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1.  A Genome- and Phenome-Wide Association Study to Identify Genetic Variants Influencing Platelet Count and Volume and their Pleiotropic Effects 
Human genetics  2013;133(1):10.1007/s00439-013-1355-7.
Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized association of variants influencing MPV and PLT using functional, pathway and disease enrichment analysis assess pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic (eMERGE) network had data for PLT and 6,291 participants had data for MPV. We identified 5 chromosomal regions associated with PLT and 8 associated with MPV at genome-wide significance (P<5E-8). In addition, we replicated 20 SNPs (out of 56 SNPs (α: 0.05/56=9E-4)) influencing PLT and 22 SNPs (out of 29 SNPs (α: 0.05/29=2E-3)) influencing MPV in a meta-analysis of GWAS of PLT and MPV. While our GWAS did not reveal any novel associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1368 diagnoses (0.05/1368=3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.
PMCID: PMC3880605  PMID: 24026423
3.  Clinical Correlates of Autosomal Chromosomal Abnormalities in an Electronic Medical Record–Linked Genome-Wide Association Study: A Case Series 
Although mosaic autosomal chromosomal abnormalities are being increasingly detected as part of high-density genotyping studies, the clinical correlates are unclear. From an electronic medical record (EMR)–based genome-wide association study (GWAS) of peripheral arterial disease, log-R-ratio and B-allele-frequency data were used to identify mosaic autosomal chromosomal abnormalities including copy number variation and loss of heterozygosity. The EMRs of patients with chromosomal abnormalities and those without chromosomal abnormalities were reviewed to compare clinical characteristics. Among 3336 study participants, 0.75% (n = 25, mean age = 74.8 ± 10.7 years, 64% men) had abnormal intensity plots indicative of autosomal chromosomal abnormalities. A hematologic malignancy was present in 8 patients (32%), of whom 4 also had a solid organ malignancy while 2 patients had a solid organ malignancy only. In 50 age- and sex-matched participants without chromosomal abnormalities, there was a lower rate of hematologic malignancies (2% vs 32%, P < .001) but not solid organ malignancies (20% vs 24%, P = .69). We also report the clinical characteristics of each patient with the observed chromosomal abnormalities. Interestingly, among 5 patients with 20q deletions, 4 had a myeloproliferative disorder while all 3 men in this group had prostate cancer. In summary, in a GWAS of 3336 adults, 0.75% had autosomal chromosomal abnormalities and nearly a third of them had hematologic malignancies. A potential novel association between 20q deletions, myeloproliferative disorders, and prostate cancer was also noted.
PMCID: PMC4130164  PMID: 25125939
copy number variation; genome-wide association studies; loss of heterozygosity; mosaic abnormalities; mosaic deletion; myeloproliferative disorders; prostate cancer; unipaternal disomy
4.  The ATXN2-SH2B3 locus is associated with peripheral arterial disease: an electronic medical record-based genome-wide association study 
Frontiers in Genetics  2014;5:166.
Objectives: In contrast to coronary heart disease (CHD), genetic variants that influence susceptibility to peripheral arterial disease (PAD) remain largely unknown.
Background: We performed a two-stage genomic association study leveraging an electronic medical record (EMR) linked-biorepository to identify genetic variants that mediate susceptibility to PAD.
Methods: PAD was defined as a resting/post-exercise ankle-brachial index (ABI) ≤0.9 or ≥1.4 and/or history of lower extremity revascularization. Controls were patients without history of PAD. In Stage I we performed a genome-wide association analysis adjusting for age and sex, of 537, 872 SNPs in 1641 PAD cases (66 ± 11 years, 64% men) and 1604 control subjects (61 ± 7 year, 60% men) of European ancestry. In Stage II we genotyped the top 48 SNPs that were associated with PAD in Stage I, in a replication cohort of 740 PAD cases (70 ± 11 year, 63% men) and 1051 controls (70 ± 12 year, 61% men).
Results: The SNP rs653178 in the ATXN2-SH2B3 locus was significantly associated with PAD in the discovery cohort (OR = 1.23; P = 5.59 × 10−5), in the replication cohort (OR = 1.22; 8.9 × 10−4) and in the combined cohort (OR = 1.22; P = 6.46 × 10−7). In the combined cohort this SNP remained associated with PAD after additional adjustment for cardiovascular risk factors including smoking (OR = 1.22; P = 2.15 × 10−6) and after excluding patients with ABI > 1.4 (OR = 1.24; P = 3.98 × 10−7). The SNP is in near-complete linkage disequilibrium (LD) (r2 = 0.99) with a missense SNP (rs3184504) in SH2B3, a gene encoding an adapter protein that plays a key role in immune and inflammatory response pathways and vascular homeostasis. The SNP has pleiotropic effects and has been previously associated with multiple phenotypes including myocardial infarction.
Conclusions: Our findings suggest that the ATXN2-SH2B3 locus influences susceptibility to PAD.
PMCID: PMC4070196  PMID: 25009551
genome-wide association study; peripheral arterial disease; ankle-brachial index; electronic medical records; biorepository
5.  Associations of Candidate Biomarkers of Vascular Disease with the Ankle–Brachial Index and Peripheral Arterial Disease 
American Journal of Hypertension  2013;26(4):495-502.
The use of multiple biomarkers representing various etiologic pathways of atherosclerosis may improve the prediction of interindividual variation in the ankle–brachial index (ABI). To this end, we investigated associations of 47 candidate biomarkers with the ABI and presence of peripheral arterial disease (PAD) in African–Americans (AAs) and non-Hispanic whites (NHWs).
Study participants included 1,291 AAs (71.1% women, mean age, 63.4±9.3 years) and 1,152 NHWs (57.5% women, mean age 58.5±10.1 years) belonging to hypertensive sibships. Peripheral arterial disease was defined as an ABI ≤ 0.90. Circulating levels of 47 candidate biomarkers were log-transformed before analysis because of skewed distribution. Multivariate regression analyses were used to identify biomarkers associated with ABI or PAD independently of age, sex, conventional risk factors, and medication use.
After adjustment for covariates, higher levels of nine biomarkers were associated with a lower ABI in AAs (all P ≤ 0.005); these biomarkers were C-reactive protein (CRP), interleukin-6, tumor necrosis factor receptor-II (TNF-R II), lipoprotein(a), N-terminal pro-brain natriuretic peptide (NT-proBNP), pro-atrial natriuretic peptide, C-terminal pro-arginine vasopressin, osteoprotegerin, and fibrinogen. Three biomarkers - myeloperoxidase, NT-proBNP, and D-dimer - were associated with ABI in NHWs (all P ≤ 0.01). C-reactive protein, interleukin-6, TNF-R II, lipoprotein(a), NT-proBNP, pro-atrial natriuretic peptide, D-dimer, and fibrinogen were associated with PAD (all P ≤ 0.005) in AAs after adjustment for covariates. None of the biomarkers were independently associated with PAD in NHWs.
A multimarker approach improved the prediction of interindividual variation in the ABI in AAs and NHWs, and improved prediction of the presence of PAD in AAs.
PMCID: PMC3626040  PMID: 23467205
ankle–brachial index; peripheral arterial disease; biomarker; hypertension; blood pressure.
6.  Return of results in the genomic medicine projects of the eMERGE network 
The electronic Medical Records and Genomics (eMERGE) (Phase I) network was established in 2007 to further genomic discovery using biorepositories linked to the electronic health record (EHR). In Phase II, which began in 2011, genomic discovery efforts continue and in addition the network is investigating best practices for implementing genomic medicine, in particular, the return of genomic results in the EHR for use by physicians at point-of-care. To develop strategies for addressing the challenges of implementing genomic medicine in the clinical setting, the eMERGE network is conducting studies that return clinically-relevant genomic results to research participants and their health care providers. These genomic medicine pilot studies include returning individual genetic variants associated with disease susceptibility or drug response, as well as genetic risk scores for common “complex” disorders. Additionally, as part of a network-wide pharmacogenomics-related project, targeted resequencing of 84 pharmacogenes is being performed and select genotypes of pharmacogenetic relevance are being placed in the EHR to guide individualized drug therapy. Individual sites within the eMERGE network are exploring mechanisms to address incidental findings generated by resequencing of the 84 pharmacogenes. In this paper, we describe studies being conducted within the eMERGE network to develop best practices for integrating genomic findings into the EHR, and the challenges associated with such work.
PMCID: PMC3972474  PMID: 24723935
genomics; electronic health records; incidental findings; implementation; genetic counseling; next generation sequencing; pharmacogenetics
7.  Ethical, legal, and social implications of incorporating genomic information into electronic health records 
The inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.
PMCID: PMC3926430  PMID: 24030434
clinical decision support, electronic health records; ethical, legal, and social implications; genomics; personalized medicine
8.  Ethnic differences in Ankle Brachial Index are Present in Middle-Aged Individuals without Peripheral Arterial Disease 
International journal of cardiology  2011;162(3):228-233.
To better understand the basis for previously reported ethnic differences in ankle brachial index (ABI), we investigated whether these differences were present in individuals without known peripheral arterial disease (PAD).
We used data from National Health and Nutrition Examination surveys (NHANES 1999–2004) to determine whether ethnic differences were present in respondents without PAD (1≤ABI≤1.3). We assessed whether ethnicity was an independent predictor of ABI and ankle systolic blood pressure (SBP) in linear regression models that adjusted for conventional and novel cardiovascular risk factors. To minimize effects of atherosclerosis on ABI, we studied adults aged ≤ 60 years, and also repeated our analyses in a subset aged ≤ 50 years that did not have risk factors for PAD.
3348 participants aged ≤ 60 years were included in the study. Mean ABI was 1.11 in non-Hispanic Blacks (NHB) and 1.13 in non-Hispanic Whites (NHW) (P <0.0001). In multivariable linear regression analysis that adjusted for age, gender, ethnicity, smoking, height, diabetes, brachial SBP, dyslipidemia, diabetes, renal function, concurrent cardiovascular disease, and plasma levels of homocysteine, fibrinogen and C-reactive protein, NHB had lower ABI than NHW (β= − 0.03± 0.004, P < 0.00001). Although, NHBs had higher ankle SBP than NHWs (by 5.3 mm Hg), NHBs had a lower mean ankle SBP (β= − 3.663 mm Hg ± 0.500, P <.0001) after adjusting for clinical covariates, including brachial SBP, in multivariable analysis.
Ethnic differences in ABI are present in middle-aged adults at low risk for peripheral atherosclerosis.
PMCID: PMC3174274  PMID: 21652099
ankle brachial index; ethnicity
9.  Sex Differences in Arterial Stiffness and Ventricular-Arterial Interactions 
To assess sex-differences in ventricular-arterial interactions.
Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women than men, but the basis for this difference remains unclear.
Echocardiography and arterial tonometry were performed to quantify arterial and ventricular stiffening and interaction in 461 participants without heart failure (189 men, age 67±9 years; 272 women, age 65±10 years). Aortic characteristic impedance (Zc), total arterial compliance (TAC, pulsatile load) and systemic vascular resistance index (SVRI, steady load) were compared between men and women, and sex-specific multivariable regression analyses were performed to assess associations of these arterial parameters with diastolic dysfunction and ventricular-arterial coupling (effective arterial elastance/left ventricular end-systolic elastance, Ea/Ees) after adjustment for potential confounders.
Zc was higher and TAC was lower in women, whereas SVRI was similar between sexes. In women but not men, higher Zc was associated with E/A ratio (β±SE: −0.17±0.07), diastolic dysfunction (OR 7.8; 95% CI: 2.0, 30.2) and Ea/Ees (β±SE: 0.13±0.0) (P≤0.01 for all). Similarly, TAC was associated with E/A ratio (β± SE: 0.12±0.04), diastolic dysfunction (OR 0.33; 95% CI: 0.12, 0.89) and Ea/Ees (β± SE: −0.09±0.03) in women only (P≤0.03 for all). SVRI was not associated with diastolic dysfunction or Ea/Ees.
Proximal aortic stiffness (Zc) is greater in women than men, and women may be more vulnerable to the deleterious effects of greater pulsatile and early arterial load on diastolic function and ventricular-arterial interaction. This may contribute to the greater risk of HFpEF in women.
PMCID: PMC3773521  PMID: 23122799
aortic stiffness; diastolic dysfunction; echocardiography; sex-specific; ventricular-arterial interaction
10.  Aortic Pulse Wave Velocity Is Associated With Measures of Subclinical Target Organ Damage 
JACC. Cardiovascular imaging  2011;4(7):10.1016/j.jcmg.2011.04.011.
Our goal was to evaluate the associations of central arterial stiffness, measured by aortic pulse wave velocity (aPWV), with subclinical target organ damage in the coronary, peripheral arterial, cerebral, and renal arterial beds.
Arterial stiffness is associated with adverse cardiovascular outcomes. We hypothesized that aPWV is associated with subclinical measures of atherosclerosis—coronary artery calcification (CAC) and ankle-brachial index (ABI) and arteriolosclerosis—brain white matter hyperintensity (WMH) and urine albumin-creatinine ratio (UACR).
Participants (n = 812; mean age 58 years; 58% women, 71% hypertensive) belonged to hypertensive sibships and had no history of myocardial infarction or stroke. aPWV was measured by applanation tonometry, CAC by electron beam computed tomography, ABI using a standard protocol, WMH volume by brain magnetic resonance, and UACR by standard methods. WMH was log-transformed, whereas CAC and UACR were log-transformed after adding 1 to reduce skewness. The associations of aPWV with CAC, ABI, WMH, and UACR were assessed by multivariable linear regression using generalized estimating equations to account for the presence of sibships. Covariates included in the models were age, sex, body mass index, history of smoking, hypertension and diabetes, total and high-density lipoprotein cholesterol, estimated glomerular filtration rate, use of aspirin and statins, and pulse pressure.
The mean ± SD aPWV was 9.8 ± 2.8 m/s. After adjustment for age, sex, conventional cardiovascular risk factors, and pulse pressure, higher aPWV (1 m/s increase) was significantly associated with higher log (CAC + 1) (β ± SE = 0.14 ± 0.04; p = 0.0003), lower ABI (β ± SE =−0.005 ± 0.002; p = 0.02), and greater log (WMH) (β ± SE = 0.03 ± 0.009; p = 0.002), but not with log (UACR + 1) (p = 0.66).
Higher aPWV was independently associated with greater burden of subclinical disease in coronary, lower extremity, and cerebral arterial beds, highlighting target organ damage as a potential mechanism underlying the association of arterial stiffness with adverse cardiovascular outcomes. (J Am Coll Cardiol Img 2011;4:754–61)
PMCID: PMC3862768  PMID: 21757166
arterial stiffness; arteriosclerosis; coronary artery calcification; hypertension; leukoariosis; peripheral arterial disease; pulse wave velocity; target organ damage
11.  Serum N-Terminal Pro-B-Type Natriuretic Peptide Levels Are Associated With Functional Capacity in Patients With Peripheral Arterial Disease 
Angiology  2011;63(6):10.1177/0003319711423095.
We hypothesized that higher serum levels of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) are associated with lower functional capacity in patients with peripheral arterial disease ([PAD] n = 481, mean age 67, 68% men). Functional capacity was quantified as distance walked on a treadmill for 5 minutes. Patients were divided into 3 groups according to the distance walked: >144 yards (group I, n = 254); 60 to 144 yards (group 2, n = 80); <60 yards or did not walk (group 3, n = 147). The association between NT-pro-BNP levels and the ordinal 3-level walking distance was assessed using multivariable ordinal logistic regression analyses that adjusted for several possible confounding variables. Higher levels of NT-pro-BNP were associated with a lower ordinal walking category independent of possible confounders (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.28-1.77; P < .001). In conclusion, higher levels of NT-pro-BNP are independently associated with lower functional capacity in patients with PAD and may be a marker of hemodynamic stress in these patients.
PMCID: PMC3855435  PMID: 22096207
N-terminal pro-B-type natriuretic peptide; natriuretic peptides; functional capacity; peripheral arterial disease
12.  Billing code algorithms to identify cases of peripheral artery disease from administrative data 
To construct and validate billing code algorithms for identifying patients with peripheral arterial disease (PAD).
We extracted all encounters and line item details including PAD-related billing codes at Mayo Clinic Rochester, Minnesota, between July 1, 1997 and June 30, 2008; 22 712 patients evaluated in the vascular laboratory were divided into training and validation sets. Multiple logistic regression analysis was used to create an integer code score from the training dataset, and this was tested in the validation set. We applied a model-based code algorithm to patients evaluated in the vascular laboratory and compared this with a simpler algorithm (presence of at least one of the ICD-9 PAD codes 440.20–440.29). We also applied both algorithms to a community-based sample (n=4420), followed by a manual review.
The logistic regression model performed well in both training and validation datasets (c statistic=0.91). In patients evaluated in the vascular laboratory, the model-based code algorithm provided better negative predictive value. The simpler algorithm was reasonably accurate for identification of PAD status, with lesser sensitivity and greater specificity. In the community-based sample, the sensitivity (38.7% vs 68.0%) of the simpler algorithm was much lower, whereas the specificity (92.0% vs 87.6%) was higher than the model-based algorithm.
A model-based billing code algorithm had reasonable accuracy in identifying PAD cases from the community, and in patients referred to the non-invasive vascular laboratory. The simpler algorithm had reasonable accuracy for identification of PAD in patients referred to the vascular laboratory but was significantly less sensitive in a community-based sample.
PMCID: PMC3861931  PMID: 24166724
peripheral artery disease; billing codes; electronic medical record; informatics
13.  Disease Location Is Associated With Survival in Patients With Peripheral Arterial Disease 
We investigated whether disease location influences survival in patients with peripheral arterial disease.
Methods and Results
Patients (n=12 731; mean age, 67.5±12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9±3.1 years for all‐cause mortality. Peripheral arterial disease (n=8930) was defined as a resting or postexercise ankle‐brachial index (ABI) ≤0.90, and normal ABI (n=3 801) was defined as a resting and postexercise ABI of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of Doppler signals in leg arteries; 42% had no PD or DD, 45% had proximal (14% postexercise PD only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and Cox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow‐up of 5.9±3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios (HRs) of death associated with PD only and DD only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting ABI, there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant (HR, 1.2; 95% CI, 1.1 to 1.3).
In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting ABI.
PMCID: PMC3835235  PMID: 24145740
atherosclerosis; Doppler; peripheral arterial disease; prognosis; survival
14.  Association of serum myeloperoxidase with the ankle—brachial index and peripheral arterial disease 
Atherosclerosis  2009;206(2):575-580.
Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle–brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals.
PMCID: PMC3773523  PMID: 19423112
ankle–brachial index; inflammation; myeloperoxidase; peripheral arterial disease
15.  Biomarkers Associated With Pulse Pressure in African-Americans and Non-Hispanic Whites 
American journal of hypertension  2011;25(2):145-151.
Pulse pressure (an indirect measure of arterial stiffness) is a robust predictor of cardiovascular events, but its pathophysiology remains poorly understood. To gain insight into the pathophysiology of arterial stiffness we conducted an exploratory investigation of the associations of 47 circulating biomarkers in etiologic pathways of arteriosclerosis with brachial artery pulse pressure.
Participants included 1,193 African-Americans and 1,145 non-Hispanic whites belonging to hypertensive sibships. Blood pressure (BP) was measured with a random-zero sphygmomanometer. Multivariable linear regression was employed to assess the associations of biomarkers with pulse pressure after adjustment for age, sex, conventional risk factors, mean arterial pressure, heart rate, and use of aspirin, statins, estrogens, and antihypertensives. Statistical significance was set at P ≤ 0.001 (Bonferroni correction for multiple testing).
Log N-terminal probrain natriuretic peptide (NT-proBNP) (African-Americans: β = 2.11 ± 0.52, non-Hispanic whites: β = 2.65 ± 0.55), log midregional proatrial natriuretic peptide (African-Americans: β = 4.83 ± 0.70, non-Hispanic whites: β = 3.70 ± 0.67), and log osteoprotegerin (African-Americans: β = 4.64 ± 1.02, non-Hispanic whites: β = 4.19 ±0.99) were independently associated with pulse pressure (P < 0.001 for all) in both ethnicities. Log C-reactive protein (CRP) (β = 1.56 ± 0.35), log midregional proadrenomedullin (MR-proADM) (β = 5.53 ± 1.19) and log matrix metalloproteinase-2 (β = 3.89 ± 1.06) were associated with greater pulse pressure in African-Americans only (P ≤ 0.001 for all), whereas higher fibrinogen was associated with pulse pressure in non-Hispanic whites only (β = 0.02 ± 0.004. P < 0.001).
Our results suggest that hemodynamic stress, vascular inflammation and calcification, and matrix remodeling may have a role in the pathogenesis and/or adverse consequences of increased pulse pressure.
PMCID: PMC3707798  PMID: 22012208
adrenomedullin; arterial stiffness; atrial natriuretic peptide; biomarkers; blood pressure; brain natriuretic peptide; fibrinogen; hypertension; matrix metalloproteinase-2; osteoprotegerin; pulse pressure
16.  Survival in Patients with Poorly Compressible Leg Arteries 
Compare survival of patients with poorly compressible arteries (PCA) to those with a normal ankle-brachial index (ABI) and those with peripheral arterial disease (PAD).
Limited data are available regarding survival in patients with PCA identified in the clinical setting by non-invasive lower extremity arterial evaluation.
We conducted a historical cohort study of consecutive patients who underwent outpatient, non-invasive lower extremity arterial evaluation at Mayo Clinic, Rochester, Minnesota, from January 1998 through December 2007, and were followed for a mean duration of 5.8±3.1 years. An ABI 1.00-1.30 was considered normal, PAD was defined as a resting or post-exercise ABI ≤0.90, and PCA defined as an ABI ≥1.4 and/or an ankle systolic blood pressure >255 mm Hg. Patients were followed for all-cause mortality through 09/30/2009.
Of 16,493 individuals (mean age ± standard deviation = 67.8±13.0 years, 59% male); 29% had normal ABI, 54% had PAD, and 17% had PCA. During follow-up (mean duration = 5.8±3.1 years), 4365 patients (26%) died. The percent alive at the end of the study period was 88%, 70%, and 60% for normal ABI, PAD, and PCA respectively. After adjustment for age, sex, cardiovascular risk factors, comorbid conditions, and medication use, the hazard ratios (confidence interval) of death associated with PCA were 2.0 (1.8-2.2) and 1.3 (1.2-1.4) compared to normal ABI and PAD groups, respectively.
Patients identified by non-invasive vascular testing to have poorly compressible leg arteries have poor survival, worse than those with a normal ABI or those with PAD.
PMCID: PMC3307094  PMID: 22261162
peripheral arterial disease; arterial calcification; mortality; ankle-brachial index
Hypertension  2011;58(5):920-925.
Left ventricular hypertrophy, a marker for adverse cardiovascular events, is more common in blacks than non-Hispanic whites. Mechanisms leading to left ventricular hypertrophy and mediating its clinical sequelae in blacks are not fully understood. We investigated the associations of 39 candidate biomarkers in distinct biological pathways with left ventricular mass and geometry in blacks. Participants included 1193 blacks (63 ± 9 years, 72% women, 78% hypertensive) belonging to hypertensive sibships. Left ventricular mass was measured by transthoracic echocardiography and indexed to height2.7. Left ventricular geometry was categorized as: normal, concentric remodeling, concentric hypertrophy and eccentric hypertrophy. Generalized estimating equations were employed to assess associations of the 39 biomarkers with left ventricular mass index after adjustment for age, sex, and conventional risk factors. After adjustment for potential confounders, log-transformed levels of the following biomarkers were independently associated with left ventricular mass index: N-terminal pro-brain natriuretic peptide (β±SE= 0.07±0.01 pg/mL, P< 0.0001), mid-regional pro-atrial natriuretic peptide (β±SE= 0.08±0.02 pmol/L, P< 0.0001), mid-regional pro-adrenomedullin (β±SE= 0.09±0.03 nmol/L, P= 0.0006), C-terminal pro-endothelin (β±SE= 0.05±0.02 pmol/L, P=0.0009) and osteoprotegerin (β±SE=0.07±0.02 pg/mL, P=0.0005). The associations of these biomarkers with left ventricular mass index were mainly due to their association with eccentric hypertrophy. Higher circulating levels of natriuretic peptides, adrenomedullin, endothelin and osteoprotegerin were associated with increased left ventricular mass index, providing insights into the pathophysiology of left ventricular hypertrophy in blacks.
PMCID: PMC3249445  PMID: 21986506
left ventricular hypertrophy; biomarkers; brain natriuretic peptide; atrial natriuretic peptide; adrenomedullin; endothelin; osteoprotegerin
18.  Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits 
Mayo Clinic Proceedings  2012;87(5):461-474.
To identify common genetic variants influencing red blood cell (RBC) traits.
Patients and Methods
We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record–based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss.
We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells.
Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.
PMCID: PMC3538470  PMID: 22560525
eMERGE, electronic MEdical Records and GEnomics; EMMAX, mixed-model association-expedited; EMR, electronic medical record; eQTL, expression quantitative trait locus; GHC, Group Health Cooperative--University of Washington; GWAS, genomewide association study; HCT, hematocrit; HGB, hemoglobin; IBS, identity-by-state; LD, linkage disequilibrium; MC, Marshfield Clinic; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MIM, Mendelian Inheritance of Man; NU, Northwestern University; RBC, red blood cell; SNP, single-nucleotide polymorphism; VUMC, Vanderbilt University Medical Center
19.  Usefulness of Red Cell Distribution Width to Predict Mortality in Patients with Peripheral Artery Disease 
The American journal of cardiology  2011;107(8):1241-1245.
Increased red cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (age 69.5 ±12.0 years, 60.9% men, 97.6% white) with PAD identified by non-invasive lower-extremity arterial testing at Mayo Clinic from 1/97 to 12/07, with follow-up through 9/09. We defined PAD as low (≤0.9) or high (≥1.4) ankle-brachial index (ABI). Cardiovascular risk factors and comorbidities were ascertained using electronic medical record (EMR)-based algorithms. RDW was obtained from the complete blood count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo EMR and Accurint® database. The association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4039 (31.0 %) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, sex, cardiovascular risk factors and comorbidities, patients in the highest quartile of RDW (>14.5%) had 66% greater risk of mortality compared to the lowest quartile (<12.8%) (P<0.0001); a 1% increment in RDW was associated with 10% greater risk of all-cause mortality (hazard ratio, 1.10, 95% confidence interval [CI], 1.08 to 1.12, P<0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08-1.12) and high (1.09, 1.06-1.12) ABI subsets. In conclusion, RDW, a routinely available measure, is an independent prognostic marker in patients with PAD.
PMCID: PMC3209662  PMID: 21296321
20.  Aortic Augmentation Index is Associated with the Ankle Brachial Index; A Community Based Study 
Atherosclerosis  2007;195(2):248-253.
Increased arterial stiffness has been associated with greater risk of cardiovascular events. We investigated whether aortic augmentation index (AIx), a measure of arterial stiffness and wave reflection, was associated with the ankle-brachial index (ABI), a measure of peripheral arterial disease (PAD).
AIx and ABI were measured in a community-based sample of 475 adults without prior history of heart attack or stroke (mean age 59.3 years, 46.5% men). Radial artery pulse waveforms were obtained by applanation tonometry and an ascending aortic pressure waveform derived by a transfer function. AIx is the difference between the first and second systolic peak of the ascending aortic pressure waveform indexed to the central pulse pressure. ABI was measured using a standard protocol, and subjects with non-compressible vessels (ABI >1.5) were excluded from the analyses. Multivariable linear and logistic generalized estimating equations (GEE) analyses were used to assess whether AIx was associated with ABI and ABI <1.00 respectively, independent of conventional risk factors.
Mean (± SD) values were: AIx, 29.3±11.6 %; ABI, 1.12±0.13; 59 (12.4%) participants had an ABI <1.00. Variables associated with a lower ABI (and ABI <1.00) included older age, shorter height, female sex, higher total cholesterol, hypertension medication use, history of smoking, and higher AIx. After adjustment for mean arterial pressure and the above variables, higher AIx remained associated with a lower ABI (P=0.015) and ABI <1.00 (P=0.002). A significant interaction (P=0.007) was present between AIx and age in the prediction of ABI; the (inverse) association of AIx with ABI was stronger in older subjects (>65 years).
AIx, a measure of arterial stiffness and wave reflection, was independently associated with a lower ABI in asymptomatic subjects from the community, and this association was modified by age.
PMCID: PMC3249443  PMID: 17254587
arterial stiffness; ankle-brachial index; arteries
21.  Leveraging informatics for genetic studies: use of the electronic medical record to enable a genome-wide association study of peripheral arterial disease 
There is significant interest in leveraging the electronic medical record (EMR) to conduct genome-wide association studies (GWAS).
A biorepository of DNA and plasma was created by recruiting patients referred for non-invasive lower extremity arterial evaluation or stress ECG. Peripheral arterial disease (PAD) was defined as a resting/post-exercise ankle-brachial index (ABI) less than or equal to 0.9, a history of lower extremity revascularization, or having poorly compressible leg arteries. Controls were patients without evidence of PAD. Demographic data and laboratory values were extracted from the EMR. Medication use and smoking status were established by natural language processing of clinical notes. Other risk factors and comorbidities were ascertained based on ICD-9-CM codes, medication use and laboratory data.
Of 1802 patients with an abnormal ABI, 115 had non-atherosclerotic vascular disease such as vasculitis, Buerger's disease, trauma and embolism (phenocopies) based on ICD-9-CM diagnosis codes and were excluded. The PAD cases (66±11 years, 64% men) were older than controls (61±8 years, 60% men) but had similar geographical distribution and ethnic composition. Among PAD cases, 1444 (85.6%) had an abnormal ABI, 233 (13.8%) had poorly compressible arteries and 10 (0.6%) had a history of lower extremity revascularization. In a random sample of 95 cases and 100 controls, risk factors and comorbidities ascertained from EMR-based algorithms had good concordance compared with manual record review; the precision ranged from 67% to 100% and recall from 84% to 100%.
This study demonstrates use of the EMR to ascertain phenocopies, phenotype heterogeneity and relevant covariates to enable a GWAS of PAD. Biorepositories linked to EMR may provide a relatively efficient means of conducting GWAS.
PMCID: PMC2995686  PMID: 20819866
22.  Serum Osteocalcin Is Associated With Measures of Insulin Resistance, Adipokine Levels, and the Presence of Metabolic Syndrome 
Osteocalcin has been reported to influence insulin secretion in experimental animals. We investigated whether serum osteocalcin was associated with measures of insulin resistance, circulating adipokine levels, and the presence of metabolic syndrome (MetSyn).
Methods and Results
Serum osteocalcin was measured by solid-phase sandwich immunoassay in 1284 blacks (64±9 years; 71% women) and 1209 non-Hispanic whites (59±10 years; 57% women) belonging to hypertensive sibships. MetSyn was defined per Adult Treatment Panel III criteria. The prevalence of MetSyn was 50% in blacks and 49% in non-Hispanic whites. In each ethnic group, after adjustment for age and gender, osteocalcin levels were inversely correlated with body mass index, fasting glucose and insulin, homeostasis model assessment of insulin resistance, triglycerides, and leptin, and positively correlated with adiponectin (P<0.001 for each variable). In multivariable regression analyses that adjusted for age, gender, smoking, serum creatinine, and statin and estrogen use, osteocalcin levels in the highest quartile (compared with the lowest quartile) were associated with a lower odds ratio (OR) of having MetSyn: OR (95% CI) in blacks, 0.33 (0.23 to 0.46); OR in non-Hispanic whites, 0.43 (0.31 to 0.63).
Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of MetSyn, suggesting a novel cross-talk between bone and adipose tissue.
PMCID: PMC2939910  PMID: 20395593
adiponectin; insulin resistance; leptin; metabolic syndrome; osteocalcin
23.  Increased Serum N-Terminal Pro–B-Type Natriuretic Peptide Levels in Patients With Medial Arterial Calcification and Poorly Compressible Leg Arteries 
To determine whether serum levels of N-terminal (NT) pro–B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD.
Methods and Results
Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (P<0.001).
Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.
PMCID: PMC3115928  PMID: 20947817
medial arterial calcification; poorly compressible arteries; peripheral artery disease; NT pro-BNP; arterial stiffness; natriuretic peptides; risk factors
24.  Plasma C-Terminal Pro–Endothelin-1 is Associated with Left Ventricular Mass Index and Aortic Root Diameter in African American Adults with Hypertension 
Journal of human hypertension  2010;25(2):106-113.
Endothelin-1 (ET-1), a circulating vasoactive peptide with a potent vasoconstricting and mitogenic properties, may contribute to target-organ damage in hypertension. A novel assay for the measurement of C-terminal pro-endothelin-1 (CT-proET-1), a stable fragment of ET-1 precursor, has been recently validated as a reliable measure of ET-1 activity in the plasma. We tested the hypothesis that in African American adults with hypertension, plasma CT-proET-1 is associated with left ventricular (LV) mass and aortic root diameter.
Participants included 1041 African Americans (65±9 y, 72% women) with hypertension. Plasma CT-proET-1 was measured by an immunoluminometric assay. LV Mass and aortic root diameter were measured according to the American Society of Echocardiography guidelines, and LV mass was indexed by height to the power 2.7 (LVMi). Multivariable regressions analyses (using generalized estimating equations) were employed to assess whether plasma CT-proET-1 was associated with LVMi and aortic root diameter independent of potential confounding variables.
Plasma CT-proET-1 was significantly correlated with LVMi (r =0.21, P <0.0001) and aortic root diameter (r =0.09, P= 0.004). In separate multivariable regression models that adjusted for age, sex, body mass index, total and high density lipoprotein cholesterol, smoking history, diabetes, previous history of myocardial infarction or stroke, and blood pressure-lowering medication and statin use, log CT-proET-1 was significantly associated with greater LVMi (P =0.001) and greater aortic root diameter (P =0.006).
CT-proET-1 is independently associated with LVMi and aortic root diameter and may be a marker of target-organ damage in African Americans adults with hypertension.
PMCID: PMC2921559  PMID: 20182452
25.  Association of Serum Osteoprotegerin With Left Ventricular Mass in African-American Adults With Hypertension 
American journal of hypertension  2010;23(7):767-774.
African-Americans with hypertension are susceptible to left ventricular hypertrophy (LVH). Serum osteoprotegerin level has been reported to be associated with LVH. We investigated the association of osteoprotegerin with LV mass (LVM) in 898 African-Americans with hypertension (mean age 65 years, 71% women).
Osteoprotegerin levels were measured in serum by an immunoassay and log-transformed for analyses. LVM index (LVMi; LVM/height2.7) was estimated using M-mode echocardiography. Linear regression analyses using generalized estimating equations were used to assess the association of osteoprotegerin with LVMi.
Serum osteoprotegerin was correlated with LVMi (r = 0.21; P < 0.0001), an estimated increase in LVMi of 5.05 (95% confidence interval 2.93, 7.17) g/m2.7 in the highest compared to the lowest osteoprotegerin quartile. This association remained statistically significant after adjustment for conventional cardiovascular risk factors (age, sex, body mass index (BMI), history of smoking, diabetes, systolic blood pressure (BP), total and high-density lipoprotein cholesterol), estimated renal function, history of myocardial infarction and stroke, lifestyle factors (physical activity score, years of education, amount of alcohol consumption), medications (aspirin, antihypertensives, statins, estrogens), and C-reactive protein (CRP) (P = 0.02). Additionally, osteoprotegerin was correlated with early/atrial (E/A) ratio (r = −0.16; P < 0.0001), LV mean wall thickness (r = 0.17; P < 0.0001) and relative wall thickness (r = 0.14; P < 0.0001) but not ejection fraction (r = 0.04; P = 0.24) or internal end-diastolic dimension (r = 0.02; P = 0.60).
In African-Americans with hypertension, a higher serum osteoprotegerin level is weakly but independently associated with a higher LVM.
PMCID: PMC2901868  PMID: 20339356
African-American; biomarker; blood pressure; cardiology; echocardiography; epidemiology; hypertension; hypertrophy; osteoprotegerin

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