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Featured researches published by Erin Austin.


The New England Journal of Medicine | 2014

Inactivating mutations in NPC1L1 and protection from coronary heart disease

Nathan O. Stitziel; Hong-Hee Won; Alanna C. Morrison; Gina M. Peloso; Ron Do; Leslie A. Lange; Pierre Fontanillas; Namrata Gupta; Stefano Duga; Anuj Goel; Martin Farrall; Danish Saleheen; Paola G. Ferrario; Inke R. König; Rosanna Asselta; Piera Angelica Merlini; Nicola Marziliano; Maria Francesca Notarangelo; Ursula M. Schick; Paul L. Auer; Themistocles L. Assimes; Muredach P. Reilly; Robert L. Wilensky; Daniel J. Rader; G. Kees Hovingh; Thomas Meitinger; Thorsten Kessler; Adnan Kastrati; Karl-Ludwig Laugwitz; David S. Siscovick

BACKGROUND Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).


Circulation | 2016

Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial).

Iftikhar J. Kullo; Hayan Jouni; Erin Austin; Sherry-Ann Brown; Teresa M. Kruisselbrink; Iyad N. Isseh; Raad A. Haddad; Tariq S. Marroush; Khader Shameer; Janet E. Olson; Ulrich Broeckel; Robert C. Green; Daniel J. Schaid; Victor M. Montori; Kent R. Bailey

Background— Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels. Methods and Results— Participants (n=203, 45–65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS (+GRS). Participants in the +GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or +GRS (n=103). At the end of the study period, the +GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P=0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not participants with low GRS (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the +GRS group than in the CRS group (39% versus 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted. Conclusions— Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936675.Background— Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels. Methods and Results— Participants (n=203, 45–65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS (+GRS). Participants in the +GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or +GRS (n=103). At the end of the study period, the +GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P =0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants ( P =0.02) but not participants with low GRS (100.9±32.2 mg/dL; P =0.18). Statins were initiated more often in the +GRS group than in the CRS group (39% versus 22%, P <0.01). No significant differences in dietary fat intake and physical activity levels were noted. Conclusions— Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone. Clinical Trial Registration— URL: . Unique identifier: [NCT01936675][1]. # CLINICAL PERSPECTIVE {#article-title-33} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01936675&atom=%2Fcirculationaha%2F133%2F12%2F1181.atom


PLOS Genetics | 2016

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance

Soto Romuald Kiando; Nathan R. Tucker; Luis Jaime Castro-Vega; Alexander Katz; Valentina d’Escamard; Cyrielle Tréard; Daniel Fraher; Juliette Albuisson; Daniella Kadian-Dodov; Zi Ye; Erin Austin; Min Lee Yang; Kristina L. Hunker; Cristina Barlassina; Daniele Cusi; Pilar Galan; Jean Philippe Empana; Xavier Jouven; Anne Paule Gimenez-Roqueplo; Patrick Bruneval; Esther S.H. Kim; Jeffrey W. Olin; Heather L. Gornik; Michel Azizi; P.-F. Plouin; Patrick T. Ellinor; Iftikhar J. Kullo; David J. Milan; Santhi K. Ganesh; P. Boutouyrie

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.


Journal of Vascular and Interventional Radiology | 2014

Cost effectiveness of radioembolization compared with conventional transarterial chemoembolization for treatment of hepatocellular carcinoma

Nassir Rostambeigi; Adrienne S. Dekarske; Erin Austin; Jafar Golzarian; Erik N. Cressman

PURPOSE To assess cost effectiveness of radioembolization versus conventional transarterial chemoembolization. MATERIALS AND METHODS The cost of radioembolization versus conventional transarterial chemoembolization was determined based on Medicare reimbursements. Three patient subgroups were defined based on the Barcelona Clinic Liver Cancer (BCLC) classification system (A, B, or C). Efficacy and safety outcomes after each procedure were obtained from the literature. A Monte Carlo case-based simulation was designed for 60 months in 250 patients in each subgroup. Survival was calculated based on average survival from the literature and the Monte Carlo model. The primary outcome was the cost effectiveness of radioembolization over transarterial chemoembolization by considering calculated survival. RESULTS The costs approached


Population Health Management | 2011

Adherence to optimal lifestyle behaviors is related to emotional health indicators among employees.

Nicolaas P. Pronk; Abigail S. Katz; Jason M. Gallagher; Erin Austin; Deborah Mullen; Marcia Lowry; Thomas E. Kottke

17,000 for transarterial chemoembolization versus


American Journal of Physiology-endocrinology and Metabolism | 2014

Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation

Lisa S. Chow; Douglas G. Mashek; Erin Austin; Lynn E. Eberly; Xuan Mai T Persson; Mara T. Mashek; Elizabeth R. Seaquist; Michael D. Jensen

31,000 or


Statistical Analysis and Data Mining | 2013

Penalized regression and risk prediction in genome‐wide association studies

Erin Austin; Wei Pan; Xiaotong Shen

48,000 for unilobar or bilobar radioembolization, respectively. Based on the simulation, median estimated survival was greater with transarterial chemoembolization than radioembolization in BCLC-A and BCLC-B subgroups (40 months vs 30 months and 23 months vs 16 months, respectively, P = .001). However, in the BCLC-C subgroup, survival was greater with radioembolization than transarterial chemoembolization (13 months vs 17 months, P = .001). The incremental cost-effectiveness ratio of radioembolization over transarterial chemoembolization in the BCLC-C subgroup was


Clinical Genetics | 2016

Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

Christopher Lee Robinson; Hayan Jouni; Teresa M. Kruisselbrink; Erin Austin; Kurt D. Christensen; Robert C. Green; Iftikhar J. Kullo

360 per month. The results were dependent on bilobar versus unilobar radioembolization and the total number of radioembolization procedures. CONCLUSIONS The model suggests radioembolization costs may be justified for patients with BCLC-C disease, whereas radioembolization may not be cost effective in patients with BCLC-A disease; however, many patients with BCLC-C disease have extensive disease precluding locoregional therapies. Secondary considerations may determine treatment choice in more borderline patients (BCLC-B disease) because there is no persistent survival benefit with radioembolization.


Journal of Electrocardiology | 2014

Shorter Minimum P-Wave Duration Is Associated with Paroxysmal Lone Atrial Fibrillation

Ian C.Y. Chang; Erin Austin; Balaji Krishnan; David G. Benditt; Chwee N. Quay; Lieng H. Ling; Lin Y. Chen

Simultaneous adherence to abstinence from smoking, adequate physical activity, eating 5 servings of fruits and vegetables each day, and consuming limited or no amount of alcohol has been associated with a variety of health outcomes, but not emotional health. The purpose of this investigation was to study the association between optimal lifestyle behaviors and self-reported emotional health indicators among employed adults. Emotional health indicators studied were feeling depressed, stress risk, and the impact of emotional health on daily life among employees (N = 34,603). Binary logistic regression models were used to predict likelihood of feeling depressed and risk of stress based on degree of adherence to optimal lifestyle. Multinomial logistic regression models were used to assess the association between adherence to optimal lifestyle and likelihood of emotional quality of life among employees. Analyses were adjusted for age, sex, socioeconomic status (using the area deprivation index), sleep, self-perceived health status, self-efficacy, and chronic conditions including depression. All data were self-reported except for the area deprivation index. Adherence to any 3 or 4 components of the optimal lifestyle was associated with all 3 emotional health issues studied: Lower odds of feeling depressed, reporting stress risk, and emotional health affecting daily life. Adherence to any 2 components of the optimal lifestyle metric was associated with lower odds of feeling depressed and emotional health affecting daily life. All 4 individual lifestyle behaviors had significant associations with at least 2 of the 3 emotional health outcomes studied. Adherence to optimal lifestyle is associated with significantly more positive emotional health states as measured by feeling depressed, risk for high stress, and impact of emotional health on daily life. While causality cannot be inferred, the strength of the associations warrants trials to determine the extent to which adopting positive lifestyles can result in improved mental health.


Circulation | 2016

Incorporating a Genetic Risk Score into Coronary Heart Disease Risk Estimates: Effect on LDL Cholesterol Levels (the MIGENES Clinical Trial)

Iftikhar J. Kullo; Hayan Jouni; Erin Austin; Sherry Ann Brown; Teresa M. Kruisselbrink; Iyad N. Isseh; Raad A. Haddad; Tariq S. Marroush; Khader Shameer; Janet E. Olson; Ulrich Broeckel; Robert C. Green; Daniel J. Schaid; Victor M. Montori; Kent R. Bailey

How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remains unclear. Because acute free fatty acid (FFA) elevation by lipid infusion reduces insulin sensitivity, we hypothesized that training status would alter accumulation of muscle triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and acylcarnitine during acute FFA elevation. Trained (n = 15) and sedentary (n = 13) participants matched for age, sex, and BMI received either a 6-h infusion of lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) during a hyperinsulinemic euglycemic clamp. Muscle biopsies were taken at 0, 120, and 360 min after infusion initiation to measure intramyocellular concentrations of TAG, DAG, ceramides, and acylcarnitines by liquid chromatography-tandem mass spectrometry. Trained participants had a higher Vo2 max and insulin sensitivity than sedentary participants. The lipid infusion produced a comparable elevation of FFA (594 ± 90 μmol/l in trained, 721 ± 30 μmol/l in sedentary, P = 0.4) and a decline in insulin sensitivity (-44.7% trained vs. -47.2% sedentary, P = 0.89). In both groups, lipid infusion increased the linoleic and linolenic acid content of TAG without changing total TAG. In the sedentary group, lipid infusion increased total, oleic, and linoleic acid and linolenic acid content of DAG. Regardless of training status, lipid infusion did not alter total ceramide, saturated ceramide, palmitoyl-carnitine, or oleoyl-carnitine. We conclude that during acute FFA elevation, trained adults have a similar decline in insulin sensitivity with less accumulation of muscle DAG than sedentary adults, suggesting that lipid-induced insulin resistance can occur without elevation of total muscle DAG.

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Lin Y. Chen

University of Minnesota

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Khader Shameer

Icahn School of Medicine at Mount Sinai

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Robert C. Green

Brigham and Women's Hospital

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