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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.
Summary
Background
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.
Methods
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.
Findings
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).
Interpretation
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.
Funding
National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.
doi:10.1016/S0140-6736(13)60681-9
PMCID: PMC3759580  PMID: 23755828
2.  Lack of Association Between Polymorphisms in the Prostaglandin F2α Receptor (PTGFR) and Solute Carrier Organic Anion Transporter Family 2A1 (SLCO2A1) Genes and Intraocular Pressure Response to Prostaglandin Analogs 
Ophthalmic genetics  2011;33(2):10.3109/13816810.2011.628357.
Purpose
To evaluate the association between variants in the prostaglandin Fα receptor (pTGFR) and solute carrier organic anion transporter family 2A1 (SLCO2A1) genes and IOP response to prostaglandin analogs
Methods
The medical records of subjects with previously diagnosed open angle glaucoma or ocular hypertension were searched for intraocular pressure measurements before and after prescriptions of prostaglandin analogs. Stored DNA samples were genotyped for the following SNPs: rs3753380 (promoter region) and rs3766355 (intronic region) of the prostaglandin F2α receptor gene, and rs34550074 (Ala396Thr) of SLCO2A1. The mean change in IOP by genotype was measured.
Results
Prostaglandin analogs were prescribed to 267 subjects; 242 (204 right eyes, 205 left eyes) met the inclusion/exclusion criteria for the current study. There was no significant association between genotype and IOP response to prostaglandin. analogs (p=0.48, p=0.54, p=0.90).
Conclusion
In summary, we found no indication for an association between SNPs in the prostaglandin F2α receptor gene or SLCO2A1 and IOP response to prostaglandin analogs in a population of European descent.
doi:10.3109/13816810.2011.628357
PMCID: PMC3832133  PMID: 22060278
glaucoma; pharmacogenetics; intraocular pressure; prostaglandin analog
3.  Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study 
Lancet  2013;382(9894):790-796.
Summary
Background
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.
Methods
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.
Findings
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).
Interpretation
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.
Funding
National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.
doi:10.1016/S0140-6736(13)60681-9
PMCID: PMC3759580  PMID: 23755828
4.  Alcohol, Genetics and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial 
Background
We tested the hypothesis that genes involved in the alcohol oxidation pathway modify the association between alcohol intake and breast cancer.
Methods
Subjects were women aged 55–74 at baseline from the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Incident breast cancers were identified through annual health surveys. Controls were frequency matched to cases by age and year of entry into the trial. A self-administered food frequency questionnaire queried frequency and usual serving size of beer, wine or wine coolers and liquor. Three SNPs in genes in the alcohol metabolism pathway were genotyped: alcohol dehydrogenase 2, alcohol dehydrogenase 3 and CYP2E1.
Results
The study included 1041 incident breast cancer cases and 1070 controls. In comparison to non-drinkers, the intake of any alcohol significantly increased the risk of breast cancer, and this risk increased with each category of daily alcohol intake, (OR=2.01, 95% CL=1.14, 3.53) for women who drank three or more standard drinks per day. Stratification by genotype revealed significant gene/environment interactions. For the ADH1B gene, there were statistically significant associations between all levels of alcohol intake and risk of breast cancer (all OR>1.34 and all lower CL >1.01), while for women with the GA or AA genotype, there were no significant associations between alcohol intake and risk of breast cancer.
Conclusion
Alcohol intake, genes involved in alcohol metabolism and their interaction increase the risk of breast cancer in post-menopausal women.
Impact
This information could be useful for primary care providers to personalize information about breast cancer risk reduction.
doi:10.1007/s10549-012-1972-1
PMCID: PMC3584637  PMID: 22331481
breast cancer; alcohol; metabolizing enzyme; genetics; risk factors
5.  Pathway analysis of genome-wide data improves warfarin dose prediction 
BMC Genomics  2013;14(Suppl 3):S11.
Background
Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations.
Results
Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association.
Conclusions
Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning.
doi:10.1186/1471-2164-14-S3-S11
PMCID: PMC3829086  PMID: 23819817
6.  Modeling Efficacy of Bevacizumab Treatment for Metastatic Colon Cancer 
Journal of Cancer  2013;4(4):330-335.
Purpose: Bevacizumab, an FDA-approved adjuvant treatment for metastatic colon cancer, has extended survival for many patients. However, factors predicting response to treatment remain undefined.
Patients and Methods: Relevant clinical and environmental data were abstracted from medical records of 149 evaluable patients treated with bevacizumab for metastatic colon cancer at a multi-specialty clinic. Tumor response was calculated from radiologic reports using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and verified by oncologist review. Patients with at least one occurrence of complete or partial response or stable disease were classified as responders; those exhibiting progressive disease were classified as non-responders.
Results: Univariate analysis demonstrated that blood in stool (P<0.05), unexplained weight loss (P<0.05), primary colon cancer site (P<0.05), chemotherapy treatment of primary tumor site (P<0.05), and adenocarcinoma versus adenoma subtype (P<0.05) was associated with tumor responsiveness. Factors remaining statistically significant following multivariate modeling included adenocarcinoma as tumor cell type versus other adenocarcinoma subtypes
(OR=6.35, 95% CI: 1.08-37.18), chemotherapy treatment applied to primary tumor (OR= 0.07, 95% CI: 0.0-0.76,), tumor localization to cecal/ascending colon (OR=0.061, 95% CI: 0.006-0.588,), and unexplained weight loss (OR=0.1, 95% CI: 0.02-0.56,). Chemotherapy treatment of primary tumor, unexplained weight loss, and cecal/ascending localization of the tumor were associated with poorer outcomes. Adenocarcinoma as cell type compared to other adenocarcinoma subtypes was associated with better response to bevacizumab treatment.
Conclusion: Results suggest that response to bevacizumab therapy may be predicted by modeling clinical factors including symptomology on presentation, tumor location and type, and initial response to chemotherapy.
doi:10.7150/jca.6083
PMCID: PMC3654489  PMID: 23678369
Bevacizumab; Colon cancer; Monoclonal antibodies; Prognosis; Vascular endothelial growth factor/VEGF.
7.  Anti-Phospholipid Antibodies in Patients Undergoing Total Joint Replacement Surgery 
Thrombosis  2012;2012:142615.
Background. Patients undergoing joint replacement remain at increased risk for venous thromboembolism (VTE) compared to other types of surgery, regardless of thromboprophylactic regimen. The pathophysiologic processes rendering this group of patients at risk for VTE are multifactorial. Procedure-specific and patient-specific exposures play a role in the postoperative development of VTE, including the development of anti-phospholipid antibodies (aPL). Methods. We measured three aPL (anti-cardiolipin, anti-β2 glycoprotein, and lupus anticoagulant) in 123 subjects undergoing total knee or hip arthroplasty to describe the presence of these antibodies preoperatively and to describe the rate of postoperative seroconversion among those people who were negative preoperatively. Postoperative antibodies were measured at day 7, 14, and 21. Results. The prevalence of aPL antibodies in the preoperative period was 44%, positive subjects were more likely to be smokers (P = 0.05) and were less likely to have undergone a previous arthroplasty procedure (P = 0.002). Subjects seroconverted in a 21 day postoperative period at a rate of 79%. Conclusions. These pilot data suggest that the prevalence of aPL in this population both preoperatively and postoperatively is higher than previously expected. Further studies are needed to describe aPL in a larger population and to establish their clinical significance in populations undergoing joint replacement surgeries.
doi:10.1155/2012/142615
PMCID: PMC3504462  PMID: 23213505
8.  The Differential Diagnosis of Pulmonary Blastomycosis Using Case Vignettes: A Wisconsin Network for Health Research (WiNHR) Study 
Wmj  2011;110(2):68-73.
Purpose
Pulmonary blastomycosis is an uncommon but serious fungal infection endemic in Wisconsin. Clinician awareness of the protean presentations of this disease may reduce diagnostic delay. This study addressed the diagnostic accuracy of physicians responding to case vignettes of pulmonary blastomycosis and the primary care differential diagnosis of this disease.
Methods
Eight pulmonary blastomycosis cases were developed from case files. From these, 2 vignettes were randomly selected and mailed to primary care physicians in the Wisconsin Network for Health Research. Respondents were asked to list the 3 most likely diagnoses for each case.
Results
Respondents listed Blastomycosis as the most likely diagnosis for 37/227 (16%) case vignettes, and 1 of the 3 most likely diagnoses for 43/227 (19%). When vignettes included patient activity in counties with an annual incidence rate of blastomycosis greater than 2/100,000, compared to counties with lower incidence rates, diagnosis was more accurate (28/61 [46%] vs 15/166 [9%]; P < 0.001). Physicians with practice locations in counties with annual blastomycosis incidence rates >2/100,000 listed blastomycosis more commonly than physicians from other counties (16/36 [44%] vs 27/177 [15%]; P < 0.001). This difference in accurate diagnosis remained significant in a multivariate model of practice demographics. Based on responses to the vignettes, pneumonia, cancer, non-infectious pulmonary disease, and tuberculosis emerged as the most-frequently noted diagnosis in the differential diagnosis of blastomycosis.
Conclusion
Blastomycosis was not listed as 1 of 3 primary diagnoses in a majority of cases when Wisconsin primary care physicians considered case vignettes of actual pulmonary blastomycosis cases. Diagnosis was more accurate if the patient vignette listed exposure to a higher incidence county, or if the physician practiced in a higher incidence county. In Wisconsin, failure to include blastomycosis in the differential diagnoses of illnesses associated with a wide variety of pulmonary symptoms suspected to represent infectious or non-infectious pulmonary, cardiac, or neoplastic disease, regardless of geographic exposure, could result in excess morbidity or mortality.
PMCID: PMC3311127  PMID: 21560560
9.  Pharmacogenetic Warfarin Dose Refinements Remain Significantly Influenced by Genetic Factors after One Week of Therapy 
Thrombosis and Haemostasis  2011;107(2):232-240.
Summary
Introduction
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Results
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
Conclusions
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
doi:10.1160/TH11-06-0388
PMCID: PMC3292349  PMID: 22186998
warfarin; VKORC1; CYP2C9; pharmacogenetic
10.  The Wisconsin Network for Health Research (WiNHR): A Statewide, Collaborative, Multi-disciplinary, Research Group 
In response to the goals of the Wisconsin Partnership Program and the National Institutes of Health (NIH) Initiatives to Improve Healthcare, the Wisconsin Network for Health Research (WiNHR) was formed. As a collaborative, multi-disciplinary statewide research network, WiNHR encourages and fosters the discovery and application of scientific knowledge for researchers and practitioners throughout Wisconsin. The 4 founding institutions—Aurora Health Care/Center for Urban Population Health (CUPH), Gundersen Lutheran Medical Foundation, Marshfield Clinic Research Foundation, and the University of Wisconsin-Madison—representing geographically diverse areas of the state, are optimistic and committed to WiNHR’s success. This optimism is based on the relevance of its goals to public health, the quality of statewide health care research, and, most importantly, the residents of Wisconsin who recognize the value of health research.
PMCID: PMC2852145  PMID: 20131687
11.  Lack of evidence of WNT3A as a candidate gene for congenital vertebral malformations 
Scoliosis  2007;2:13.
Background
Prior investigations have not identified a major locus for vertebral malformations, providing evidence that there is genetic heterogeneity for this condition. WNT3A has recently been identified as a negative regulator of Notch signaling and somitogenesis. Mice with mutations in Wnt3a develop caudal vertebral malformations. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. We hypothesized that WNT3A mutations might account for a subset of congenital vertebral malformations.
Methods
A pilot study was performed using a cohort of patients with congenital vertebral malformations spanning the entire vertebral column was characterized. DNA sequence analysis of the WNT3A gene in these 50 patients with congenital vertebral malformations was performed.
Results
A female patient of African ancestry with congenital scoliosis and a T12-L1 hemivertebrae was found to be heterozygous for a missense variant resulting in the substitution of alanine by threonine at codon 134 in highly conserved exon 3 of the WNT3A gene. This variant was found at a very low prevalence (0.35%) in a control population of 443 anonymized subjects and 1.1% in an African population.
Conclusion
These data suggest that WNT3A does not contribute towards the development of congenital vertebral malformations. Factors such as phenotypic and genetic heterogeneity may underlie our inability to detect mutations in WNT3A in our patient sample.
doi:10.1186/1748-7161-2-13
PMCID: PMC2064903  PMID: 17888180

Results 1-11 (11)