6.  Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study 
Aging cell  2014;14(1):49-59.
Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = − 0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.
PMCID: PMC4324456  PMID: 25476875
apolipoprotein E; age; DNA methylation; variants; epidemiology; interaction
7.  Neurogenomics in Africa: Perspectives, progress, possibilities and priorities 
The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.
PMCID: PMC4920548  PMID: 27288810
Africa; Burden of disease; Capacity building; Genomics; Genetics; Neurological disorders
8.  A family-specific linkage analysis of blood lipid response to fenofibrate in the Genetics of Lipid Lowering Drug and Diet Network (GOLDN) 
Pharmacogenetics and genomics  2015;25(10):511-514.
Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-C on chromosome 7 (peak LOD score=4.76) in the full sample (n=821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N=19), we observed a peak LOD score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.
PMCID: PMC4558213  PMID: 26203732
fenofibrate; lipids; family study
Heart (British Cardiac Society)  2015;101(19):1584-1590.
Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesized that women with a history of hypertensive pregnancy would have altered left ventricular (LV) geometry and function when compared to women with only normotensive pregnancies.
In this cohort study, we analyzed echocardiograms of 2637 women who participated in the Family Blood Pressure Program (FBPP). We compared LV mass and function in women with hypertensive pregnancy compared to those with normotensive pregnancies.
Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared to women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42, 95% CI 1.01-1.99, p=0.05), after adjusting for age, race, research network of the FBPP, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19, CI 0.08-1.78 p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups.
A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy.
PMCID: PMC4568146  PMID: 26243788
Hypertension; Pregnancy; Left ventricular hypertrophy; Women; Diastolic function
10.  Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization 
Scientific Reports  2016;6:33188.
Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.
PMCID: PMC5021998  PMID: 27624874
11.  Association of Apolipoprotein E (ApoE) Polymorphism with the Prevalence of Metabolic Syndrome: The National Heart, Lung and Blood Institute Family Heart Study 
Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. The effects of Apolipoprotein E (Apo E) polymorphism on MetS are not well established.
We conducted a cross-sectional study consisting of 1,551 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the AHA-NHLBI-IDF-WHO Harmonized Criteria. We used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis.
Our study population had a mean age (SD) of 56.5 (11.0) years and 49.7% had MetS. There was no association between the Apo E genotypes and MetS. The multivariable adjusted ORs (95% CI) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47), and 1.87 (0.91-3.85) for the ε3/ε3, ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε4, and ε4/ε4 genotypes, respectively. In a secondary analysis, ε2/ε3 genotype was associated with 41% lower prevalence odds of low HDL [multivariable adjusted ORs (95% CI) = 0.59 (0.36-0.95)] compared to ε3/ε3 genotype.
Our findings do not support an association between Apo E polymorphism and MetS in a multi-center population based study of predominantly white US men and women.
PMCID: PMC4720970  PMID: 25656378
Apolipoprotein E (Apo E) polymorphism; metabolic syndrome; blood pressure; glucose; dyslipidemia; high-density lipoprotein cholesterol
12.  Lipid changes due to fenofibrate treatment are not associated with changes in DNA methylation patterns in the GOLDN study 
Frontiers in Genetics  2015;6:304.
Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-α, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation.
PMCID: PMC4586504  PMID: 26483836
fenofibrate; lipid lowering drug; epigenetic changes; DNA methylation; dyslipidemia; cardiovascular disease
13.  The effects of genes implicated in cardiovascular disease on blood-pressure response to treatment among treatment-naïve hypertensive African Americans in the GenHAT study 
Journal of human hypertension  2016;30(9):549-554.
African Americans have the highest prevalence of hypertension in the United States. Blood-pressure control is important to reduce cardiovascular disease (CVD)-related morbidity and mortality in this ethnic group. Genetic variants have been found to be associated with BP response to treatment. Previous pharmacogenetic studies of blood-pressure response to treatment in African Americans suffer limitations of small sample size as well as a limited number of candidate genes, and often focused on one antihypertensive treatment. Using 1,131 African-American treatment naïve participants from the Genetics of Hypertension Associated Treatment (GenHAT) Study, we examined whether variants in 35 candidate genes might modulate blood-pressure response to four different antihypertensive medications, including an angiotensin converting enzyme (ACE) inhibitor (lisinopril), a calcium channel blocker (amlodipine), and an α-adrenergic blocker (doxazosin) as compared to a thiazide diuretic (chlorthalidone) after 6 months of follow-up. Several suggestive gene by treatment interactions were identified. For example, among participants with two minor alleles of REN rs6681776, diastolic blood-pressure response was much improved on doxazosin compared to chlorthalidone (on average −9.49 mmHg vs. −1.70 mmHg) (P=0.007). Although several suggestive loci were identified, none of the findings passed significance criteria after correction for multiple testing. Given the impact of hypertension and its sequelae in this population, this research highlights the potential for genetic factors to contribute to blood-pressure response to treatment. Continued concerted research efforts focused on genetics are needed to improve treatment response in this high risk group.
PMCID: PMC4956602  PMID: 26791477
African American; antihypertensive drugs; treatment naïve; blood-pressure response; Genetics of Hypertension Associated Treatment Study
14.  Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci 
Human Molecular Genetics  2015;24(15):4464-4479.
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10−7; Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
PMCID: PMC4492394  PMID: 25935004
15.  Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: meta-analysis of 9 studies in the CHARGE consortium 
Molecular nutrition & food research  2015;59(7):1373-1383.
Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear.
We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA).
Methods and Results
We conducted meta-analyses (N to 11,668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein) and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma vs. erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary ALA and linoleic acid for DHA and DPA.
Our findings reinforce earlier reports that genetically-based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.
PMCID: PMC4491005  PMID: 25626431
FADS1; gene-diet interactions; meta-analysis; omega-3 fatty acids
16.  Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study 
Aging Cell  2014;14(1):49-59.
Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = −0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.
PMCID: PMC4324456  PMID: 25476875
apolipoprotein E; age; DNA methylation; variants; epidemiology; interaction
17.  The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study 
Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.
PMCID: PMC4165277  PMID: 25278896
AGT gene; antihypertensive drugs; hypertension; coronary heart disease; heart failure
18.  The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter 
Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6.
Methods and results
Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 10−7). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes.
Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs.
PMCID: PMC4844557  PMID: 26518637
DNA methylation; Gene-by-environment interaction; Genetic variant; Interleukin-6; n-3 polyunsaturated fatty acids
19.  Future Translational Applications From the Contemporary Genomics Era 
Circulation  2015;131(19):1715-1736.
The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.
PMCID: PMC4825323  PMID: 25882488
AHA Scientific Statements; adrenergic beta-antagonists; DNA; genetics; genome-wide association study; HapMap Project; Human Genome Project; PCSK9 protein; mouse; polymorphism; single nucleotide
20.  The Role of Genetic Variants in CRP in Radiographic Severity in African Americans with Early and Established Rheumatoid Arthritis 
Genes and immunity  2015;16(7):446-451.
This study investigates the association of CRP single nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available in 294 individuals from CLEAR 1 [median (IQR 25-75) disease duration of 1 (0.6-1.6) year] and in 407 persons from CLEAR 2 [median (IQR 25-75) disease duration of 8.9 (3.5 – 17.7) years]. In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score [incident rate ratio (IRR) 0.37 (95% CI 0.19-0.74), p value =0.0051]. In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (p value =0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg/dL when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.
PMCID: PMC4707038  PMID: 26226010
C reactive protein; genetics; rheumatoid arthritis; joint damage; radiography
21.  Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia 
Berndt, Sonja I. | Camp, Nicola J. | Skibola, Christine F. | Vijai, Joseph | Wang, Zhaoming | Gu, Jian | Nieters, Alexandra | Kelly, Rachel S. | Smedby, Karin E. | Monnereau, Alain | Cozen, Wendy | Cox, Angela | Wang, Sophia S. | Lan, Qing | Teras, Lauren R. | Machado, Moara | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Vajdic, Claire M. | Cocco, Pierluigi | Zhang, Yawei | Giles, Graham G. | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Montalvan, Rebecca | Burdett, Laurie | Hutchinson, Amy | Ye, Yuanqing | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Cunningham, Julie M. | Allmer, Cristine | Hjalgrim, Henrik | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Diver, W Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Arnett, Donna K. | Zhi, Degui | Leach, Justin M. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Sala, Núria | Casabonne, Delphine | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Chaffee, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R. | Strom, Sara S. | Leis, Jose F. | Weinberg, J. Brice | Caporaso, Neil E. | Norman, Aaron D. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María- Dolores | Vermeulen, Roel C. H. | Travis, Ruth C. | Southey, Melissa C. | Milne, Roger L. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R. | Villano, Danylo J. | Maria, Ann | Spinelli, John J. | Gascoyne, Randy D. | Connors, Joseph M. | Bertrand, Kimberly A. | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Ma, Baoshan | Huang, Jinyan | Crouch, Simon | Park, Ju-Hyun | Chatterjee, Nilanjan | North, Kari E. | Snowden, John A. | Wright, Josh | Fraumeni, Joseph F. | Offit, Kenneth | Wu, Xifeng | de Sanjose, Silvia | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature Communications  2016;7:10933.
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
PMCID: PMC4786871  PMID: 26956414
22.  Association of ideal cardiovascular health and calcified atherosclerotic plaque in the coronary arteries: the National Heart, Lung, and Blood Institute Family Heart Study 
American heart journal  2015;169(3):371-378.e1.
The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease (CVD) by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease (CHD). We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries.
Methods and Results
In a cross-sectional design, we studied 1731 predominantly Caucasian men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent CHD. Diet was assessed by a semi-quantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac CT. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age was 56.8 years and 41% were male. The median number of ideal CVH metrics was 3, and no participants met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29–0.45), 0.35 (0.26–0.44), and 0.27 (0.20–0.36) among subjects with 0–1, 2, 3, and 4+ ideal CVH metrics, respectively (p for trend: 0.0001), adjusting for sex, age, field center, alcohol, income, education, and calorie consumption.
These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women.
PMCID: PMC4346707  PMID: 25728727
cardiovascular health; epidemiology; subclinical disease; coronary calcium
23.  The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions 
Journal of human genetics  2008;53(8):10.1007/s10038-008-0302-2.
The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggested that the SCARB1 gene may contribute to variation in plasma lipid levels at the fasting; however, the results have been inconsistent and it is unclear if SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with post-fenofibrate change for triglyceride (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response as well as response to fenofibrate intervention.
PMCID: PMC3836273  PMID: 18542840
Scavenger receptor class B type 1; lipid; genetics; fenofibrate; postprandial
24.  Variants for HDL-C, LDL-C and Triglycerides Identified from Admixture Mapping and Fine-Mapping Analysis in African-American Families 
Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African-Americans.
Methods and Results
The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides. The analysis was performed in 1,905 unrelated African-American subjects from the National Heart, Lung and Blood Institute’s Family Blood Pressure Program. Regions showing admixture evidence were followed-up with family-based association analysis in 3,556 African-American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age2, sex, body-mass-index, and genome-wide mean ancestry to minimize the confounding due to population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (LDL-C), 8 (HDL-C), 14 (triglycerides) and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52,939 SNPs were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with HDL-C (2 SNPs), LDL-C (4 SNPs) and triglycerides (5 SNPs). The family data was used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions including genes with known associations for cardiovascular disease.
This study identified regions on chromosomes 7, 8, 14 and 19 and 11 SNPs from the fine-mapping analysis that were associated with HDL-C, LDL-C and triglycerides for further studies of cardiovascular disease in African-Americans.
PMCID: PMC4378661  PMID: 25552592
lipids; genetics; association studies; African-Americans; admixture mapping analysis
25.  Association of DNA Methylation at CPT1A Locus with Metabolic Syndrome in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study 
PLoS ONE  2016;11(1):e0145789.
In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10−7 was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10-14 and P for cg17058475 = 1.2x10-9). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future.
PMCID: PMC4726462  PMID: 26808626

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