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1.  Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study 
Lancet  2013;382(9894):790-796.
VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans.
We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10−8 in the discovery cohort and p<0·0038 in the replication cohort.
The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10−8). This association was confirmed in the replication cohort (p=5·04×10−5); analysis of the two cohorts together produced a p value of 4·5×10−12. Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement).
A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population.
National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.
PMCID: PMC3759580  PMID: 23755828
2.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
3.  Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial 
Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.
Methods and Results
TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals.
Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.
Clinical Trial Registration
URL: Unique identifier: NCT00403767.
PMCID: PMC3603243  PMID: 23525418
anticoagulants; arrhythmia; embolism; prevention; risk factors
4.  Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU 
Pharmacogenomics  2011;13(3):297-307.
To determine if copy number variants contribute to warfarin dose requirements, we investigated CYP2C9, VKORC1, CYP4F2, GGCX and CALU for deletions and duplications in a multiethnic patient population treated with therapeutic doses of warfarin.
Patients & methods
DNA samples from 178 patients were subjected to copy number analyses by multiplex ligation-dependent probe amplification or quantitative PCR assays. Additionally, the CYP2C9 exon 8 insertion/deletion polymorphism (rs71668942) was examined among the patient cohort and 1750 additional multiethnic healthy individuals.
All patients carried two copies of CYP2C9 by multiplex ligation-dependent probe amplification and no exon 8 deletion carriers were detected. Similarly, quantitative PCR assays for VKORC1, CYP4F2, GGCX and CALU identified two copies in all populations.
These data indicate that copy number variants in the principal genes involved in warfarin dose variability (CYP2C9, VKORC1), including genes with lesser effect (CYP4F2, GGCX), and those that may be more relevant among certain racial groups (CALU), are rare in multiethnic populations, including African–Americans.
PMCID: PMC3292047  PMID: 22188360
CALU; CNV; copy number variation; CYP2C9; CYP4F2; GGCX; pharmacogenetics; VKORC1; warfarin
5.  Association of Chronic Kidney Disease with Atrial Fibrillation Among Adults in the United States: Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Atrial fibrillation (AF) is common among patients with end-stage renal disease, but few data are available on its prevalence among adults with chronic kidney disease (CKD) of lesser severity.
Methods and Results
We evaluated the association of CKD with electrocardiogram-detected AF among 26,917 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a population-based cohort of African-American and white US adults ≥45 years of age. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation and albuminuria was defined as a urinary albumin to creatinine ratio ≥30 mg/g. Participants were categorized by renal function: no CKD (eGFR ≥60 ml/min/1.73m2 without albuminuria, n=21,081), stage 1–2 CKD (eGFR ≥60 ml/min/1.73m2 with albuminuria n=2,938), stage 3 CKD (eGFR 30 to 59 ml/min/1.73m2, n=2,683) and stage 4–5 CKD (eGFR <30 ml/min/1.73m2, n=215). The prevalence of AF among participants without CKD, and with stage 1–2, stage 3, and stage 4–5 CKD was 1.0%, 2.8%, 2.7% and 4.2%, respectively. Compared to participants without CKD, the age, race, sex adjusted odds ratios for prevalent AF were 2.67 (95% CI 2.04 – 3.48), 1.68 (95% CI 1.26 – 2.24) and 3.52 (95% CI 1.73–7.15) among those with stage 1–2, stage 3 and stage 4–5 CKD. The association between CKD and prevalent AF remained statistically significant after further multivariable adjustment and was consistent across numerous subgroups.
- Regardless of severity, CKD is associated with an increased prevalence of AF among US adults.
PMCID: PMC3049935  PMID: 21076159
chronic kidney disease; atrial fibrillation; electrocardiography
6.  Bisphosphonate use and the Prevalence of Valvular and Vascular Calcification in Women: The Multi-Ethnic Study of Atherosclerosis 
To determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification.
Cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP may limit cardiovascular calcification, which has implications for disease prevention.
The relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,636 women within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling.
Analyses were age-stratified because of a significant interaction between age and NCBP use (interaction p-values: AVC p<0.0001; AVRC p<0.0001; MAC p=0.002; TAC p<0.0001; CAC p=0.046). After adjusting for age, body mass index, demographics, diabetes, smoking, blood pressure, cholesterol levels, and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥65 years old (prevalence ratio [95% confidence interval]: AVC 0.68 [0.41, 1.13]; AVRC 0.65 [0.51, 0.84]; MAC 0.54 [0.33, 0.93]; TAC 0.69 [0.54, 0.88]; CAC 0.89 [0.78, 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years old (AVC 4.00 [2.33, 6.89]; AVRC 1.92 [1.42, 2.61]; MAC 2.35 [1.12, 4.84]; TAC 2.17 [1.49, 3.15]; CAC 1.23 [0.97, 1.57]).
Among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects, but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.
PMCID: PMC3004769  PMID: 21070928
bisphosphonate; calcification; coronary artery; valve; vascular
7.  CYP2C9*8 is prevalent among African–Americans: implications for pharmacogenetic dosing 
Pharmacogenomics  2009;10(8):1243-1255.
Although the frequencies of pharmacogenetic variants differ among racial groups, most pharmacogenetic algorithms for genotype-guided warfarin dosing only include two CYP2C9 alleles (*2 and *3) and a single VKORC1 allele (g.-1639G>A or g.1173C>T) commonly found among Caucasians. Therefore, this study sought to identify other CYP2C9 and VKORC1 alleles important in warfarin dose variability and to determine their frequencies in different racial and ethnic groups.
Materials & methods
The CYP2C9 and VKORC1 genes were sequenced in selected sensitive (<21 mg/week) and resistant (>49 mg/week) individuals with discrepant therapeutic and algorithm-predicted warfarin doses based on prior CYP2C9 and VKORC1 genotyping. The CYP2C9 and VKORC1 allele frequencies were determined in healthy, racially self-identified blood donors.
Sequencing identified an African–American male with a lower than predicted therapeutic warfarin dose (14.4 mg/week), previously genotyped as CYP2C9*1/*1, who was homozygous for CYP2C9*8 (c.449G>A; p.R150H). Genotyping 600 African–American alleles identified CYP2C9*8 as their most frequent variant CYP2C9 allele (0.047), and the combined allele frequency of CYP2C9*2, *3, *5, *6, *8 and *11 was 0.133. Given most warfarin pharmacogenetic dosing algorithms only include CYP2C9*2 and *3, the inclusion of CYP2C9*8 alone could reclassify the predicted metabolic phenotypes of almost 10% of African–Americans, or when combined with CYP2C9*5, *6 and *11, more than 15%. In addition, the African–American VKORC1 g.-1639A allele frequency was 0.108 and three g.1331G>A (p.V66M) carriers were identified.
CYP2C9*8 is prevalent among African–Americans (~1 in 11 individuals). Thus, in this racial group, the incorporation of CYP2C9*8 into genotyping panels may improve dose prediction of CYP2C9-metabolized drugs, including warfarin.
PMCID: PMC2737687  PMID: 19663669
African-American; allele frequencies; CYP2C9*8; pharmacogenetics; VKORC1; warfarin

Results 1-8 (8)