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Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment.
Smieszek S, Jia P, Samuels DC, Zhao Z, Barnholtz-Sloan J, Kaur H, Letendre S, Ellis R, Franklin DR, Hulgan T, Kallianpur A, Bush WS, CHARTER Study Group
(2019) Mitochondrion 46: 247-255
MeSH Terms: AIDS Dementia Complex, Cell Nucleus, Continental Population Groups, Genetic Association Studies, HIV Infections, Haplotypes, Humans, Mitochondria, Mitochondrial Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Prospective Studies
Show Abstract · Added December 11, 2019
HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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MeSH Terms
Race- and Sex-related Differences in Nephrolithiasis Risk Among Blacks and Whites in the Southern Community Cohort Study.
Hsi RS, Kabagambe EK, Shu X, Han X, Miller NL, Lipworth L
(2018) Urology 118: 36-42
MeSH Terms: Adult, African Americans, Aged, Cohort Studies, Continental Population Groups, European Continental Ancestry Group, Female, Humans, Incidence, Kidney Calculi, Male, Medicaid, Medicare, Middle Aged, Proportional Hazards Models, Risk Assessment, Risk Factors, Sex Factors, Socioeconomic Factors, United States
Show Abstract · Added July 18, 2018
OBJECTIVE - To investigate race-sex associations with risk among whites and blacks in the southeastern United States. The relationship between race, sex, and kidney stone risk is poorly understood.
METHODS - Participants were 42,136 black and white adults enrolled in the Southern Community Cohort Study between 2002 and 2009, with no history of kidney stones and receiving Medicare or Medicaid services. Incident kidney stone diagnoses through December 2014 were determined via linkage with Centers for Medicare and Medicaid Services research files. Hazard ratios (HRs) for associations with race and sex were computed from multivariable Cox proportional hazards models adjusting for baseline characteristics, comorbid diseases, and dietary intakes.
RESULTS - During 116,931 and 270,917 person-years of follow-up for whites and blacks, respectively, age-adjusted incidence rates (95% confidence interval [CI]) were 5.98 (4.73-7.23) and 4.50 (3.86-5.14) per 1000 person-years for white men and women, respectively, while corresponding rates among blacks were 2.19 (1.71-2.67) and 2.47 (2.19-2.75) per 1000 person-years. Risk was higher among whites compared to blacks (HR = 2.23, 95% CI 1.97-2.53). Male sex was significantly associated with risk among whites (HR = 1.45, 95% CI 1.20-1.75), but not among blacks (HR = 0.90, 95% CI 0.75-1.07). Formal tests of interaction by race and sex were statistically significant for all models (P = .01 for fully adjusted model).
CONCLUSION - The association of incident kidney stones with sex differs between whites and blacks. White men have the highest risk, while no difference in risk is observed between black men and women.
Copyright © 2018 Elsevier Inc. All rights reserved.
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20 MeSH Terms
A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.
Sung YJ, Winkler TW, de Las Fuentes L, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Li C, Feitosa MF, Kilpeläinen TO, Richard MA, Noordam R, Aslibekyan S, Aschard H, Bartz TM, Dorajoo R, Liu Y, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Warren HR, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, Horimoto ARVR, Hsu FC, Jackson AU, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, 'an Luan J, McKenzie CA, Meian H, Nelson CP, Rauramaa R, Schupf N, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cabrera CP, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, CHARGE Neurology Working Group, Chauhan G, Christensen K, Cocca M, COGENT-Kidney Consortium, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Debette S, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Fisher VA, Forouhi NG, Franco OH, Friedlander Y, Gao H, GIANT Consortium, Gigante B, Graff M, Gu CC, Gu D, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng CK, Hirata M, Hofman A, Howard BV, Hunt S, Irvin MR, Jia Y, Joehanes R, Justice AE, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh WP, Koistinen HA, Komulainen P, Kooperberg C, Krieger JE, Kubo M, Kuusisto J, Langefeld CD, Langenberg C, Launer LJ, Lehne B, Lewis CE, Li Y, Lifelines Cohort Study, Lim SH, Lin S, Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman KK, Long J, Louie T, Mägi R, Mahajan A, Meitinger T, Metspalu A, Milani L, Momozawa Y, Morris AP, Mosley TH, Munson P, Murray AD, Nalls MA, Nasri U, Norris JM, North K, Ogunniyi A, Padmanabhan S, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Seshadri S, Sever P, Sitlani CM, Smith JA, Snieder H, Starr JM, Strauch K, Tang H, Taylor KD, Teo YY, Tham YC, Uitterlinden AG, Waldenberger M, Wang L, Wang YX, Wei WB, Williams C, Wilson G, Wojczynski MK, Yao J, Yuan JM, Zonderman AB, Becker DM, Boehnke M, Bowden DW, Chambers JC, Chen YI, de Faire U, Deary IJ, Esko T, Farrall M, Forrester T, Franks PW, Freedman BI, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas JB, Kato N, Kooner JS, Laakso M, Lehtimäki T, Liang KW, Magnusson PKE, Newman AB, Oldehinkel AJ, Pereira AC, Redline S, Rettig R, Samani NJ, Scott J, Shu XO, van der Harst P, Wagenknecht LE, Wareham NJ, Watkins H, Weir DR, Wickremasinghe AR, Wu T, Zheng W, Kamatani Y, Laurie CC, Bouchard C, Cooper RS, Evans MK, Gudnason V, Kardia SLR, Kritchevsky SB, Levy D, O'Connell JR, Psaty BM, van Dam RM, Sims M, Arnett DK, Mook-Kanamori DO, Kelly TN, Fox ER, Hayward C, Fornage M, Rotimi CN, Province MA, van Duijn CM, Tai ES, Wong TY, Loos RJF, Reiner AP, Rotter JI, Zhu X, Bierut LJ, Gauderman WJ, Caulfield MJ, Elliott P, Rice K, Munroe PB, Morrison AC, Cupples LA, Rao DC, Chasman DI
(2018) Am J Hum Genet 102: 375-400
MeSH Terms: Blood Pressure, Cohort Studies, Continental Population Groups, Diastole, Epistasis, Genetic, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Smoking, Systole
Show Abstract · Added April 10, 2018
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Copyright © 2018 American Society of Human Genetics. All rights reserved.
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15 MeSH Terms
Differences in Natriuretic Peptide Levels by Race/Ethnicity (From the Multi-Ethnic Study of Atherosclerosis).
Gupta DK, Daniels LB, Cheng S, deFilippi CR, Criqui MH, Maisel AS, Lima JA, Bahrami H, Greenland P, Cushman M, Tracy R, Siscovick D, Bertoni AG, Cannone V, Burnett JC, Carr JJ, Wang TJ
(2017) Am J Cardiol 120: 1008-1015
MeSH Terms: Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Continental Population Groups, Ethnic Groups, Female, Follow-Up Studies, Humans, Male, Middle Aged, Morbidity, Natriuretic Peptide, Brain, Peptide Fragments, Prevalence, Prognosis, Prospective Studies, Risk Factors, United States
Show Abstract · Added September 11, 2017
Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardiometabolic actions. Low NP levels are associated with increased risks of hypertension and diabetes mellitus, conditions with variable prevalence by race and ethnicity. Heritable factors underlie a significant proportion of the interindividual variation in NP concentrations, but the specific influences of race and ancestry are unknown. In 5597 individuals (40% white, 24% black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis, multivariable linear regression and restricted cubic splines were used to estimate differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to, ethnicity, and ancestry. Ancestry was determined using genetic ancestry informative markers. NT-proBNP concentrations differed significantly by race and ethnicity (black, median 43 pg/ml [interquartile range 17 to 94], Chinese 43 [17 to 90], Hispanic 53 [23 to 107], white 68 [34 to 136]; p = 0.0001). In multivariable models, NT-proBNP was 44% lower (95% confidence interval -48 to -40) in black and 46% lower (-50 to -41) in Chinese, compared with white individuals. Hispanic individuals had intermediate concentrations. Self-identified blacks and Hispanics were the most genetically admixed. Among self-identified black individuals, a 20% increase in genetic European ancestry was associated with 12% higher (1% to 23%) NT-proBNP. Among Hispanic individuals, genetic European and African ancestry were positively and negatively associated with NT-proBNP levels, respectively. In conclusion, NT-proBNP levels differ according to race and ethnicity, with the lowest concentrations in black and Chinese individuals. Racial and ethnic differences in NT-proBNP may have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP concentrations, respectively.
Copyright © 2017 Elsevier Inc. All rights reserved.
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19 MeSH Terms
and Loci Associate with Plasma Osmolality.
Böger CA, Gorski M, McMahon GM, Xu H, Chang YC, van der Most PJ, Navis G, Nolte IM, de Borst MH, Zhang W, Lehne B, Loh M, Tan ST, Boerwinkle E, Grams ME, Sekula P, Li M, Wilmot B, Moon JG, Scheet P, Cucca F, Xiao X, Lyytikäinen LP, Delgado G, Grammer TB, Kleber ME, Sedaghat S, Rivadeneira F, Corre T, Kutalik Z, Bergmann S, Nielson CM, Srikanth P, Teumer A, Müller-Nurasyid M, Brockhaus AC, Pfeufer A, Rathmann W, Peters A, Matsumoto M, de Andrade M, Atkinson EJ, Robinson-Cohen C, de Boer IH, Hwang SJ, Heid IM, Gögele M, Concas MP, Tanaka T, Bandinelli S, Nalls MA, Singleton A, Tajuddin SM, Adeyemo A, Zhou J, Doumatey A, McWeeney S, Murabito J, Franceschini N, Flessner M, Shlipak M, Wilson JG, Chen G, Rotimi CN, Zonderman AB, Evans MK, Ferrucci L, Devuyst O, Pirastu M, Shuldiner A, Hicks AA, Pramstaller PP, Kestenbaum B, Kardia SLR, Turner ST, Study LC, Briske TE, Gieger C, Strauch K, Meisinger C, Meitinger T, Völker U, Nauck M, Völzke H, Vollenweider P, Bochud M, Waeber G, Kähönen M, Lehtimäki T, März W, Dehghan A, Franco OH, Uitterlinden AG, Hofman A, Taylor HA, Chambers JC, Kooner JS, Fox CS, Hitzemann R, Orwoll ES, Pattaro C, Schlessinger D, Köttgen A, Snieder H, Parsa A, Cohen DM
(2017) J Am Soc Nephrol 28: 2311-2321
MeSH Terms: Aged, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Osmolar Concentration, Plasma, Sodium, Sodium-Bicarbonate Symporters, Transcription Factors, Water-Electrolyte Imbalance
Show Abstract · Added September 19, 2017
Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at <5.0 × 10 Of these, rs9980 at replicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of =5.6 × 10 Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 at showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10). encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for and are expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in and expression and function in the central nervous system may affect the regulation of systemic water balance.
Copyright © 2017 by the American Society of Nephrology.
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14 MeSH Terms
Strategies for processing and quality control of Illumina genotyping arrays.
Zhao S, Jing W, Samuels DC, Sheng Q, Shyr Y, Guo Y
(2018) Brief Bioinform 19: 765-775
MeSH Terms: Algorithms, Cluster Analysis, Computational Biology, Continental Population Groups, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Male, Models, Genetic, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quality Control, Software
Show Abstract · Added April 18, 2017
Illumina genotyping arrays have powered thousands of large-scale genome-wide association studies over the past decade. Yet, because of the tremendous volume and complicated genetic assumptions of Illumina genotyping data, processing and quality control (QC) of these data remain a challenge. Thorough QC ensures the accurate identification of single-nucleotide polymorphisms and is required for the correct interpretation of genetic association results. By processing genotyping data on > 100 000 subjects from >10 major Illumina genotyping arrays, we have accumulated extensive experience in handling some of the most peculiar scenarios related to the processing and QC of Illumina genotyping data. Here, we describe strategies for processing Illumina genotyping data from the raw data to an analysis ready format, and we elaborate on the necessary QC procedures required at each processing step. High-quality Illumina genotyping data sets can be obtained by following our detailed QC strategies.
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17 MeSH Terms
Using an Implementation Research Framework to Identify Potential Facilitators and Barriers of an Intervention to Increase HPV Vaccine Uptake.
Selove R, Foster M, Mack R, Sanderson M, Hull PC
(2017) J Public Health Manag Pract 23: e1-e9
MeSH Terms: Adult, Continental Population Groups, Female, Health Knowledge, Attitudes, Practice, Health Personnel, Humans, Incidence, Male, Middle Aged, Papillomavirus Infections, Papillomavirus Vaccines, Patient Acceptance of Health Care, Qualitative Research, Tennessee, United States, Uterine Cervical Neoplasms, Vaccination
Show Abstract · Added February 21, 2017
BACKGROUND - Although the incidence of cervical cancer has been decreasing in the United States over the last decade, Hispanic and African American women have substantially higher rates than Caucasian women. The human papillomavirus (HPV) is a necessary, although insufficient, cause of cervical cancer. In the United States in 2013, only 37.6% of girls 13 to 17 years of age received the recommended 3 doses of a vaccine that is almost 100% efficacious for preventing infection with viruses that are responsible for 70% of cervical cancers. Implementation research has been underutilized in interventions for increasing vaccine uptake. The Consolidated Framework for Implementation Research (CFIR), an approach for designing effective implementation strategies, integrates 5 domains that may include barriers and facilitators of HPV vaccination. These include the innovative practice (Intervention), communities where youth and parents live (Outer Setting), agencies offering vaccination (Inner Setting), health care staff (Providers), and planned execution and evaluation of intervention delivery (Implementation Process).
METHODS - Secondary qualitative analysis of transcripts of interviews with 30 community health care providers was conducted using the CFIR to code potential barriers and facilitators of HPV vaccination implementation.
RESULTS - All CFIR domains except Implementation Process were well represented in providers' statements about challenges and supports for HPV vaccination.
CONCLUSION - A comprehensive implementation framework for promoting HPV vaccination may increase vaccination rates in ethnically diverse communities. This study suggests that the CFIR can be used to guide clinicians in planning implementation of new approaches to increasing HPV vaccine uptake in their settings. Further research is needed to determine whether identifying implementation barriers and facilitators in all 5 CFIR domains as part of developing an intervention contributes to improved HPV vaccination rates.
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17 MeSH Terms
Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Liu CT, Raghavan S, Maruthur N, Kabagambe EK, Hong J, Ng MC, Hivert MF, Lu Y, An P, Bentley AR, Drolet AM, Gaulton KJ, Guo X, Armstrong LL, Irvin MR, Li M, Lipovich L, Rybin DV, Taylor KD, Agyemang C, Palmer ND, Cade BE, Chen WM, Dauriz M, Delaney JA, Edwards TL, Evans DS, Evans MK, Lange LA, Leong A, Liu J, Liu Y, Nayak U, Patel SR, Porneala BC, Rasmussen-Torvik LJ, Snijder MB, Stallings SC, Tanaka T, Yanek LR, Zhao W, Becker DM, Bielak LF, Biggs ML, Bottinger EP, Bowden DW, Chen G, Correa A, Couper DJ, Crawford DC, Cushman M, Eicher JD, Fornage M, Franceschini N, Fu YP, Goodarzi MO, Gottesman O, Hara K, Harris TB, Jensen RA, Johnson AD, Jhun MA, Karter AJ, Keller MF, Kho AN, Kizer JR, Krauss RM, Langefeld CD, Li X, Liang J, Liu S, Lowe WL, Mosley TH, North KE, Pacheco JA, Peyser PA, Patrick AL, Rice KM, Selvin E, Sims M, Smith JA, Tajuddin SM, Vaidya D, Wren MP, Yao J, Zhu X, Ziegler JT, Zmuda JM, Zonderman AB, Zwinderman AH, AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, Adeyemo A, Boerwinkle E, Ferrucci L, Hayes MG, Kardia SL, Miljkovic I, Pankow JS, Rotimi CN, Sale MM, Wagenknecht LE, Arnett DK, Chen YD, Nalls MA, MAGIC Consortium, Province MA, Kao WH, Siscovick DS, Psaty BM, Wilson JG, Loos RJ, Dupuis J, Rich SS, Florez JC, Rotter JI, Morris AP, Meigs JB
(2016) Am J Hum Genet 99: 56-75
MeSH Terms: African Continental Ancestry Group, Asian Continental Ancestry Group, Blood Glucose, Continental Population Groups, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Ethnic Groups, European Continental Ancestry Group, Fasting, Female, Gene Frequency, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Introns, Islets of Langerhans, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Factors
Show Abstract · Added July 10, 2016
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
Copyright © 2016 American Society of Human Genetics. All rights reserved.
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Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression.
Waleh N, Barrette AM, Dagle JM, Momany A, Jin C, Hills NK, Shelton EL, Reese J, Clyman RI
(2015) J Pediatr 167: 1033-41.e2
MeSH Terms: Aorta, Continental Population Groups, DNA, Ductus Arteriosus, Ductus Arteriosus, Patent, Female, Gene Expression Regulation, Developmental, Genotype, Gestational Age, Humans, Indomethacin, Nitric Oxide Synthase Type III, Organic Anion Transporters, Oxygen, Polymerase Chain Reaction, Polymorphism, Genetic, Pregnancy, Pregnancy Trimester, Second, Regression Analysis, Signal Transduction, Time Factors
Show Abstract · Added February 21, 2016
OBJECTIVE - To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).
STUDY DESIGN - We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression.
RESULTS - Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA.
CONCLUSIONS - Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin.
Copyright © 2015 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome.
Calfee CS, Matthay MA, Kangelaris KN, Siew ED, Janz DR, Bernard GR, May AK, Jacob P, Havel C, Benowitz NL, Ware LB
(2015) Crit Care Med 43: 1790-7
MeSH Terms: APACHE, Adult, Aged, Alcoholism, Biomarkers, Continental Population Groups, Critical Illness, Diabetes Mellitus, Female, Humans, Male, Middle Aged, Nitrosamines, Prevalence, Prospective Studies, Pyridines, Respiratory Distress Syndrome, Adult, Risk Factors, Sepsis, Smoking, Tertiary Care Centers, Time Factors, Tobacco Smoke Pollution
Show Abstract · Added June 29, 2015
OBJECTIVE - The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort.
DESIGN - Prospective cohort.
SETTING - Tertiary care center.
PATIENTS - Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion)
INTERVENTIONS - : None.
MEASUREMENTS AND MAIN RESULTS - We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with nonpulmonary sepsis as the primary acute respiratory distress syndrome risk factor (n = 212), 39% of those with acute respiratory distress syndrome were current smokers by history compared with 22% of those without acute respiratory distress syndrome (odds ratio, 2.28; 95% CI, 1.24-4.19; p = 0.008). Likewise, cigarette smoke exposure as measured by urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was significantly associated with acute respiratory distress syndrome in this group. The increased risk of acute respiratory distress syndrome in nonpulmonary sepsis was restricted to patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels consistent with active smoking and was robust to adjustment for other acute respiratory distress syndrome predictors. Cigarette smoke exposure as measured by history or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was not associated with acute respiratory distress syndrome in patients with other risk factors (e.g., pneumonia and aspiration).
CONCLUSIONS - Cigarette smoking measured both by history and biomarker is associated with an increased risk of acute respiratory distress syndrome in patients with nonpulmonary sepsis. This finding has important implications for tobacco product regulation and for understanding the pathogenesis of acute respiratory distress syndrome.
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23 MeSH Terms