%0 Journal Article %J Genome Med %D 2021 %T Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. %A Kasela, Silva %A Ortega, Victor E %A Martorella, Molly %A Garudadri, Suresh %A Nguyen, Jenna %A Ampleford, Elizabeth %A Pasanen, Anu %A Nerella, Srilaxmi %A Buschur, Kristina L %A Barjaktarevic, Igor Z %A Barr, R Graham %A Bleecker, Eugene R %A Bowler, Russell P %A Comellas, Alejandro P %A Cooper, Christopher B %A Couper, David J %A Criner, Gerard J %A Curtis, Jeffrey L %A Han, MeiLan K %A Hansel, Nadia N %A Hoffman, Eric A %A Kaner, Robert J %A Krishnan, Jerry A %A Martinez, Fernando J %A McDonald, Merry-Lynn N %A Meyers, Deborah A %A Paine, Robert %A Peters, Stephen P %A Castro, Mario %A Denlinger, Loren C %A Erzurum, Serpil C %A Fahy, John V %A Israel, Elliot %A Jarjour, Nizar N %A Levy, Bruce D %A Li, Xingnan %A Moore, Wendy C %A Wenzel, Sally E %A Zein, Joe %A Langelier, Charles %A Woodruff, Prescott G %A Lappalainen, Tuuli %A Christenson, Stephanie A %K Adult %K Aged %K Aged, 80 and over %K Angiotensin-Converting Enzyme 2 %K Asthma %K Bronchi %K Cardiovascular Diseases %K COVID-19 %K Gene Expression %K Genetic Variation %K Humans %K Middle Aged %K Obesity %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K Respiratory Mucosa %K Risk Factors %K SARS-CoV-2 %K Smoking %X

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

%B Genome Med %V 13 %P 66 %8 2021 04 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33883027?dopt=Abstract %R 10.1186/s13073-021-00866-2 %0 Journal Article %J Mol Genet Genomic Med %D 2020 %T Community-based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability. %A Sabo, Aniko %A Murdock, David %A Dugan, Shannon %A Meng, Qingchang %A Gingras, Marie-Claude %A Hu, Jianhong %A Muzny, Donna %A Gibbs, Richard %K Adult %K Female %K Genetic Testing %K Humans %K Independent Living %K Intellectual Disability %K Male %K Mediator Complex %K Membrane Proteins %K Nuclear Proteins %K Patient Selection %K Sensitivity and Specificity %K Tumor Suppressor Proteins %K Whole Exome Sequencing %X

BACKGROUND: Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation.

METHODS: Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family.

RESULTS: All five families enrolled in the study opted-in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow-up in an appointment with a board certified clinical geneticist.

CONCLUSION: Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing-based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID.

%B Mol Genet Genomic Med %V 8 %P e1439 %8 2020 10 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32767738?dopt=Abstract %R 10.1002/mgg3.1439 %0 Journal Article %J Epilepsia %D 2020 %T Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort. %A Rochtus, Anne %A Olson, Heather E %A Smith, Lacey %A Keith, Louisa G %A El Achkar, Christelle %A Taylor, Alan %A Mahida, Sonal %A Park, Meredith %A Kelly, McKenna %A Shain, Catherine %A Rockowitz, Shira %A Rosen Sheidley, Beth %A Poduri, Annapurna %K Adolescent %K Adult %K Age of Onset %K Brain Diseases %K Child %K Child, Preschool %K Chromosomes, Human %K Cohort Studies %K Epilepsy %K Epilepsy, Generalized %K Exome %K Female %K Genetic Testing %K Genetic Variation %K Humans %K Infant %K Male %K Microarray Analysis %K Phenotype %K Whole Exome Sequencing %K Young Adult %X

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

%B Epilepsia %V 61 %P 249-258 %8 2020 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31957018?dopt=Abstract %R 10.1111/epi.16427 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2020 %T Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease. %A Hindy, George %A Aragam, Krishna G %A Ng, Kenney %A Chaffin, Mark %A Lotta, Luca A %A Baras, Aris %A Drake, Isabel %A Orho-Melander, Marju %A Melander, Olle %A Kathiresan, Sekar %A Khera, Amit V %K Adult %K Aged %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Disease Risk Factors %K Heredity %K Humans %K Incidence %K Male %K Middle Aged %K Multifactorial Inheritance %K Phenotype %K Prognosis %K Risk Assessment %K Sweden %K Time Factors %K United Kingdom %X

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPS decile to 48% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

CONCLUSIONS: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

%B Arterioscler Thromb Vasc Biol %V 40 %P 2738-2746 %8 2020 11 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/32957805?dopt=Abstract %R 10.1161/ATVBAHA.120.314856 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, François %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Gonçalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %K Adult %K Africa %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K alpha Karyopherins %K Cell Self Renewal %K Clonal Hematopoiesis %K DNA-Binding Proteins %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Germ-Line Mutation %K Hematopoietic Stem Cells %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Precision Medicine %K Proto-Oncogene Proteins %K Tripartite Motif Proteins %K United States %K Whole Genome Sequencing %X

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.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract %R 10.1038/s41586-020-2819-2 %0 Journal Article %J N Engl J Med %D 2020 %T RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. %A Orange, Dana E %A Yao, Vicky %A Sawicka, Kirsty %A Fak, John %A Frank, Mayu O %A Parveen, Salina %A Blachère, Nathalie E %A Hale, Caryn %A Zhang, Fan %A Raychaudhuri, Soumya %A Troyanskaya, Olga G %A Darnell, Robert B %K Adult %K Arthritis, Rheumatoid %K B-Lymphocytes %K Female %K Fibroblasts %K Flow Cytometry %K Gene Expression %K Humans %K Male %K Mesenchymal Stem Cells %K Middle Aged %K Patient Acuity %K Sequence Analysis, RNA %K Surveys and Questionnaires %K Symptom Flare Up %K Synovial Fluid %X

BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.

METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings.

RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis.

CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).

%B N Engl J Med %V 383 %P 218-228 %8 2020 07 16 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32668112?dopt=Abstract %R 10.1056/NEJMoa2004114 %0 Journal Article %J Am J Clin Nutr %D 2020 %T Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). %A Chen, Guo-Chong %A Chai, Jin Choul %A Yu, Bing %A Michelotti, Gregory A %A Grove, Megan L %A Fretts, Amanda M %A Daviglus, Martha L %A Garcia-Bedoya, Olga L %A Thyagarajan, Bharat %A Schneiderman, Neil %A Cai, Jianwen %A Kaplan, Robert C %A Boerwinkle, Eric %A Qi, Qibin %K Adolescent %K Adult %K Aged %K Diabetes Mellitus %K Female %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Prospective Studies %K Risk Factors %K Sphingolipids %K United States %K Young Adult %X

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031).

CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

%B Am J Clin Nutr %V 112 %P 57-65 %8 2020 07 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32469399?dopt=Abstract %R 10.1093/ajcn/nqaa114 %0 Journal Article %J J Am Coll Cardiol %D 2020 %T Titin Truncating Variants in Adults Without Known Congestive Heart Failure. %A Pirruccello, James P %A Bick, Alexander %A Chaffin, Mark %A Aragam, Krishna G %A Choi, Seung Hoan %A Lubitz, Steven A %A Ho, Carolyn Y %A Ng, Kenney %A Philippakis, Anthony %A Ellinor, Patrick T %A Kathiresan, Sekar %A Khera, Amit V %K Adult %K Aged %K Asymptomatic Diseases %K Connectin %K Female %K Genetic Variation %K Heart Failure %K Humans %K Male %K Middle Aged %B J Am Coll Cardiol %V 75 %P 1239-1241 %8 2020 03 17 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32164899?dopt=Abstract %R 10.1016/j.jacc.2020.01.013 %0 Journal Article %J J Am Coll Cardiol %D 2020 %T Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians. %A Wang, Minxian %A Menon, Ramesh %A Mishra, Sanghamitra %A Patel, Aniruddh P %A Chaffin, Mark %A Tanneeru, Deepak %A Deshmukh, Manjari %A Mathew, Oshin %A Apte, Sanika %A Devanboo, Christina S %A Sundaram, Sumathi %A Lakshmipathy, Praveena %A Murugan, Sakthivel %A Sharma, Krishna Kumar %A Rajendran, Karthikeyan %A Santhosh, Sam %A Thachathodiyl, Rajesh %A Ahamed, Hisham %A Balegadde, Aniketh Vijay %A Alexander, Thomas %A Swaminathan, Krishnan %A Gupta, Rajeev %A Mullasari, Ajit S %A Sigamani, Alben %A Kanchi, Muralidhar %A Peterson, Andrew S %A Butterworth, Adam S %A Danesh, John %A Di Angelantonio, Emanuele %A Naheed, Aliya %A Inouye, Michael %A Chowdhury, Rajiv %A Vedam, Ramprasad L %A Kathiresan, Sekar %A Gupta, Ravi %A Khera, Amit V %K Adult %K Aged %K Bangladesh %K Case-Control Studies %K Coronary Artery Disease %K Female %K Genome-Wide Association Study %K Humans %K India %K Male %K Middle Aged %K Multifactorial Inheritance %X

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.

METHODS: This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

RESULTS: The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each).

CONCLUSIONS: The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

%B J Am Coll Cardiol %V 76 %P 703-714 %8 2020 08 11 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/32762905?dopt=Abstract %R 10.1016/j.jacc.2020.06.024 %0 Journal Article %J Hum Genet %D 2018 %T Genetic variants in microRNA genes and targets associated with cardiovascular disease risk factors in the African-American population. %A Li, Chang %A Grove, Megan L %A Yu, Bing %A Jones, Barbara C %A Morrison, Alanna %A Boerwinkle, Eric %A Liu, Xiaoming %K 3' Untranslated Regions %K Adult %K African Americans %K Cardiovascular Diseases %K Female %K Genetic Predisposition to Disease %K Genotyping Techniques %K Humans %K Male %K MicroRNAs %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Whole Genome Sequencing %X

The purpose of this study is to identify microRNA (miRNA) related polymorphism, including single nucleotide variants (SNVs) in mature miRNA-encoding sequences or in miRNA-target sites, and their association with cardiovascular disease (CVD) risk factors in African-American population. To achieve our objective, we examined 1900 African-Americans from the Atherosclerosis Risk in Communities study using SNVs identified from whole-genome sequencing data. A total of 971 SNVs found in 726 different mature miRNA-encoding sequences and 16,057 SNVs found in the three prime untranslated region (3'UTR) of 3647 protein-coding genes were identified and interrogated their associations with 17 CVD risk factors. Using single-variant-based approach, we found 5 SNVs in miRNA-encoding sequences to be associated with serum Lipoprotein(a) [Lp(a)], high-density lipoprotein (HDL) or triglycerides, and 2 SNVs in miRNA-target sites to be associated with Lp(a) and HDL, all with false discovery rates of 5%. Using a gene-based approach, we identified 3 pairs of associations between gene NSD1 and platelet count, gene HSPA4L and cardiac troponin T, and gene AHSA2 and magnesium. We successfully validated the association between a variant specific to African-American population, NR_039880.1:n.18A>C, in mature hsa-miR-4727-5p encoding sequence and serum HDL level in an independent sample of 2135 African-Americans. Our study provided candidate miRNAs and their targets for further investigation of their potential contribution to ethnic disparities in CVD risk factors.

%B Hum Genet %V 137 %P 85-94 %8 2018 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29264654?dopt=Abstract %R 10.1007/s00439-017-1858-8 %0 Journal Article %J J Am Coll Cardiol %D 2017 %T ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. %A Stitziel, Nathan O %A Khera, Amit V %A Wang, Xiao %A Bierhals, Andrew J %A Vourakis, A Christina %A Sperry, Alexandra E %A Natarajan, Pradeep %A Klarin, Derek %A Emdin, Connor A %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Erdmann, Jeanette %A Schunkert, Heribert %A Samani, Nilesh J %A Kraus, William E %A Shah, Svati H %A Yu, Bing %A Boerwinkle, Eric %A Rader, Daniel J %A Gupta, Namrata %A Frossard, Philippe M %A Rasheed, Asif %A Danesh, John %A Lander, Eric S %A Gabriel, Stacey %A Saleheen, Danish %A Musunuru, Kiran %A Kathiresan, Sekar %K Adult %K Angiopoietin-Like Protein 3 %K Angiopoietin-like Proteins %K Angiopoietins %K Animals %K Atherosclerosis %K Case-Control Studies %K Coronary Artery Disease %K Female %K Humans %K Lipids %K Male %K Mice, Inbred C57BL %K Mice, Knockout %K Middle Aged %K Mutation, Missense %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

%B J Am Coll Cardiol %V 69 %P 2054-2063 %8 2017 Apr 25 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/28385496?dopt=Abstract %R 10.1016/j.jacc.2017.02.030 %0 Journal Article %J Nat Commun %D 2017 %T Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. %A Kim-Hellmuth, Sarah %A Bechheim, Matthias %A Pütz, Benno %A Mohammadi, Pejman %A Nédélec, Yohann %A Giangreco, Nicholas %A Becker, Jessica %A Kaiser, Vera %A Fricker, Nadine %A Beier, Esther %A Boor, Peter %A Castel, Stephane E %A Nöthen, Markus M %A Barreiro, Luis B %A Pickrell, Joseph K %A Müller-Myhsok, Bertram %A Lappalainen, Tuuli %A Schumacher, Johannes %A Hornung, Veit %K Acetylmuramyl-Alanyl-Isoglutamine %K Adjuvants, Immunologic %K Adolescent %K Adult %K Autoimmune Diseases %K Gene Expression %K Gene Expression Profiling %K Gene Expression Regulation %K Genetic Predisposition to Disease %K Healthy Volunteers %K Humans %K Indicators and Reagents %K Lipids %K Lipopolysaccharides %K Male %K Monocytes %K Quantitative Trait Loci %K Regulatory Sequences, Nucleic Acid %K RNA, Double-Stranded %K RNA, Messenger %K Young Adult %X

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5'-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

%B Nat Commun %V 8 %P 266 %8 2017 08 16 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28814792?dopt=Abstract %R 10.1038/s41467-017-00366-1 %0 Journal Article %J Circulation %D 2017 %T Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting. %A Natarajan, Pradeep %A Young, Robin %A Stitziel, Nathan O %A Padmanabhan, Sandosh %A Baber, Usman %A Mehran, Roxana %A Sartori, Samantha %A Fuster, Valentin %A Reilly, Dermot F %A Butterworth, Adam %A Rader, Daniel J %A Ford, Ian %A Sattar, Naveed %A Kathiresan, Sekar %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cohort Studies %K Cost of Illness %K Female %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Multifactorial Inheritance %K Primary Prevention %K Risk Factors %K Young Adult %X

BACKGROUND: Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.

METHODS: We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).

RESULTS: Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; <0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; =0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others ( for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque.

CONCLUSIONS: Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.

%B Circulation %V 135 %P 2091-2101 %8 2017 May 30 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/28223407?dopt=Abstract %R 10.1161/CIRCULATIONAHA.116.024436