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1.  Gene-body mass index interactions are associated with methotrexate toxicity in rheumatoid arthritis 
Annals of the rheumatic diseases  2013;73(4):785-786.
PMCID: PMC3970399  PMID: 24291656
Gene polymorphism; methotrexate; rheumatoid arthritis
2.  Divided States of America: Regional Variation in Cardiovascular Health 
PMCID: PMC3540676  PMID: 23316334
editorials; disparities; health status; heart; regional variation
3.  Has pharmacogenetics brought us closer to “personalized medicine” for initial drug treatment of hypertension? 
Current opinion in cardiology  2009;24(4):333-339.
Purpose of review
To describe recent advances in antihypertensive pharmacogenetics and discuss challenges related to translating this knowledge into “personalized medicine” for the initial drug treatment of hypertension.
Recent findings
Recent studies included both prospective and retrospective analyses ranging from small clinical investigations of 42 participants to large, multicenter, randomized, outcome-based clinical trials of nearly 40,000 subjects. Treatment with drugs from five classes of antihypertensives was evaluated in these studies. The duration of treatment ranged from weeks-long follow up for BP response to a decade long follow up for clinical outcomes. In total, associations with 12 different candidate genes were assessed. These studies present the now familiar mix of significant and nonsignificant pharmacogenetic findings that are sometimes consistent with, sometimes inconsistent with, previous findings in antihypertensive pharmacogenetics.
Recent research in antihypertensive pharmacogenetics has added to the existing evidence base, and novel genes and variants as well as new methodologies are cause for continued optimism. However, translation of genomic science to clinical settings has not kept pace with growing interest in personalized medicine for hypertension. New research paradigms may be needed to translate pharmacogenetics into clinical tools. Clinical application will also require a trained clinical workforce, validated genetic tests, and payors willing to fund pre-treatment testing.
PMCID: PMC3926658  PMID: 19509486
antihypertensive pharmacogenetics; personalized medicine; genes; hypertension
4.  RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment 
The pharmacogenomics journal  2012;13(4):330-334.
Nearly one-third of adults in the U.S. have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment (GenHAT) study and using a case-only design, we examined whether single nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca+2 in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on heart failure, the strongest of which was for rs877087, with the smallest p-value =.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3,058 CHD cases and 1,940 heart failure cases show that a hypertensive patient’s genetic profile may help predict which medication(s) might better lower cardiovascular disease risk.
PMCID: PMC3435442  PMID: 22664477
RYR3 gene; calcium channel blocker; hypertension; coronary heart disease; heart failure; genetic interaction
5.  Partial normalization of components of metabolic syndrome does not influence prevalent echocardiographic abnormalities: the HyperGEN Study 
Background and Aims
Metabolic syndrome (MetS) is a complex condition characterized by different phenotypes, according to combinations of risk factors and is associated with cardiovascular abnormalities. Whether control of MetS components by treatment produces improvement in the associated cardiovascular abnormalities is unknown. We investigated whether partial control of components of MetS was associated with less echocardiographic abnormalities than the complete presentation of MetS based on measured components.
Methods and Results
We evaluated markers of echocardiographic preclinical cardiovascular disease in MetS (ATPIII) defined by measured components or by history of treatment, in 1,421 African- American and 1,195 Caucasian non-diabetic HyperGEN participants, without prevalent cardiovascular disease or serum creatinine>2 mg/dL. Of 2,616 subjects, 512 subjects had MetS by measured components and 328 by history. Hypertension was found in 16% of participants without MetS, 6% of those with MetS by history and 42% of those with MetS by measured components. Obesity and central fat distribution had similar prevalence in both MetS groups (both p<0.0001 vs No-MetS). Blood pressure was similar in MetS by history and No-MetS, and lower than in MetS by measured components (p<0.0001). LV mass and midwall shortening, left atrial (LA) dimension and LA systolic force were similarly abnormal in both MetS groups (all p<0.0001 vs. No-MetS) without difference between them.
There is little impact of control by treatment of single components of MetS (namely hypertension) on echocardiographic abnormalities. Lower blood pressure in participants with MetS by history was not associated with substantially reduced alterations in cardiac geometry and function.
PMCID: PMC3158296  PMID: 21570269
6.  Associations Between NOS1AP Single Nucleotide Polymorphisms (SNPs) and QT Interval Duration in Four Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis (MESA) 
QT is a risk factor for sudden cardiac death (SCD). A genome wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used MESA to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African-Americans (AFA), Hispanics (HIS) and Chinese (CHN)), age 45–84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates.
More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9msec, p= 7.20×10-7). Significant associations in CAU and HIS were located at the 5′ end, while associations in CHN were located at the 3′ end.
NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3′ end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. Further investigations are needed across ethnically diverse population cohorts.
PMCID: PMC3642094  PMID: 23347024
Genetics; Electrocardiography; Arrhythmia; Electrophysiology
7.  The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN 
Frontiers in Genetics  2013;4:304.
Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.
PMCID: PMC3872290  PMID: 24400021
blood pressure; hypertension; loop diuretic; gene-drug interaction; genome-wide association; african americans; european americans
8.  The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate 
Journal of cardiovascular pharmacology  2012;59(3):10.1097/FJC.0b013e31823de86b.
CYP7A1 encodes cholesterol 7α-hydroxylase an enzyme crucial to cholesterol homeostasis. Its transcriptional activity is down-regulated by fenofibrate. The goal of this study was to determine the effect of CYP7A1 polymorphisms on lipid changes in response to fenofibrate. We examined associations of three tagging single nuclear polymorphisms (SNP) (i6782C>T, m204T>G, 3U12536A>C) at CYP7A1 with triglyceride (TG) and HDL-C responses to a 3-week treatment with fenofibrate 160 mg/d in 864 US White participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. The m204T>G variant significantly associated TG and HDL-C responses to fenofibrate. Individual homozygous for the common T allele of m204T>G SNP displayed both the greater reduction of TG (−32% for TT, −28% for GT, −25% for GG, P = 0.004) and an increase of HDL-C response compared to non-carriers (4.1% for TT, 3.4% for GT, 1.2% for GG, P = 0.01). Conversely, individuals homozygous for the minor allele of i6782C>T showed greater increase of HDL-C response compared to non-carriers (2.8% CC, 4.5% for CT, 5.8% for TT, P=0.02) albeit no significant effect on TG response. Our data suggest that common variants at CYP7A1 locus modulate the TG lowering and HDL-C raising effects of fenofibrate, and contribute to the interindividual variation of the drug responses.
PMCID: PMC3868459  PMID: 22075751
CYP7A1; polymorphism; TG response; fenofibrate
9.  Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: The GenHAT Study 
Stroke; a journal of cerebral circulation  2010;42(2):10.1161/STROKEAHA.110.593798.
Background and Purpose
Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (MMP3) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the GenHAT study, ancillary to ALLHAT, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine if it modifies clinical outcome response to blood pressure lowering drugs.
The effect of the MMP3 5A/6A polymorphism on stroke rates were examined using multivariate-adjusted Cox regression models including testing interactions between genotype and antihypertensive drug class.
Compared to participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (HR, 1.32; 95% CI, 1.08-1.61; P = 0.007), 5A/6A individuals taking lisinopril had lower stroke rates (HRinteraction = 0.74; Pinteraction = 0.08; 95% CI, 0.53-1.04), while 5A/5A individuals taking lisinopril had the lowest stroke rate (HRinteraction=0.51; Pinteraction=0.009; 95% CI, 0.31-0.85). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin versus chlorthalidone.
The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared to patients treated with chlorthalidone, while a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated.
PMCID: PMC3859235  PMID: 21183746
hypertension; pharmacogenetics; genetic polymorphism; cardiovascular; Stroke; Matrix Metalloproteinase 3; Antihypertensive Agents
10.  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
11.  Genetic and Adverse Health Outcome Associations with Treatment Resistant Hypertension in GenHAT 
Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics of TRH are largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36% AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants. The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12–1.44), P = 0.0001, and OR = 1.36 (1.20–1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051). This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients.
PMCID: PMC3833110  PMID: 24288596
12.  Genome-Wide Contribution of Genotype by Environment Interaction to Variation of Diabetes-Related Traits 
PLoS ONE  2013;8(10):e77442.
While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-β-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.
PMCID: PMC3810463  PMID: 24204828
13.  Normal Limits in Relation to Age, Body Size and Gender of Two-Dimensional Echocardiographic Aortic Root Dimensions in Persons ≥15 Years of Age 
The American journal of cardiology  2012;110(8):1189-1194.
Nomograms to predict normal aortic root diameter for body surface area (BSA) in broad ranges of age have been widely used, but are limited by lack of consideration of gender effects, jumps in upper limits of aortic diameter between age strata, and data from older teenagers. Sinuses of Valsalva diameter was measured by American Society of Echocardiography convention in normal-weight, non-hypertensive, non-diabetic individuals ≥15 years old without aortic valve disease from clinical or population-based samples. Analyses of covariance and linear regression with assessment of residuals identified determinants and developed predictive models for normal aortic root diameter. Among 1,207 apparently normal individuals ≥15 years old (54% female), aortic root diameter was 2.1 to 4.3 cm. Aortic root diameter was strongly related to BSA and height (both r=0.48), age (r=0.36) and male gender (+2.7 mm adjusted for BSA and age) (all p<0.001). Multivariable equations using age, gender, and either BSA or height predicted aortic diameter strongly (both R=0.674, p <0.001) with minimal relation of residuals to age or body size: for BSA: 2.423+(age [yrs]*0.009) + (bsa [m2]*0.461) -(sex [1=M, 2=F]*.267) SEE = 0.261 cmfor height: 1.519+(age [yrs]*0.010) + (ht [cm]*.010)-(sex [1=M, 2=F]*.247) SEE = 0.215 cm.
In conclusion, aortic root diameter is larger in men and increases with body size and age. Regression models incorporating body size, age and gender are applicable to adolescents and adults without limitations of previous nomograms.
PMCID: PMC3462295  PMID: 22770936
Aortic root; echocardiography; normal limits
14.  Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate 
Pharmacogenetics and genomics  2012;22(10):750-757.
A shift towards overall larger very low-density lipoprotein (VLDL), and smaller low-density lipoprotein and high-density lipoprotein (HDL) diameters occurs in insulin resistance (IR), which reflects shifts in the distribution of the subfraction concentrations. Fenofibrate, indicated for hypertriglyceridemia, simultaneously reduces IR and shifts in lipoprotein diameter. Individual responses to fenofibrate vary, and we conducted a genome-wide association study to identify genetic differences that could contribute to such differences.
Association analysis was conducted between single nucleotide polymorphisms (SNPs) on the Affymetrix 6.0 array and fasting particle diameter responses to a 12-week fenofibrate trial, in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network. Linear models were conducted, which adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. The top three SNPs associated with each fraction were examined subsequently for associations with changes in subfraction concentrations.
SNPs in AHCYL2 and CD36 genes reached, or closely approached, genome-wide levels of significance with VLDL and HDL diameter responses to fenofibrate, respectively (P=4 × 10−9 and 8 × 10−8). SNPs in AHCYL2 were associated with a decrease in the concentration of the large VLDL subfraction only (P = 0.002). SNPs associated with HDL diameter change were not associated with a single subfraction concentration change (P > 0.05) indicating small shifts across all subfractions.
We report novel associations between lipoprotein diameter responses to fenofibrate and the AHCYL2 and CD36 genes. Previous associations of these genes with IR emphasize the role of IR in mediating lipoprotein response to fenofibrate.
PMCID: PMC3760420  PMID: 22890011
AHCYL2; CD36; fenofibrate; inflammation; insulin resistance; insulin signaling; lipoprotein diameter; methylation; PPARγ; subclass
15.  Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status 
Atherosclerosis  2011;215(2):435-439.
Fenofibrate therapy reduces serum triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C) and thus addresses the atherogenic dyslipidemia associated with metabolic syndrome (MetS). Our hypothesis is that genetic factors contribute to the variability of lipid response to fenofibrate differently in subjects with MetS and without MetS.
We investigated the association in 25 candidate genes with lipid responses to a 3-weeks trial on fenofibrate in subjects with and without MetS. We employed growth curve mixed models to generate the response phenotypes to fenofibrate in TG, HDL-C, and low-density lipoprotein-cholesterol (LDL-C) and examined the genetic associations accounting for family dependencies.
After correcting for multiple testing (p<0.05) and accounting for significant differences in the association effect sizes between subjects with and without MetS (p<0.05), variants of APOA5 (rs662799) and APOE (rs429358) were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 (rs675)was associated with TG response in non-MetS subjects. There was also suggestive evidence that MetS may interact with APOA4 (p=0.017), APOA5 (p=0.06), and APOE (p=0.09) to the variation to lipid responses.
Genetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. This research may provide guidance for more personalized and effective therapies.
PMCID: PMC3777277  PMID: 21324458
16.  Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: The HyperGEN Study 
Journal of human hypertension  2011;26(2):133-140.
Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (ACE I/D; AGT -6G-A, M235T, -20A-C) in the renin-angiotension system (RAS) on left ventricular mass (LVM) among hypertensive participants in the HyperGEN study.
Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: Adjusted mean LVM (g/m2.7) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; p=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction p=0.03): Among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1).
These findings indicate that RAS variants in at least two genes may interact to modulate LVM.
PMCID: PMC3775641  PMID: 21248783
Left ventricular mass; left ventricular hypertrophy; ACE gene; AGT gene; epistasis; hypertension
17.  Measurement of Erythrocyte Methotrexate Polyglutamate Levels: Ready for Clinical Use in Rheumatoid Arthritis? 
Current rheumatology reports  2010;12(5):342-347.
Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identification of biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring methotrexate polyglutamates (MTX PGs) levels in circulating red blood cells (RBC) has been proposed as an objective measure that can help to optimize MTX therapy in RA. There is conflicting data with regard to the clinical utility of measurement of MTX PGs measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy and toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in RA.
PMCID: PMC3769795  PMID: 20665136
Rheumatoid Arthritis; Methotrexate; Polyglutamates
18.  Obesity–insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice 
Identifying metabolic syndrome (MetS) genes is important for novel drug development and health care. This study extends the findings on human chromosome 3p26-25 for an identified obesity–insulin factor QTL, with an LOD score above 3. A focused association analysis comprising up to 9578 African American and Caucasian subjects from the HyperGEN Network (908 African Americans and 1025 whites), the Family Heart Study (3035 whites in time 1 and 1943 in time 2), and the Framingham Heart Study (1317 in Offspring and 1320 in Generation 3) was performed. The homologous mouse region was explored in an F16 generation of an advanced intercross between the LG/J and SM/J inbred strains, in an experiment where 1002 animals were fed low-fat (247 males; 254 females) or high-fat (253 males; 248 females) diets. Association results in humans indicate pleiotropic effects for SNPs within or surrounding CNTN4 on obesity, lipids and blood pressure traits and for SNPs near IL5RA, TRNT1, CRBN, and LRRN1 on central obesity and blood pressure. Linkage analyses of this region in LG/J × SM/J mice identify a highly significant pleiotropic QTL peak for insulin and glucose levels, as well as response to glucose challenge. The mouse results show that insulin and glucose levels interact with high and low fat diets and differential gene expression was identified for Crbn and Arl8b. In humans, ARL8B resides ~137 kbps away from BHLHE40, expression of which shows up-regulation in response to insulin treatment. This focused human genetic analysis, incorporating mouse research evidenced that 3p26-25 has important genetic contributions to MetS components. Several of the candidate genes have functions in the brain. Their interaction with MetS and the brain warrants further investigation.
PMCID: PMC3586585  PMID: 22386932
19.  Replication of RYR3 gene polymorphism association with cIMT among HIV-infected whites 
AIDS (London, England)  2012;26(12):1571-1573.
To replicate the association of variants in RYR3 gene with common carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis, we genotyped single nucleotide polymorphisms (SNPs) rs2229116 and rs7177922 in a sub-population of 244 HIV-positive and HIV-negative men. SNP rs2229116 was associated with common cIMT in HIV infected white men after adjusting for age and use of stavudine (d4T). The association was more evident at younger ages and decreased among older individuals.
PMCID: PMC3606588  PMID: 22627881
20.  Genotype Imputation for African Americans using data from HapMap Phase II versus 1000 Genomes Projects 
Genetic epidemiology  2012;36(5):508-516.
Genotype imputation provides imputation of untyped SNPs that are present on a reference panel such as those from the HapMap Project. It is popular for increasing statistical power and comparing results across studies using different platforms. Imputation for African American populations is challenging because their LD blocks are shorter and also because no ideal reference panel is available due to admixture. In this paper, we evaluated three imputation strategies for African Americans. The intersection strategy used a combined panel consisting of SNPs polymorphic in both CEU and YRI. The union strategy used a panel consisting of SNPs polymorphic in either CEU or YRI. The merge strategy merged results from two separate imputations, one using CEU and the other using YRI. Because recent investigators are increasingly using the data from the 1000 Genomes (1KG) Project for genotype imputation, we evaluated both 1KG-based imputations and HapMap-based imputations. We used 23,707 SNPs from chromosomes 21 and 22 on Affymetrix SNP Array 6.0 genotyped for 1,075 HyperGEN African Americans. We found that 1KG-based imputations provided a substantially larger number of variants than HapMap-based imputations, about three times as many common variants and eight times as many rare and low frequency variants. This higher yield is expected because the 1KG panel includes more SNPs. Accuracy rates using 1KG data were slightly lower than those using HapMap data before filtering, but slightly higher after filtering. The union strategy provided the highest imputation yield with next highest accuracy. The intersection strategy provided the lowest imputation yield but the highest accuracy. The merge strategy provided the lowest imputation accuracy. We observed that SNPs polymorphic only in CEU had much lower accuracy, reducing the accuracy of the union strategy. Our findings suggest that 1KG-based imputations can facilitate discovery of significant associations for SNPs across the whole MAF spectrum. Because the 1KG Project is still underway, we expect that later versions will provide better imputation performance.
PMCID: PMC3703942  PMID: 22644746
21.  Copy number variations associated with obesity related traits in African Americans: a joint analysis between GENOA and HyperGEN 
Obesity (Silver Spring, Md.)  2012;20(12):2431-2437.
Obesity is a highly heritable trait and a growing public health problem. African Americans are a genetically diverse, yet understudied population with a high prevalence of obesity (body mass index (BMI) greater than 30 kg/m2). Recent studies based upon single nucleotide polymorphisms (SNPs) have identified genetic markers associated with obesity. However, a large proportion of the heritability of obesity remains unexplained. Copy number variation (CNV) has been cited as a possible source of missing heritability in common diseases such as obesity. We conducted a CNV genome-wide association study of BMI in two African American cohorts from GENOA and HyperGEN. We performed independent and identical association analyses in each study, then combined the results in a meta-analysis. We identified three CNVs associated with BMI, obesity, and other obesity-related traits after adjusting for multiple testing. These CNVs overlap the PARK2, GYPA and SGCZ genes. Our results suggest that CNV may play a role in the etiology of obesity in African Americans.
PMCID: PMC3484176  PMID: 22836685
Obesity; CNVs; Meta-analysis; BMI; African Americans
22.  Gene panels to help identify subgroups at high and low risk of CHD among those randomized to antihypertensive treatment: The GenHAT Study 
Pharmacogenetics and Genomics  2012;22(5):355-366.
To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment.
Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score.
For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09).
Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.
PMCID: PMC3325375  PMID: 22388798
pharmacogenetics; antihypertensive pharmacogenetics; CVD; gene panels
23.  Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease 
The American Journal of Medicine  2012;125(4):399-410.
The role of renin-angiotensin inhibition in older systolic heart failure patients with chronic kidney disease remains unclear.
Of the 1665 patients, age ≥65 years, with systolic heart failure (ejection fraction <45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 1046 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the receipts of these drugs, estimated for each of the 1665 patients, were used to assemble a matched cohort of 444 pairs of patients receiving and not receiving these drugs who were balanced on 56 baseline characteristics.
During over 8 years of follow-up, all-cause mortality occurred in 75% and 79% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.86; 95% confidence interval {CI}, 0.74–0.996; p=0.045). There was no significant association with heart failure hospitalization (HR, 0.86; 95% CI, 0.72–1.03; p=0.094). Similar mortality reduction (HR, 0.83; 95% CI, 0.70–1.00; p=0.046) occurred in a subgroup of matched patients with estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 171 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was associated with significant reduction in all-cause mortality (HR, 0.72; 95% CI, 0.55–0.94; p=0.015) and heart failure hospitalization (HR, 0.71; 95% CI, 0.52–0.95; p=0.023).
Discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant modest reduction in all-cause mortality in older systolic heart failure patients with chronic kidney disease including those with more advanced chronic kidney disease.
PMCID: PMC3324926  PMID: 22321760
systolic heart failure; chronic kidney disease; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers
24.  Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained 
Wu, Ying | Waite, Lindsay L. | Jackson, Anne U. | Sheu, Wayne H-H. | Buyske, Steven | Absher, Devin | Arnett, Donna K. | Boerwinkle, Eric | Bonnycastle, Lori L. | Carty, Cara L. | Cheng, Iona | Cochran, Barbara | Croteau-Chonka, Damien C. | Dumitrescu, Logan | Eaton, Charles B. | Franceschini, Nora | Guo, Xiuqing | Henderson, Brian E. | Hindorff, Lucia A. | Kim, Eric | Kinnunen, Leena | Komulainen, Pirjo | Lee, Wen-Jane | Le Marchand, Loic | Lin, Yi | Lindström, Jaana | Lingaas-Holmen, Oddgeir | Mitchell, Sabrina L. | Narisu, Narisu | Robinson, Jennifer G. | Schumacher, Fred | Stančáková, Alena | Sundvall, Jouko | Sung, Yun-Ju | Swift, Amy J. | Wang, Wen-Chang | Wilkens, Lynne | Wilsgaard, Tom | Young, Alicia M. | Adair, Linda S. | Ballantyne, Christie M. | Bůžková, Petra | Chakravarti, Aravinda | Collins, Francis S. | Duggan, David | Feranil, Alan B. | Ho, Low-Tone | Hung, Yi-Jen | Hunt, Steven C. | Hveem, Kristian | Juang, Jyh-Ming J. | Kesäniemi, Antero Y. | Kuusisto, Johanna | Laakso, Markku | Lakka, Timo A. | Lee, I-Te | Leppert, Mark F. | Matise, Tara C. | Moilanen, Leena | Njølstad, Inger | Peters, Ulrike | Quertermous, Thomas | Rauramaa, Rainer | Rotter, Jerome I. | Saramies, Jouko | Tuomilehto, Jaakko | Uusitupa, Matti | Wang, Tzung-Dau | Boehnke, Michael | Haiman, Christopher A. | Chen, Yii-Der I. | Kooperberg, Charles | Assimes, Themistocles L. | Crawford, Dana C. | Hsiung, Chao A. | North, Kari E. | Mohlke, Karen L. | Gibson, Greg
PLoS Genetics  2013;9(3):e1003379.
Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Author Summary
Lipid traits are heritable, but many of the DNA variants that influence lipid levels remain unknown. In a genomic region, more than one variant may affect gene expression or function, and the frequencies of these variants can differ across populations. Genotyping densely spaced variants in individuals with different ancestries may increase the chance of identifying variants that affect gene expression or function. We analyzed high-density genotyped variants for association with TG, HDL-C, and LDL-C in African Americans, East Asians, and Europeans. At several genomic regions, we provide evidence that two or more variants can influence lipid traits; across loci, these additional signals increase the proportion of trait variation that can be explained by genes. At some association signals shared across populations, combining data from individuals of different ancestries narrowed the set of likely functional variants. At PCSK9 and APOA5, the data suggest that different variants influence trait levels in different populations. Variants previously reported to alter gene expression or function frequently exhibited the strongest association at those signals. The multiple signals and population-specific characteristics of the loci described here may be shared by genetic loci for other complex traits.
PMCID: PMC3605054  PMID: 23555291
25.  Gender differences in the association of visceral and subcutaneous adiposity with adiponectin in African Americans: the Jackson Heart Study 
Adiponectin, paradoxically reduced in obesity and with lower levels in African Americans (AA), modulates several cardiometabolic risk factors. Because abdominal visceral adipose tissue (VAT), known to be reduced in AA, and subcutaneous adipose tissue (SAT) compartments may confer differential metabolic risk profiles, we investigated the associations of VAT and SAT with serum adiponectin, separately by gender, with the hypothesis that VAT is more strongly inversely associated with adiponectin than SAT.
Participants from the Jackson Heart Study, an ongoing cohort of AA (n = 2,799; 64% women; mean age, 55 ± 11 years) underwent computer tomography assessment of SAT and VAT volumes, and had stored serum specimens analyzed for adiponectin levels. These levels were examined by gender in relation to increments of VAT and SAT.
Compared to women, men had significantly lower mean levels of adiponectin (3.9 ± 3.0 μg/mL vs. 6.0 ± 4.4 μg/mL; p < 0.01) and mean volume of SAT (1,721 ± 803 cm3 vs. 2,668 ± 968 cm3; p < 0.01) but significantly higher mean volume of VAT (884 ± 416 cm3 vs. 801 ± 363 cm3; p < 0.01). Among women, a one standard deviation increment in VAT was inversely associated with adiponectin (β = − 0.13; p < 0.0001) after controlling for age, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, education, pack-years of smoking and daily intake of alcohol. The statistically significant inverse association of VAT and adiponectin persisted after additionally adjusting for SAT, body mass index (BMI) and waist circumference (WC), suggesting that VAT provides significant information above and beyond BMI and WC. Among men, after the same multivariable adjustment, there was a direct association of SAT and adiponectin (β = 0.18; p = 0.002) that persisted when controlling for BMI and WC, supporting a beneficial effect of SAT. Insulin resistance mediated the association of SAT with adiponectin in women.
In African Americans, abdominal visceral adipose tissue had an inverse association with serum adiponectin concentrations only among women. Abdominal subcutaneous adipose tissue appeared as a protective fat depot in men.
PMCID: PMC3586352  PMID: 23433085

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