Publications by authors named "M Ryan Irvin"

206 Publications

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Authors:
Pradeep Natarajan Akhil Pampana Sarah E Graham Sanni E Ruotsalainen James A Perry Paul S de Vries Jai G Broome James P Pirruccello Michael C Honigberg Krishna Aragam Brooke Wolford Jennifer A Brody Lucinda Antonacci-Fulton Moscati Arden Stella Aslibekyan Themistocles L Assimes Christie M Ballantyne Lawrence F Bielak Joshua C Bis Brian E Cade Ron Do Harsha Doddapaneni Leslie S Emery Yi-Jen Hung Marguerite R Irvin Alyna T Khan Leslie Lange Jiwon Lee Rozenn N Lemaitre Lisa W Martin Ginger Metcalf May E Montasser Jee-Young Moon Donna Muzny Jeffrey R O'Connell Nicholette D Palmer Juan M Peralta Patricia A Peyser Adrienne M Stilp Michael Tsai Fei Fei Wang Daniel E Weeks Lisa R Yanek James G Wilson Goncalo Abecasis Donna K Arnett Lewis C Becker John Blangero Eric Boerwinkle Donald W Bowden Yi-Cheng Chang Yii-Der I Chen Won Jung Choi Adolfo Correa Joanne E Curran Mark J Daly Susan K Dutcher Patrick T Ellinor Myriam Fornage Barry I Freedman Stacey Gabriel Soren Germer Richard A Gibbs Jiang He Kristian Hveem Gail P Jarvik Robert C Kaplan Sharon L R Kardia Eimear Kenny Ryan W Kim Charles Kooperberg Cathy C Laurie Seonwook Lee Don M Lloyd-Jones Ruth J F Loos Steven A Lubitz Rasika A Mathias Karine A Viaud Martinez Stephen T McGarvey Braxton D Mitchell Deborah A Nickerson Kari E North Aarno Palotie Cheol Joo Park Bruce M Psaty D C Rao Susan Redline Alexander P Reiner Daekwan Seo Jeong-Sun Seo Albert V Smith Russell P Tracy Ramachandran S Vasan Sekar Kathiresan L Adrienne Cupples Jerome I Rotter Alanna C Morrison Stephen S Rich Samuli Ripatti Cristen Willer Gina M Peloso

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
April 2021

Science and Math Interest and Gender Stereotypes: The Role of Educator Gender in Informal Science Learning Sites.

Front Psychol 2021 26;12:503237. Epub 2021 Mar 26.

Department of Psychology, North Carolina State University, Raleigh, NC, United States.

Interest in science and math plays an important role in encouraging STEM motivation and career aspirations. This interest decreases for girls between late childhood and adolescence. Relatedly, positive mentoring experiences with female teachers can protect girls against losing interest. The present study examines whether visitors to informal science learning sites (ISLS; science centers, zoos, and aquariums) differ in their expressed science and math interest, as well as their science and math stereotypes following an interaction with either a male or female educator. Participants ( = 364; early childhood, = 151, = 6.73; late childhood, = 136, = 10.01; adolescence, = 59, = 13.92) were visitors to one of four ISLS in the United States and United Kingdom. Following an interaction with a male or female educator, they reported their math and science interest and responded to math and science gender stereotype measures. Female participants reported greater interest in math following an interaction with a female educator, compared to when they interacted with a male educator. In turn, female participants who interacted with a female educator were less likely to report male-biased math gender stereotypes. Self-reported science interest did not differ as a function of educator gender. Together these findings suggest that, when aiming to encourage STEM interest and challenge gender stereotypes in informal settings, we must consider the importance of the gender of educators and learners.
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http://dx.doi.org/10.3389/fpsyg.2021.503237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033013PMC
March 2021

DNA Methylation and Blood Pressure Phenotypes: A Review of the Literature.

Am J Hypertens 2021 Apr;34(3):267-273

Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, Kentucky, USA.

Genetic studies of DNA have been unable to explain a significant portion of the variance of the estimated heritability of blood pressure (BP). Epigenetic mechanisms, particularly DNA methylation, have helped explain additional biological processes linked to BP phenotypes and diseases. Candidate gene methylation studies and genome-wide methylation studies of BP have highlighted impactful cytosine-phosphate-guanine (CpG) markers across different ethnicities. Furthermore, many of these BP-related CpG sites are also linked to metabolism-related phenotypes. Integrating epigenome-wide association study data with other layers of molecular data such as genotype data (from single nucleotide polymorphism arrays or sequencing), other epigenetic data, and/or transcriptome data can provide additional information about the significance and complexity of these relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of BP variation. Finally, these data can give insight into downstream effects of long-standing high BP (due to target organ damage (TOD)). The current review provides a literature overview of epigenetic modifications in BP and TOD. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in BP and TOD for relevant biological insights, reliable biomarkers, and possible future therapeutics.
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http://dx.doi.org/10.1093/ajh/hpab026DOI Listing
April 2021

Age and sex are associated with the plasma lipidome: findings from the GOLDN study.

Lipids Health Dis 2021 Apr 3;20(1):30. Epub 2021 Apr 3.

Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.

Background: Developing an understanding of the biochemistry of aging in both sexes is critical for managing disease throughout the lifespan. Lipidomic associations with age and sex have been reported, but prior studies are limited by measurements in serum rather than plasma or by participants taking lipid-lowering medications.

Methods: Our study included lipidomic data from 980 participants aged 18-87 years old from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN). Participants were off lipid-lowering medications for at least 4 weeks, and signal intensities of 413 known lipid species were measured in plasma. We examined linear age and sex associations with signal intensity of (a) 413 lipid species; (b) 6 lipid classes (glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, fatty acids, and acylcarnitines); and (c) 15 lipid subclasses; as well as with the particle sizes of three lipoproteins.

Results: Significant age associations were identified in 4 classes, 11 subclasses, 147 species, and particle size of one lipoprotein while significant sex differences were identified in 5 classes, 12 subclasses, 248 species, and particle sizes of two lipoproteins. For many lipid species (n = 97), age-related associations were significantly different between males and females. Age*sex interaction effects were most prevalent among phosphatidylcholines, sphingomyelins, and triglycerides.

Conclusion: We identified several lipid species, subclasses, and classes that differ by age and sex; these lipid phenotypes may serve as useful biomarkers for lipid changes and associated cardiovascular risk with aging in the future. Future studies of age-related changes throughout the adult lifespan of both sexes are warranted.

Trial Registration: ClinicalTrials.gov NCT00083369 ; May 21, 2004.
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http://dx.doi.org/10.1186/s12944-021-01456-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019182PMC
April 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Authors:
Mariaelisa Graff Anne E Justice Kristin L Young Eirini Marouli Xinruo Zhang Rebecca S Fine Elise Lim Victoria Buchanan Kristin Rand Mary F Feitosa Mary K Wojczynski Lisa R Yanek Yaming Shao Rebecca Rohde Adebowale A Adeyemo Melinda C Aldrich Matthew A Allison Christine B Ambrosone Stefan Ambs Christopher Amos Donna K Arnett Larry Atwood Elisa V Bandera Traci Bartz Diane M Becker Sonja I Berndt Leslie Bernstein Lawrence F Bielak William J Blot Erwin P Bottinger Donald W Bowden Jonathan P Bradfield Jennifer A Brody Ulrich Broeckel Gregory Burke Brian E Cade Qiuyin Cai Neil Caporaso Chris Carlson John Carpten Graham Casey Stephen J Chanock Guanjie Chen Minhui Chen Yii-Der I Chen Wei-Min Chen Alessandra Chesi Charleston W K Chiang Lisa Chu Gerry A Coetzee David V Conti Richard S Cooper Mary Cushman Ellen Demerath Sandra L Deming Latchezar Dimitrov Jingzhong Ding W Ryan Diver Qing Duan Michele K Evans Adeyinka G Falusi Jessica D Faul Myriam Fornage Caroline Fox Barry I Freedman Melissa Garcia Elizabeth M Gillanders Phyllis Goodman Omri Gottesman Struan F A Grant Xiuqing Guo Hakon Hakonarson Talin Haritunians Tamara B Harris Curtis C Harris Brian E Henderson Anselm Hennis Dena G Hernandez Joel N Hirschhorn Lorna Haughton McNeill Timothy D Howard Barbara Howard Ann W Hsing Yu-Han H Hsu Jennifer J Hu Chad D Huff Dezheng Huo Sue A Ingles Marguerite R Irvin Esther M John Karen C Johnson Joanne M Jordan Edmond K Kabagambe Sun J Kang Sharon L Kardia Brendan J Keating Rick A Kittles Eric A Klein Suzanne Kolb Laurence N Kolonel Charles Kooperberg Lewis Kuller Abdullah Kutlar Leslie Lange Carl D Langefeld Loic Le Marchand Hampton Leonard Guillaume Lettre Albert M Levin Yun Li Jin Li Yongmei Liu Youfang Liu Simin Liu Kurt Lohman Vaneet Lotay Yingchang Lu William Maixner JoAnn E Manson Barbara McKnight Yan Meng Keri L Monda Kris Monroe Jason H Moore Thomas H Mosley Poorva Mudgal Adam B Murphy Rajiv Nadukuru Mike A Nalls Katherine L Nathanson Uma Nayak Amidou N'Diaye Barbara Nemesure Christine Neslund-Dudas Marian L Neuhouser Sarah Nyante Heather Ochs-Balcom Temidayo O Ogundiran Adesola Ogunniyi Oladosu Ojengbede Hayrettin Okut Olufunmilayo I Olopade Andrew Olshan Badri Padhukasahasram Julie Palmer Cameron D Palmer Nicholette D Palmer George Papanicolaou Sanjay R Patel Curtis A Pettaway Patricia A Peyser Michael F Press D C Rao Laura J Rasmussen-Torvik Susan Redline Alex P Reiner Suhn K Rhie Jorge L Rodriguez-Gil Charles N Rotimi Jerome I Rotter Edward A Ruiz-Narvaez Benjamin A Rybicki Babatunde Salako Michele M Sale Maureen Sanderson Eric Schadt Pamela J Schreiner Claudia Schurmann Ann G Schwartz Daniel A Shriner Lisa B Signorello Andrew B Singleton David S Siscovick Jennifer A Smith Shad Smith Elizabeth Speliotes Margaret Spitz Janet L Stanford Victoria L Stevens Alex Stram Sara S Strom Lara Sucheston Yan V Sun Salman M Tajuddin Herman Taylor Kira Taylor Bamidele O Tayo Michael J Thun Margaret A Tucker Dhananjay Vaidya David J Van Den Berg Sailaja Vedantam Mara Vitolins Zhaoming Wang Erin B Ware Sylvia Wassertheil-Smoller David R Weir John K Wiencke Scott M Williams L Keoki Williams James G Wilson John S Witte Margaret Wrensch Xifeng Wu Jie Yao Neil Zakai Krista Zanetti Babette S Zemel Wei Zhao Jing Hua Zhao Wei Zheng Degui Zhi Jie Zhou Xiaofeng Zhu Regina G Ziegler Joe Zmuda Alan B Zonderman Bruce M Psaty Ingrid B Borecki L Adrienne Cupples Ching-Ti Liu Christopher A Haiman Ruth Loos Maggie C Y Ng Kari E North

Am J Hum Genet 2021 Apr 12;108(4):564-582. Epub 2021 Mar 12.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
April 2021

Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Authors:
Alexander G Bick Joshua S Weinstock Satish K Nandakumar Charles P Fulco Erik L Bao Seyedeh M Zekavat Mindy D Szeto Xiaotian Liao Matthew J Leventhal Joseph Nasser Kyle Chang Cecelia Laurie Bala Bharathi Burugula Christopher J Gibson Abhishek Niroula Amy E Lin Margaret A Taub Francois Aguet Kristin Ardlie Braxton D Mitchell Kathleen C Barnes Arden Moscati Myriam Fornage Susan Redline Bruce M Psaty Edwin K Silverman Scott T Weiss Nicholette D Palmer Ramachandran S Vasan Esteban G Burchard Sharon L R Kardia Jiang He Robert C Kaplan Nicholas L Smith Donna K Arnett David A Schwartz Adolfo Correa Mariza de Andrade Xiuqing Guo Barbara A Konkle Brian Custer Juan M Peralta Hongsheng Gui Deborah A Meyers Stephen T McGarvey Ida Yii-Der Chen M Benjamin Shoemaker Patricia A Peyser Jai G Broome Stephanie M Gogarten Fei Fei Wang Quenna Wong May E Montasser Michelle Daya Eimear E Kenny Kari E North Lenore J Launer Brian E Cade Joshua C Bis Michael H Cho Jessica Lasky-Su Donald W Bowden L Adrienne Cupples Angel C Y Mak Lewis C Becker Jennifer A Smith Tanika N Kelly Stella Aslibekyan Susan R Heckbert Hemant K Tiwari Ivana V Yang John A Heit Steven A Lubitz Jill M Johnsen Joanne E Curran Sally E Wenzel Daniel E Weeks Dabeeru C Rao Dawood Darbar Jee-Young Moon Russell P Tracy Erin J Buth Nicholas Rafaels Ruth J F Loos Peter Durda Yongmei Liu Lifang Hou Jiwon Lee Priyadarshini Kachroo Barry I Freedman Daniel Levy Lawrence F Bielak James E Hixson James S Floyd Eric A Whitsel Patrick T Ellinor Marguerite R Irvin Tasha E Fingerlin Laura M Raffield Sebastian M Armasu Marsha M Wheeler Ester C Sabino John Blangero L Keoki Williams Bruce D Levy Wayne Huey-Herng Sheu Dan M Roden Eric Boerwinkle JoAnn E Manson Rasika A Mathias Pinkal Desai Kent D Taylor Andrew D Johnson Paul L Auer Charles Kooperberg Cathy C Laurie Thomas W Blackwell Albert V Smith Hongyu Zhao Ethan Lange Leslie Lange Stephen S Rich Jerome I Rotter James G Wilson Paul Scheet Jacob O Kitzman Eric S Lander Jesse M Engreitz Benjamin L Ebert Alexander P Reiner Siddhartha Jaiswal Gonçalo Abecasis Vijay G Sankaran Sekar Kathiresan Pradeep Natarajan

Nature 2021 Mar;591(7851):E27

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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http://dx.doi.org/10.1038/s41586-021-03280-1DOI Listing
March 2021

Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify , , and of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population.

Front Genet 2021 19;12:588452. Epub 2021 Feb 19.

College of Public Health, University of Kentucky, Lexington, KY, United States.

: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. We conducted an exome-wide association study of LV mass (LVM) adjusted to height, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (), trafficking protein particle complex 11 (), and solute carrier family 27 member 6 ()] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. knockdowns showed a significant decrease in atrial natriuretic factor () and brain natriuretic peptide () expression. Knockdowns of the heart long chain fatty acid (FA) transporter resulted in downregulated caveolin 3 () expression, which has been linked to hypertrophic phenotypes in animal models. Finally, knockdown was linked to deficient calcium handling. : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.
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http://dx.doi.org/10.3389/fgene.2021.588452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933688PMC
February 2021

Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities.

Eur J Hum Genet 2021 Feb 26. Epub 2021 Feb 26.

Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.
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http://dx.doi.org/10.1038/s41431-021-00830-zDOI Listing
February 2021

Neighborhood Walkability as a Predictor of Incident Hypertension in a National Cohort Study.

Front Public Health 2021 1;9:611895. Epub 2021 Feb 1.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.

The built environment (BE) has been associated with health outcomes in prior studies. Few have investigated the association between neighborhood walkability, a component of BE, and hypertension. We examined the association between neighborhood walkability and incident hypertension in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Walkability was measured using Street Smart Walk Score based on participants' residential information at baseline (collected between 2003 and 2007) and was dichotomized as more (score ≥70) and less (score <70) walkable. The primary outcome was incident hypertension defined at the second visit (collected between 2013 and 2017). We derived risk ratios (RR) using modified Poisson regression adjusting for age, race, sex, geographic region, income, alcohol use, smoking, exercise, BMI, dyslipidemia, diabetes, and baseline blood pressure (BP). We further stratified by race, age, and geographic region. Among 6,894 participants, 6.8% lived in more walkable areas and 38% ( = 2,515) had incident hypertension. In adjusted analysis, neighborhood walkability (Walk Score ≥70) was associated with a lower risk of incident hypertension (RR [95%CI]: 0.85[0.74, 0.98], = 0.02), with similar but non-significant trends in race and age strata. In secondary analyses, living in a more walkable neighborhood was protective against being hypertensive at both study visits (OR [95%CI]: 0.70[0.59, 0.84], < 0.001). Neighborhood walkability was associated with incident hypertension in the REGARDS cohort, with the relationship consistent across race groups. The results of this study suggest increased neighborhood walkability may be protective for high blood pressure in black and white adults from the general US population.
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http://dx.doi.org/10.3389/fpubh.2021.611895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882902PMC
February 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Authors:
Daniel Taliun Daniel N Harris Michael D Kessler Jedidiah Carlson Zachary A Szpiech Raul Torres Sarah A Gagliano Taliun André Corvelo Stephanie M Gogarten Hyun Min Kang Achilleas N Pitsillides Jonathon LeFaive Seung-Been Lee Xiaowen Tian Brian L Browning Sayantan Das Anne-Katrin Emde Wayne E Clarke Douglas P Loesch Amol C Shetty Thomas W Blackwell Albert V Smith Quenna Wong Xiaoming Liu Matthew P Conomos Dean M Bobo François Aguet Christine Albert Alvaro Alonso Kristin G Ardlie Dan E Arking Stella Aslibekyan Paul L Auer John Barnard R Graham Barr Lucas Barwick Lewis C Becker Rebecca L Beer Emelia J Benjamin Lawrence F Bielak John Blangero Michael Boehnke Donald W Bowden Jennifer A Brody Esteban G Burchard Brian E Cade James F Casella Brandon Chalazan Daniel I Chasman Yii-Der Ida Chen Michael H Cho Seung Hoan Choi Mina K Chung Clary B Clish Adolfo Correa Joanne E Curran Brian Custer Dawood Darbar Michelle Daya Mariza de Andrade Dawn L DeMeo Susan K Dutcher Patrick T Ellinor Leslie S Emery Celeste Eng Diane Fatkin Tasha Fingerlin Lukas Forer Myriam Fornage Nora Franceschini Christian Fuchsberger Stephanie M Fullerton Soren Germer Mark T Gladwin Daniel J Gottlieb Xiuqing Guo Michael E Hall Jiang He Nancy L Heard-Costa Susan R Heckbert Marguerite R Irvin Jill M Johnsen Andrew D Johnson Robert Kaplan Sharon L R Kardia Tanika Kelly Shannon Kelly Eimear E Kenny Douglas P Kiel Robert Klemmer Barbara A Konkle Charles Kooperberg Anna Köttgen Leslie A Lange Jessica Lasky-Su Daniel Levy Xihong Lin Keng-Han Lin Chunyu Liu Ruth J F Loos Lori Garman Robert Gerszten Steven A Lubitz Kathryn L Lunetta Angel C Y Mak Ani Manichaikul Alisa K Manning Rasika A Mathias David D McManus Stephen T McGarvey James B Meigs Deborah A Meyers Julie L Mikulla Mollie A Minear Braxton D Mitchell Sanghamitra Mohanty May E Montasser Courtney Montgomery Alanna C Morrison Joanne M Murabito Andrea Natale Pradeep Natarajan Sarah C Nelson Kari E North Jeffrey R O'Connell Nicholette D Palmer Nathan Pankratz Gina M Peloso Patricia A Peyser Jacob Pleiness Wendy S Post Bruce M Psaty D C Rao Susan Redline Alexander P Reiner Dan Roden Jerome I Rotter Ingo Ruczinski Chloé Sarnowski Sebastian Schoenherr David A Schwartz Jeong-Sun Seo Sudha Seshadri Vivien A Sheehan Wayne H Sheu M Benjamin Shoemaker Nicholas L Smith Jennifer A Smith Nona Sotoodehnia Adrienne M Stilp Weihong Tang Kent D Taylor Marilyn Telen Timothy A Thornton Russell P Tracy David J Van Den Berg Ramachandran S Vasan Karine A Viaud-Martinez Scott Vrieze Daniel E Weeks Bruce S Weir Scott T Weiss Lu-Chen Weng Cristen J Willer Yingze Zhang Xutong Zhao Donna K Arnett Allison E Ashley-Koch Kathleen C Barnes Eric Boerwinkle Stacey Gabriel Richard Gibbs Kenneth M Rice Stephen S Rich Edwin K Silverman Pankaj Qasba Weiniu Gan George J Papanicolaou Deborah A Nickerson Sharon R Browning Michael C Zody Sebastian Zöllner James G Wilson L Adrienne Cupples Cathy C Laurie Cashell E Jaquish Ryan D Hernandez Timothy D O'Connor Gonçalo R Abecasis

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

School and Teacher Factors That Promote Adolescents' Bystander Responses to Social Exclusion.

Front Psychol 2020 11;11:581089. Epub 2021 Jan 11.

Department of Educational Studies, University of South Carolina, Columbia, SC, United States.

Schools may be one important context where adolescents learn and shape the behaviors necessary for promoting global inclusivity in adulthood. Given the importance of bystanders in halting bullying and peer aggression, the focus of this study is on both moral judgments regarding one type of bullying, social exclusion, and factors that are associated with bystander intervention. The study includes 896 adolescents, who were 6th ( = 450, = 11.73), and 9th ( = 446, = 14.82) graders, approximately evenly divided by gender. Participants were primarily European-American (63.3%). Results revealed that girls and participants who perceived better relationships between students and teachers were more likely to judge exclusion to be wrong. Further, ethnic minority participants, those who were more anxious about being rejected by their teachers and reported more teacher discrimination were less likely to judge exclusion as wrong. Participants who reported more positive student-teacher relationships, perceptions of a more positive school social environment and more prior experiences of teacher discrimination were more likely to report that they would seek help for the victim. On the other hand, participants who reported being more angry about teacher rejection, experiencing either peer or teacher discrimination, and perceiving they are excluded from opportunities at school were less likely to intervene to come to the aid of a peer who is being excluded. The results document the complex interplay of school and teacher factors in shaping adolescents' bystander responses to social exclusion. Our findings suggest that positive school climate can promote intentions to intervene. However, findings indicate that adolescents who are marginalized in their school environments, and who report experiences of rejection, exclusion or discrimination are not willing or likely to intervene to prevent others from experiencing exclusion.
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http://dx.doi.org/10.3389/fpsyg.2020.581089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829334PMC
January 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States. Electronic address:

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Division of General Internal Medicine, Weill Cornell Medicine, New York, New York.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Authors:
Jonas B Nielsen Oren Rom Ida Surakka Sarah E Graham Wei Zhou Tanmoy Roychowdhury Lars G Fritsche Sarah A Gagliano Taliun Carlo Sidore Yuhao Liu Maiken E Gabrielsen Anne Heidi Skogholt Brooke Wolford William Overton Ying Zhao Jin Chen He Zhang Whitney E Hornsby Akua Acheampong Austen Grooms Amanda Schaefer Gregory J M Zajac Luis Villacorta Jifeng Zhang Ben Brumpton Mari Løset Vivek Rai Pia R Lundegaard Morten S Olesen Kent D Taylor Nicholette D Palmer Yii-Der Chen Seung H Choi Steven A Lubitz Patrick T Ellinor Kathleen C Barnes Michelle Daya Nicholas Rafaels Scott T Weiss Jessica Lasky-Su Russell P Tracy Ramachandran S Vasan L Adrienne Cupples Rasika A Mathias Lisa R Yanek Lewis C Becker Patricia A Peyser Lawrence F Bielak Jennifer A Smith Stella Aslibekyan Bertha A Hidalgo Donna K Arnett Marguerite R Irvin James G Wilson Solomon K Musani Adolfo Correa Stephen S Rich Xiuqing Guo Jerome I Rotter Barbara A Konkle Jill M Johnsen Allison E Ashley-Koch Marilyn J Telen Vivien A Sheehan John Blangero Joanne E Curran Juan M Peralta Courtney Montgomery Wayne H-H Sheu Ren-Hua Chung Karen Schwander Seyed M Nouraie Victor R Gordeuk Yingze Zhang Charles Kooperberg Alexander P Reiner Rebecca D Jackson Eugene R Bleecker Deborah A Meyers Xingnan Li Sayantan Das Ketian Yu Jonathon LeFaive Albert Smith Tom Blackwell Daniel Taliun Sebastian Zollner Lukas Forer Sebastian Schoenherr Christian Fuchsberger Anita Pandit Matthew Zawistowski Sachin Kheterpal Chad M Brummett Pradeep Natarajan David Schlessinger Seunggeun Lee Hyun Min Kang Francesco Cucca Oddgeir L Holmen Bjørn O Åsvold Michael Boehnke Sekar Kathiresan Goncalo R Abecasis Y Eugene Chen Cristen J Willer Kristian Hveem

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Cardiovascular Health and Transition From Controlled Blood Pressure to Apparent Treatment Resistant Hypertension: The Jackson Heart Study and the REGARDS Study.

Hypertension 2020 12 2;76(6):1953-1961. Epub 2020 Nov 2.

From the Department of Epidemiology (O.P.A., S.S., C.L.C., S.T.H., M.R.I., R.T., P.M.), University of Alabama at Birmingham.

Almost 1 in 5 US adults with hypertension has apparent treatment resistant hypertension (aTRH). Identifying modifiable risk factors for incident aTRH may guide interventions to reduce the need for additional antihypertensive medication. We evaluated the association between cardiovascular health and incident aTRH among participants with hypertension and controlled blood pressure (BP) at baseline in the Jackson Heart Study (N=800) and the Reasons for Geographic and Racial Differences in Stroke study (N=2316). Body mass index, smoking, physical activity, diet, BP, cholesterol and glucose, categorized as ideal, intermediate, or poor according to the American Heart Association's Life's Simple 7 were assessed at baseline and used to define cardiovascular health. Incident aTRH was defined by uncontrolled BP, systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg, while taking ≥3 classes of antihypertensive medication or controlled BP, systolic BP <130 mm Hg and diastolic BP <80 mm Hg, while taking ≥4 classes of antihypertensive medication at a follow-up visit. Over a median 9 years of follow-up, 605 (19.4%) participants developed aTRH. Incident aTRH developed among 25.8%, 18.2%, and 15.7% of participants with 0 to 1, 2, and 3 to 5 ideal Life's Simple 7 components, respectively. No participants had 6 or 7 ideal Life's Simple 7 components at baseline. The multivariable adjusted hazard ratios (95% CIs) for incident aTRH associated with 2 and 3 to 5 versus 0 to 1 ideal components were 0.75 (0.61-0.92) and 0.67 (0.54-0.82), respectively. These findings suggest optimizing cardiovascular health may reduce the pill burden and high cardiovascular risk associated with aTRH among individuals with hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15890DOI Listing
December 2020

Genetic-Based Hypertension Subtype Identification Using Informative SNPs.

Genes (Basel) 2020 Oct 27;11(11). Epub 2020 Oct 27.

Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

In this work, we proposed a process to select informative genetic variants for identifying clinically meaningful subtypes of hypertensive patients. We studied 575 African American (AA) and 612 Caucasian hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study and analyzed each race-based group separately. All study participants underwent GWAS (Genome-Wide Association Studies) and echocardiography. We applied a variety of statistical methods and filtering criteria, including generalized linear models, F statistics, burden tests, deleterious variant filtering, and others to select the most informative hypertension-related genetic variants. We performed an unsupervised learning algorithm non-negative matrix factorization (NMF) to identify hypertension subtypes with similar genetic characteristics. Kruskal-Wallis tests were used to demonstrate the clinical meaningfulness of genetic-based hypertension subtypes. Two subgroups were identified for both African American and Caucasian HyperGEN participants. In both AAs and Caucasians, indices of cardiac mechanics differed significantly by hypertension subtypes. African Americans tend to have more genetic variants compared to Caucasians; therefore, using genetic information to distinguish the disease subtypes for this group of people is relatively challenging, but we were able to identify two subtypes whose cardiac mechanics have statistically different distributions using the proposed process. The research gives a promising direction in using statistical methods to select genetic information and identify subgroups of diseases, which may inform the development and trial of novel targeted therapies.
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http://dx.doi.org/10.3390/genes11111265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693873PMC
October 2020

Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.

Epigenetics 2020 10 26:1-14. Epub 2020 Oct 26.

Department of Epidemiology, School of Public Health, University of Michigan , Ann Arbor, Michigan, USA.

Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near , cg09155024, cg10254690 near , cg07660512, cg12661888 near , and cg02264946 near ) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with -gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.
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http://dx.doi.org/10.1080/15592294.2020.1827717DOI Listing
October 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Authors:
Alexander G Bick Joshua S Weinstock Satish K Nandakumar Charles P Fulco Erik L Bao Seyedeh M Zekavat Mindy D Szeto Xiaotian Liao Matthew J Leventhal Joseph Nasser Kyle Chang Cecelia Laurie Bala Bharathi Burugula Christopher J Gibson Amy E Lin Margaret A Taub Francois Aguet Kristin Ardlie Braxton D Mitchell Kathleen C Barnes Arden Moscati Myriam Fornage Susan Redline Bruce M Psaty Edwin K Silverman Scott T Weiss Nicholette D Palmer Ramachandran S Vasan Esteban G Burchard Sharon L R Kardia Jiang He Robert C Kaplan Nicholas L Smith Donna K Arnett David A Schwartz Adolfo Correa Mariza de Andrade Xiuqing Guo Barbara A Konkle Brian Custer Juan M Peralta Hongsheng Gui Deborah A Meyers Stephen T McGarvey Ida Yii-Der Chen M Benjamin Shoemaker Patricia A Peyser Jai G Broome Stephanie M Gogarten Fei Fei Wang Quenna Wong May E Montasser Michelle Daya Eimear E Kenny Kari E North Lenore J Launer Brian E Cade Joshua C Bis Michael H Cho Jessica Lasky-Su Donald W Bowden L Adrienne Cupples Angel C Y Mak Lewis C Becker Jennifer A Smith Tanika N Kelly Stella Aslibekyan Susan R Heckbert Hemant K Tiwari Ivana V Yang John A Heit Steven A Lubitz Jill M Johnsen Joanne E Curran Sally E Wenzel Daniel E Weeks Dabeeru C Rao Dawood Darbar Jee-Young Moon Russell P Tracy Erin J Buth Nicholas Rafaels Ruth J F Loos Peter Durda Yongmei Liu Lifang Hou Jiwon Lee Priyadarshini Kachroo Barry I Freedman Daniel Levy Lawrence F Bielak James E Hixson James S Floyd Eric A Whitsel Patrick T Ellinor Marguerite R Irvin Tasha E Fingerlin Laura M Raffield Sebastian M Armasu Marsha M Wheeler Ester C Sabino John Blangero L Keoki Williams Bruce D Levy Wayne Huey-Herng Sheu Dan M Roden Eric Boerwinkle JoAnn E Manson Rasika A Mathias Pinkal Desai Kent D Taylor Andrew D Johnson Paul L Auer Charles Kooperberg Cathy C Laurie Thomas W Blackwell Albert V Smith Hongyu Zhao Ethan Lange Leslie Lange Stephen S Rich Jerome I Rotter James G Wilson Paul Scheet Jacob O Kitzman Eric S Lander Jesse M Engreitz Benjamin L Ebert Alexander P Reiner Siddhartha Jaiswal Gonçalo Abecasis Vijay G Sankaran Sekar Kathiresan Pradeep Natarajan

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A.

Am J Clin Nutr 2020 11;112(5):1200-1211

Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

Background: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown.

Objectives: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases.

Methods: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator.

Results: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; β = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases.

Conclusions: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121.
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http://dx.doi.org/10.1093/ajcn/nqaa233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657341PMC
November 2020

Genome-Wide Association Meta-Analysis of Individuals of European Ancestry Identifies Suggestive Loci for Sodium Intake, Potassium Intake, and Their Ratio Measured from 24-Hour or Half-Day Urine Samples.

J Nutr 2020 10;150(10):2635-2645

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Background: Excess sodium intake and insufficient potassium intake are risk factors for hypertension, but there is limited knowledge regarding genetic factors that influence intake. Twenty-hour or half-day urine samples provide robust estimates of sodium and potassium intake, outperforming other measures such as spot urine samples and dietary self-reporting.

Objective: The aim of this study was to investigate genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio measured from 24-h or half-day urine samples.

Methods: Using samples of European ancestry (mean age: 54.2 y; 52.3% women), we conducted a meta-analysis of genome-wide association studies in 4 cohorts with 24-h or half-day urine samples (n = 6,519), followed by gene-based analysis. Suggestive loci (P < 10-6) were examined in additional European (n = 844), African (n = 1,246), and Asian (n = 2,475) ancestry samples.

Results: We found suggestive loci (P < 10-6) for all 3 traits, including 7 for 24-h sodium excretion, 4 for 24-h potassium excretion, and 4 for sodium-to-potassium ratio. The most significant locus was rs77958157 near cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) , a gene involved in eating behavior and appetite regulation (P = 2.3 × 10-8 with sodium-to-potassium ratio). Two suggestive loci were replicated in additional samples: for sodium excretion, rs12094702 near zinc finger SWIM-type containing 5 (ZSWIM5) was replicated in the Asian ancestry sample reaching Bonferroni-corrected significance (P = 0.007), and for potassium excretion rs34473523 near sodium leak channel (NALCN) was associated at a nominal P value with potassium excretion both in European (P = 0.043) and African (P = 0.043) ancestry cohorts. Gene-based tests identified 1 significant gene for sodium excretion, CDC42 small effector 1 (CDC42SE1), which is associated with blood pressure regulation.

Conclusions: We identified multiple suggestive loci for sodium and potassium intake near genes associated with eating behavior, nervous system development and function, and blood pressure regulation in individuals of European ancestry. Further research is needed to replicate these findings and to provide insight into the underlying genetic mechanisms by which these genomic regions influence sodium and potassium intake.
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http://dx.doi.org/10.1093/jn/nxaa241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549298PMC
October 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

The Relations and Role of Social Competencies and Belonging with Math and Science Interest and Efficacy for Adolescents in Informal STEM Programs.

J Youth Adolesc 2021 Feb 17;50(2):314-323. Epub 2020 Aug 17.

North Carolina State University, Raleigh, NC, USA.

Adolescence represents a developmental period of waning academic motivation, particularly in STEM domains. To combat this, better understanding the factors that might foster STEM motivation and interest is of importance. Social factors like social competencies and feelings of belonging become increasingly important in adolescence. The current study investigated structural relations between social competencies, feelings of belonging to an informal STEM learning program, math and science efficacy and interest in a sample of 268 adolescents (M = 15.25; 66.8% girls; 42.5% White British or European American, 25.7% South Asian British or Asian American, 15.7% Afro-Caribbean Black British or African American 5.6% Bi-racial, and 3.0% other). Adolescents were recruited from six different informal learning sites (e.g., science museums, zoos, or aquariums) in the United States (n = 147) and the United Kingdom (n = 121). The results revealed positive relations between social competencies and belonging, and between belonging and math and science efficacy and interest. Further, the results also indicated a positive indirect effect of social competencies on efficacy and interest, via belonging. These findings have implications for guiding informal STEM programming in ways that can enhance STEM motivation and interest.
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http://dx.doi.org/10.1007/s10964-020-01302-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875952PMC
February 2021

Serum magnesium concentration and incident cognitive impairment: the reasons for geographic and racial differences in stroke study.

Eur J Nutr 2021 Apr 31;60(3):1511-1520. Epub 2020 Jul 31.

Department of Obstetrics and Gynecology and Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, USA.

Purpose: To examine the prospective association between serum Mg level and the incidence of cognitive impairment.

Methods: A random sub-cohort (n = 2063) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort was included in this study. Baseline serum Mg concentration was measured using inductively coupled plasma mass spectrometry. According to the current reference interval of serum magnesium (0.75-0.95 mmol/L), we classified participants below the interval as Level 1 and used it as the referent. The rest of the study population were equally divided into three groups, named Level 2 to 4. Incident cognitive impairment was identified using the Six-Item Screener. Multivariable-adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using logistic regression models.

Results: After adjustment for potential confounders, an inverse threshold association between serum Mg level and incident cognitive impairment was observed. Compared to those with hypomagnesemia (Level 1: < 0.75 mmol/L), the relative odds of incident cognitive impairment was reduced by 41% in the second level [OR (95% CI) = 0.59 (0.37, 0.94)]; higher serum Mg level did not provide further benefits [Level 3 and 4 versus Level 1: OR (95% CI) = 0.54 (0.34, 0.88) and 0.59 (0.36, 0.96), P for linear trend = 0.08].

Conclusions: Findings from this prospective study suggest that sufficient Mg status within the normal range may be beneficial to cognitive health in the US general population.
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http://dx.doi.org/10.1007/s00394-020-02353-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854858PMC
April 2021

Interest and learning in informal science learning sites: Differences in experiences with different types of educators.

PLoS One 2020 23;15(7):e0236279. Epub 2020 Jul 23.

North Carolina State University, Raleigh, North Carolina, United States of America.

This study explored topic interest, perceived learning and actual recall of exhibit content in 979 children and adolescents and 1,184 adults who visited informal science learning sites and interacted with an adult or youth educator or just the exhibit itself as part of family visits to the sites. Children in early childhood reported greater topic interest and perceived learning, but actually recalled less content, than participants in middle childhood or adolescence. Youth visitors reported greater interest after interacting with a youth educator than just the exhibit, and perceived that they learn more if they interact with an educator (youth or adult). Participants in middle childhood recall more when they encounter a youth educator. Adult visitors reported greater interest after interaction with a youth educator than with the exhibit alone or an adult educator. They also perceived that they learn more if they interact with an educator (youth or adult) than just the exhibit and perceived that they learned more if they interacted with a youth educator than an adult educator. Results highlight the benefits of educators in informal science learning sites and document the importance of attention to developmental needs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236279PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377401PMC
September 2020

A lipidome-wide association study of the lipoprotein insulin resistance index.

Lipids Health Dis 2020 Jun 25;19(1):153. Epub 2020 Jun 25.

Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL, 35294, USA.

Background: The lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear.

Objective: To identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980).

Methods: Linear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p <  0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590).

Results: In GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10 to 49.50 × 10). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (β = 0.025, p = 4.52 × 10 and β = 0.021, p = 5.84 × 10, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (β = - 0.013, p = 2.28 × 10) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (β = 0.10, p = 1.21 × 10 for storage, β = - 0.13, p = 3.14 × 10 for non-storage, and β = 0.19, p = 8.40 × 10 for mixed lipids).

Conclusions: Non-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.
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http://dx.doi.org/10.1186/s12944-020-01321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318473PMC
June 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Authors:
Lisa de Las Fuentes Yun Ju Sung Raymond Noordam Thomas Winkler Mary F Feitosa Karen Schwander Amy R Bentley Michael R Brown Xiuqing Guo Alisa Manning Daniel I Chasman Hugues Aschard Traci M Bartz Lawrence F Bielak Archie Campbell Ching-Yu Cheng Rajkumar Dorajoo Fernando P Hartwig A R V R Horimoto Changwei Li Ruifang Li-Gao Yongmei Liu Jonathan Marten Solomon K Musani Ioanna Ntalla Tuomo Rankinen Melissa Richard Xueling Sim Albert V Smith Salman M Tajuddin Bamidele O Tayo Dina Vojinovic Helen R Warren Deng Xuan Maris Alver Mathilde Boissel Jin-Fang Chai Xu Chen Kaare Christensen Jasmin Divers Evangelos Evangelou Chuan Gao Giorgia Girotto Sarah E Harris Meian He Fang-Chi Hsu Brigitte Kühnel Federica Laguzzi Xiaoyin Li Leo-Pekka Lyytikäinen Ilja M Nolte Alaitz Poveda Rainer Rauramaa Muhammad Riaz Rico Rueedi Xiao-Ou Shu Harold Snieder Tamar Sofer Fumihiko Takeuchi Niek Verweij Erin B Ware Stefan Weiss Lisa R Yanek Najaf Amin Dan E Arking Donna K Arnett Sven Bergmann Eric Boerwinkle Jennifer A Brody Ulrich Broeckel Marco Brumat Gregory Burke Claudia P Cabrera Mickaël Canouil Miao Li Chee Yii-Der Ida Chen Massimiliano Cocca John Connell H Janaka de Silva Paul S de Vries Gudny Eiriksdottir Jessica D Faul Virginia Fisher Terrence Forrester Ervin F Fox Yechiel Friedlander He Gao Bruna Gigante Franco Giulianini Chi Charles Gu Dongfeng Gu Tamara B Harris Jiang He Sami Heikkinen Chew-Kiat Heng Steven Hunt M Arfan Ikram Marguerite R Irvin Mika Kähönen Maryam Kavousi Chiea Chuen Khor Tuomas O Kilpeläinen Woon-Puay Koh Pirjo Komulainen Aldi T Kraja J E Krieger Carl D Langefeld Yize Li Jingjing Liang David C M Liewald Ching-Ti Liu Jianjun Liu Kurt K Lohman Reedik Mägi Colin A McKenzie Thomas Meitinger Andres Metspalu Yuri Milaneschi Lili Milani Dennis O Mook-Kanamori Mike A Nalls Christopher P Nelson Jill M Norris Jeff O'Connell Adesola Ogunniyi Sandosh Padmanabhan Nicholette D Palmer Nancy L Pedersen Thomas Perls Annette Peters Astrid Petersmann Patricia A Peyser Ozren Polasek David J Porteous Leslie J Raffel Treva K Rice Jerome I Rotter Igor Rudan Oscar-Leonel Rueda-Ochoa Charumathi Sabanayagam Babatunde L Salako Pamela J Schreiner James M Shikany Stephen S Sidney Mario Sims Colleen M Sitlani Jennifer A Smith John M Starr Konstantin Strauch Morris A Swertz Alexander Teumer Yih Chung Tham André G Uitterlinden Dhananjay Vaidya M Yldau van der Ende Melanie Waldenberger Lihua Wang Ya-Xing Wang Wen-Bin Wei David R Weir Wanqing Wen Jie Yao Bing Yu Caizheng Yu Jian-Min Yuan Wei Zhao Alan B Zonderman Diane M Becker Donald W Bowden Ian J Deary Marcus Dörr Tõnu Esko Barry I Freedman Philippe Froguel Paolo Gasparini Christian Gieger Jost Bruno Jonas Candace M Kammerer Norihiro Kato Timo A Lakka Karin Leander Terho Lehtimäki Patrik K E Magnusson Pedro Marques-Vidal Brenda W J H Penninx Nilesh J Samani Pim van der Harst Lynne E Wagenknecht Tangchun Wu Wei Zheng Xiaofeng Zhu Claude Bouchard Richard S Cooper Adolfo Correa Michele K Evans Vilmundur Gudnason Caroline Hayward Bernardo L Horta Tanika N Kelly Stephen B Kritchevsky Daniel Levy Walter R Palmas A C Pereira Michael M Province Bruce M Psaty Paul M Ridker Charles N Rotimi E Shyong Tai Rob M van Dam Cornelia M van Duijn Tien Yin Wong Kenneth Rice W James Gauderman Alanna C Morrison Kari E North Sharon L R Kardia Mark J Caulfield Paul Elliott Patricia B Munroe Paul W Franks Dabeeru C Rao Myriam Fornage

Mol Psychiatry 2020 May 5. Epub 2020 May 5.

Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 70808, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
May 2020

Gout is associated with an increased risk for incident heart failure among older adults: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study.

Arthritis Res Ther 2020 04 16;22(1):86. Epub 2020 Apr 16.

Department of Epidemiology, University of Alabama at Birmingham, 1720 2nd Ave South, RPHB 527C, Birmingham, AL, 35294-0013, USA.

Background: Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some prior studies. Few studies have assessed the association of gout with incident heart failure (HF).

Methods: We analyzed data from 5713 black and white men and women ≥ 65.5 years of age in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study who had Medicare coverage without a history of HF, CHD, or stroke at baseline between 2003 and 2007. Gout was defined by ≥ 1 hospitalization or ≥ 2 outpatient visits with a diagnosis code for gout in Medicare claims prior to each participant's baseline study examination. REGARDS study participants were followed for HF hospitalization, CHD, stroke, and all-cause mortality as separate outcomes through December 31, 2016. Analyses were replicated in a random sample of 839,059 patients ≥ 65.5 years of age with Medicare coverage between January 1, 2008, and June 30, 2015, who were followed through December 31, 2017.

Results: Among REGARDS study participants included in the current analysis, the mean age at baseline was 72.6 years, 44.9% were men, 31.4% were black, and 3.3% had gout. Over a median follow-up of 10.0 years, incidence rates per 1000 person-years among participants with and without gout were 13.1 and 4.4 for HF hospitalization, 16.0 and 9.3 for CHD, 9.3 and 8.2 for stroke, and 55.0 and 37.1 for all-cause mortality, respectively. After multivariable adjustment for sociodemographic variables and cardiovascular risk factors, hazard ratios (95% CI) comparing participants with versus without gout were 1.97 (1.22, 3.19) for HF hospitalization, 1.21 (0.79, 1.84) for CHD, 0.83 (0.48, 1.43) for stroke, and 1.08 (0.86, 1.35) for all-cause mortality. The multivariable-adjusted hazard ratio for HF hospitalization with reduced and preserved left ventricular ejection fraction among participants with versus without gout was 1.77 (95% CI 0.83, 3.79) and 2.32 (95% CI 1.12, 4.79), respectively. The multivariable-adjusted hazard ratio for heart failure hospitalization associated with gout among the 839,059 Medicare beneficiaries was 1.32 (95% CI 1.25, 1.39).

Conclusion: Among older adults, gout was associated with an increased risk for incident HF but not for incident CHD, incident stroke, or all-cause mortality.
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http://dx.doi.org/10.1186/s13075-020-02175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164141PMC
April 2020

STEM gender stereotypes from early childhood through adolescence at informal science centers.

J Appl Dev Psychol 2020 Mar-Apr;67:101109

University of Exeter, UK.

Stereotypes about science, technology, engineering and mathematics (STEM) are associated with reduced STEM engagement amongst girls and women. The present study examined these stereotypes from early childhood through adolescence within informal science learning sites (ISLS; science museums, zoos, aquariums). Further, the study explored whether interactions with male or female educators influenced STEM stereotypes. Participants ( = 997, female = 572) were ISLS visitors in the UK and USA who either interacted with an educator, or no educator. With age participants were more likely to report that "both boys and girls" are "usually", "should" be, and "can" be good at STEM. Independent of age, male participants reported that their own gender group "should" be good at STEM. Educator interactions did not influence stereotype responses. These results highlight early childhood as a key developmental window in which to challenge ideas about who can and should be proficient in STEM.
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http://dx.doi.org/10.1016/j.appdev.2020.101109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104893PMC
April 2020

Soluble CD14, Ischemic Stroke, and Coronary Heart Disease Risk in a Prospective Study: The REGARDS Cohort.

J Am Heart Assoc 2020 03 11;9(6):e014241. Epub 2020 Mar 11.

Department of Pathology and Laboratory Medicine Larner College of Medicine University of Vermont Burlington VT.

Background Soluble CD14 (sCD14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case-cohort study, sCD14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease (CHD), and a cohort random sample (n=1039). Cox models estimated hazards ratios (HR) of incident ischemic stroke or CHD per 1 SD higher sCD14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD14 was 1.42 (95% CI: 1.12, 1.80), with no association among whites (HR 1.02 [95% CI: 0.82, 1.27]). Higher sCD14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD14 among blacks at age 45 years was 2.30 (95% CI: 1.45, 3.65) compared with 1.56 (95% CI: 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI: 1.20, 1.91) among blacks and 1.02 (95% CI: 0.80, 1.31) among whites. Conclusions sCD14 may be a race-specific stroke and CHD risk marker.
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http://dx.doi.org/10.1161/JAHA.119.014241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335508PMC
March 2020

Transfusion Outcomes in Patients Undergoing Unifocalization and Repair of Tetralogy of Fallot With Major Aortopulmonary Collaterals.

World J Pediatr Congenit Heart Surg 2020 03;11(2):159-165

Clinical and Translational Research Program, Lucile Packard Children's Hospital Heart Center, Stanford University, Stanford, CA, USA.

Background: Surgical repair of tetralogy of Fallot and major aortopulmonary collaterals (TOF/MAPCAs) involves unifocalization of MAPCAs and reconstruction of the pulmonary arterial circulation. Surgical and cardiopulmonary bypass (CPB) times are long and suture lines are extensive. Maintaining patency of the newly anastomosed vessels while achieving hemostasis is important, and assessment of transfusion practices is critical to successful outcomes.

Methods: Clinical, surgical, and transfusion data in patients with TOF/MAPCAs repaired at our institution (2013-2018) were reviewed. Types and volumes of blood products used in the perioperative period, in addition to the use of antifibrinolytics and/or procoagulants (factor VIII inhibitor bypassing activity [FEIBA]; anti-inhibitor coagulant complex), were assessed. Outcome measures included days on mechanical ventilation (DOMV), postoperative intensive care unit and hospital length of stay (LoS), and incidence of thrombosis.

Results: Perioperative transfusion data from 279 patients were analyzed. Surgical (879 ± 175 minutes vs 684 ± 257 minutes) and CPB times (376 ± 124 minutes vs 234 ± 122 minutes) were longer in patients who received FEIBA than those who did not. Although the indexed volume of packed red blood cells (128.4 ± 82.2 mL/kg) and fresh frozen plasma (64.2 ± 41.1 mL/kg) was similar in patients who did and did not receive FEIBA, the amounts of cryoprecipitate (5.5 ± 5.2 mL/kg vs 5.8 ± 4.8 mL/kg) and platelets (19.5 ± 20.7 mL/kg vs 20.8 ± 13 mL/kg) transfused were more in those who did receive FEIBA.

Conclusion: Perioperative transfusion is an important component in the overall surgical and anesthetic management of patients with TOF/MAPCAs. The intraoperative use of FEIBA was not associated with a decrease in the amount of blood products transfused, DOMV, or LoS or with an increase in thrombotic complications.
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http://dx.doi.org/10.1177/2150135119892192DOI Listing
March 2020