Publications by authors named "Arthur Ko"

40 Publications

Electrical impedance tomography for non-invasive identification of fatty liver infiltrate in overweight individuals.

Sci Rep 2021 Oct 6;11(1):19859. Epub 2021 Oct 6.

Department of Bioengineering, UCLA, Los Angeles, CA, USA.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of cardiometabolic diseases in overweight individuals. While liver biopsy is the current gold standard to diagnose NAFLD and magnetic resonance imaging (MRI) is a non-invasive alternative still under clinical trials, the former is invasive and the latter costly. We demonstrate electrical impedance tomography (EIT) as a portable method for detecting fatty infiltrate. We enrolled 19 overweight subjects to undergo liver MRI scans, followed by EIT measurements. The MRI images provided the a priori knowledge of the liver boundary conditions for EIT reconstruction, and the multi-echo MRI data quantified liver proton-density fat fraction (PDFF%) to validate fat infiltrate. Using the EIT electrode belts, we circumferentially injected pairwise current to the upper abdomen, followed by acquiring the resulting surface-voltage to reconstruct the liver conductivity. Pearson's correlation analyses compared EIT conductivity or MRI PDFF with body mass index, age, waist circumference, height, and weight variables. We reveal that the correlation between liver EIT conductivity or MRI PDFF with demographics is statistically insignificant, whereas liver EIT conductivity is inversely correlated with MRI PDFF (R = -0.69, p = 0.003, n = 16). As a pilot study, EIT conductivity provides a portable method for operator-independent and cost-effective detection of hepatic steatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-99132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494919PMC
October 2021

The gut microbiome in konzo.

Nat Commun 2021 09 10;12(1):5371. Epub 2021 Sep 10.

Center for Genetic Medicine Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA.

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25694-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433213PMC
September 2021

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes.

Genome Med 2021 Aug 2;13(1):123. Epub 2021 Aug 2.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.

Background: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.

Methods: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.

Results: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.

Conclusions: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327600PMC
August 2021

Dealing with Anxious Patients: A Systematic Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

J Altern Complement Med 2021 Sep 1;27(9):717-726. Epub 2021 Jun 1.

Orthopedic Physical Therapy Program, Walk the Line Recovery Therapy, Southfield, MI, USA.

State (situational) anxiety can create suboptimal outcomes for patients across a variety of health care specializations. While anxiolytic medications reduce anxiety, problematic side effects can compromise outcomes. These challenges have spurred searches for nonpharmaceutical approaches to alleviate patient anxiety. This systematic literature review, largely following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to determine patterns and effectiveness of interventions across medical health care specialty areas, including dentistry. A systematic review was conducted, using PubMed, CINAHL, and PsycINFO databases, with search terms related to anxiety, specific interventions, and medical or dental procedures. Hand searching for additional citations was performed on the bibliographies of dissertations, meta-analyses, and systematic reviews that met article inclusion criteria. The search process yielded 48,324 articles and 257 dissertations published in English between 1974 and 2018. Each abstract was evaluated for inclusion by two reviewers, yielding 718 articles that were read and evaluated for outcomes, risk of bias, pretest and post-test, controls and quality, using a Critical Appraisal Skills Programme instrument. Of these, 408 articles, describing 501 experimental trials, were accepted for inclusion in this analysis. A total of 50,343 patients were included in these experiments, with an overall success rate of 71% for reducing patient anxiety. Results are summarized by health care specialty area: surgery, oncology, cardiology, obstetrics/gynecology, dentistry, and pain/trauma, and the following diagnostic testing and intervention areas: imaging, colonoscopy, mechanical ventilation, and other. The largest number of experiments (114) was in the surgery category. The types of interventions included , , , , , , , , , , , , , and . The largest numbers of experiments were done with (143) and (130). The following interventions were most successful, reducing anxiety in over 70% of experiments: , , , , , , Confidence in results is limited by publication bias, small sample sizes, and the lack of placebo controls. Directions for future research are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/acm.2020.0504DOI Listing
September 2021

Dealing with Anxious Patients: An Integrative Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

J Altern Complement Med 2021 Sep 1;27(9):727-737. Epub 2021 Jun 1.

Department of Psychology, University of Detroit Mercy, Detroit, MI, USA.

A previous systematic literature review (SLR) evaluated 501 experiments on reducing patient anxiety across medical and dental environments. This integrative review examines those interventions and explores possible mechanisms leading to relative success or failure within those environments, in the interest of interprofessional education and communication. Reviewers evaluated 501 experiments testing interventions for reducing patient anxiety in a variety of medical and dental health care settings. Methodology for the SLR, largely following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, is briefly reviewed. A total of 501 experiments (from 408 articles) met review criteria. One hundred and forty-three experiments were included, and interventions were largely effective, except in the case of colonoscopy. is the only intervention that occasionally (5 times of 130 experiments) raised patient anxiety in the face of a procedure; the discussion focuses on the wisdom of assessing patient need for information. Thirty-seven experiments of various types are included, with a success rate of 89%, with a particularly high rate of success (12 of 12 experiments) in dentistry. has a success rate that is similar to that of , but has been tested in far fewer specialty areas. has been tested in every specialty area, except mechanical ventilation, with promising results. and have not been widely tested, but their effectiveness rate is 100% when it comes to reducing patient anxiety in various procedural settings. Similarly, experiments show to be successful in 90% of trials. In contrast, was successful in only 40% of the experiments summarized, although it was more effective in dentistry. A variety of were highly successful across a variety of settings. Possible mechanisms are discussed, along with commentary on feasibility. Limitations include publication bias, small sample sizes, and the lack of placebo controls. Future areas of research are pointed out.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/acm.2020.0505DOI Listing
September 2021

Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Cell Rep Med 2021 Apr 30;2(4):100226. Epub 2021 Mar 30.

Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xcrm.2021.100226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080113PMC
April 2021

Brilliant at the Basics: An Academic Practice Partnership to Build Nursing Management Expertise.

J Contin Educ Nurs 2021 Mar;52(3):136-141

This article describes the importance of building academic and practice partnerships, and the process in developing and implementing a successful leadership academy in transforming emerging nurse leaders. In addition, this article highlighted the value on the evaluation and outcomes of the educational program pertaining to positive changes in the workplace. In its initial phase, the health system conducted a needs assessment that provided vital information to enhance nursing management development skills through the initiation of a leadership training academy for nurse leaders. The vital information obtained in the needs assessment was used as a framework in working on topical outline and content objectives developed as a joint initiative between the university-based school of nursing and health professions and the health system that shared a similar mission, vision, and goals. Thus, "Brilliant at the Basics" nursing leadership academy was formed. [J Contin Educ Nurs. 2021;52(3):136-141.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/00220124-20210216-08DOI Listing
March 2021

Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.

Am J Hum Genet 2021 03 23;108(3):411-430. Epub 2021 Feb 23.

A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. Electronic address:

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008493PMC
March 2021

Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery.

J Clin Endocrinol Metab 2021 04;106(5):1312-1324

Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.

Context: Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown.

Objective: To investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies.

Methods: The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up.

Results: Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001).

Conclusions: Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063261PMC
April 2021

The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

PLoS Genet 2020 09 14;16(9):e1009018. Epub 2020 Sep 14.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515203PMC
September 2020

Publisher Correction: Accurate estimation of cell composition in bulk expression through robust integration of single-cell information.

Nat Commun 2020 06 3;11(1):2891. Epub 2020 Jun 3.

Department of Human Genetics, David Geffen School ofMedicine at UCLA, Los Angeles, CA, 90095, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16607-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270096PMC
June 2020

Accurate estimation of cell composition in bulk expression through robust integration of single-cell information.

Nat Commun 2020 04 24;11(1):1971. Epub 2020 Apr 24.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.

We present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data. These transformations significantly improve decomposition performance compared to existing methods when there is significant technical variation in the generation of the reference profile and observed bulk expression. Importantly, compared to existing methods, our approach is extremely efficient, making it suitable for the analysis of large genomic datasets that are becoming ubiquitous. When applied to subcutaneous adipose and dorsolateral prefrontal cortex expression datasets with both bulk RNA-seq and snRNA-seq data, Bisque replicates previously reported associations between cell type proportions and measured phenotypes across abundant and rare cell types. We further propose an additional mode of operation that merely requires a set of known marker genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15816-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181686PMC
April 2020

Efficient Estimation and Applications of Cross-Validated Genetic Predictions to Polygenic Risk Scores and Linear Mixed Models.

J Comput Biol 2020 04 20;27(4):599-612. Epub 2020 Feb 20.

Neurology, UCLA, Los Angeles, California.

Large-scale cohorts with combined genetic and phenotypic data, coupled with methodological advances, have produced increasingly accurate genetic predictors of complex human phenotypes called polygenic risk scores (PRSs). In addition to the potential translational impacts of identifying at-risk individuals, PRS are being utilized for a growing list of scientific applications, including causal inference, identifying pleiotropy and genetic correlation, and powerful gene-based and mixed-model association tests. Existing PRS approaches rely on external large-scale genetic cohorts that have also measured the phenotype of interest. They further require matching on ancestry and genotyping platform or imputation quality. In this work, we present a novel reference-free method to produce a PRS that does not rely on an external cohort. We show that naive implementations of reference-free PRS either result in substantial overfitting or prohibitive increases in computational time. We show that our algorithm avoids both of these issues and can produce informative in-sample PRSs over a single cohort without overfitting. We then demonstrate several novel applications of reference-free PRSs, including detection of pleiotropy across 246 metabolic traits and efficient mixed-model association testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cmb.2019.0325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185352PMC
April 2020

Colocalization of GWAS and eQTL signals at loci with multiple signals identifies additional candidate genes for body fat distribution.

Hum Mol Genet 2019 12;28(24):4161-4172

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

Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impacting the same phenotype. We previously identified eQTL in subcutaneous adipose tissue from 770 participants in the Metabolic Syndrome in Men (METSIM) study and detected 15 eQTL signals that colocalized with GWAS signals for waist-hip ratio adjusted for body mass index (WHRadjBMI) from the Genetic Investigation of Anthropometric Traits consortium. Here, we reevaluated evidence of colocalization using two approaches, conditional analysis and the Bayesian test COLOC, and show that providing COLOC with approximate conditional summary statistics at multi-signal GWAS loci can reconcile disagreements in colocalization classification between the two tests. Next, we performed conditional analysis on the METSIM subcutaneous adipose tissue data to identify conditionally distinct or secondary eQTL signals. We used the two approaches to test for colocalization with WHRadjBMI GWAS signals and evaluated the differences in colocalization classification between the two tests. Through these analyses, we identified four GWAS signals colocalized with secondary eQTL signals for FAM13A, SSR3, GRB14 and FMO1. Thus, at loci with multiple eQTL and/or GWAS signals, analyzing each signal independently enabled additional candidate genes to be identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddz263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202621PMC
December 2019

A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.

Nat Commun 2019 10 21;10(1):4788. Epub 2019 Oct 21.

Department of Computational Biology - USR 3756 CNRS, Institut Pasteur, Paris, France.

Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12703-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803661PMC
October 2019

Novel Lipid Long Intervening Noncoding RNA, Oligodendrocyte Maturation-Associated Long Intergenic Noncoding RNA, Regulates the Liver Steatosis Gene Stearoyl-Coenzyme A Desaturase As an Enhancer RNA.

Hepatol Commun 2019 Oct 14;3(10):1356-1372. Epub 2019 Aug 14.

Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA.

The global obesity epidemic is driving the concomitant rise in nonalcoholic fatty liver disease (NAFLD). To identify new genes involved in central liver functions, we examined liver RNA-sequence data from 259 patients who underwent morbidly obese bariatric surgery. Of these patients, 84 had normal liver histology, 40 simple steatosis, 43 nonalcoholic steatohepatitis, and the remaining 92 patients had varying degrees of NAFLD based on liver histology. We discovered oligodendrocyte maturation-associated long intergenic noncoding RNA () a long intervening noncoding RNA (lincRNA) in a human liver co-expression network (n = 75 genes) that was strongly associated with statin use and serum triglycerides (TGs). liver expression was highly correlated with the expression of known cholesterol biosynthesis genes and stearoyl-coenzyme A desaturase (). is the rate-limiting enzyme in monounsaturated fatty acids and a key TG gene that is known to be up-regulated in liver steatosis and NAFLD and resides adjacent to on the human chromosome 10q24.31. Next, we functionally demonstrated that regulates as an enhancer-RNA (eRNA), thus describing the first lincRNA that functions as an eRNA to regulate lipid metabolism. Specifically, we show that promotes liver expression of in through regional chromosomal DNA-DNA looping interactions. The primate-specific lincRNA is a novel epigenetic regulator of the key TG and NAFLD gene .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771395PMC
October 2019

Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits.

Am J Hum Genet 2019 10 26;105(4):773-787. Epub 2019 Sep 26.

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817527PMC
October 2019

Reverse gene-environment interaction approach to identify variants influencing body-mass index in humans.

Nat Metab 2019 06 14;1(6):630-642. Epub 2019 Jun 14.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, 90095.

Identifying gene-environment interactions (GxEs) contributing to human cardiometabolic disorders is challenging. Here we apply a reverse GxE candidate search by deriving candidate variants from promoter-enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in human primary adipocytes. We then test all variants residing in the lipid-responsive open chromatin sites within adipocyte promoter-enhancer contacts for interaction effects between the genotype and dietary saturated fat intake on body mass index (BMI) in the UK Biobank. We discover 14 novel GxE variants in 12 lipid-responsive promoters, including well-known lipid genes (, and ) and novel genes, such as , for which we provide further functional and integrative genomics evidence. We further identify 24 GxE variants in enhancers, totaling 38 new GxE variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can discover new functional GxE mechanisms in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-019-0071-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752726PMC
June 2019

Reverse GWAS: Using genetics to identify and model phenotypic subtypes.

PLoS Genet 2019 04 5;15(4):e1008009. Epub 2019 Apr 5.

Department of Medicine, UCSF, San Francisco, California, United States of America.

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469799PMC
April 2019

Genetic and environmental perturbations lead to regulatory decoherence.

Elife 2019 03 5;8. Epub 2019 Mar 5.

Department of Ecology and Evolution, Princeton University, Princeton, United States.

Correlation among traits is a fundamental feature of biological systems that remains difficult to study. To address this problem, we developed a flexible approach that allows us to identify factors associated with inter-individual variation in correlation. We use data from three human cohorts to study the effects of genetic and environmental variation on correlations among mRNA transcripts and among NMR metabolites. We first show that environmental exposures (infection and disease) lead to a systematic loss of correlation, which we define as 'decoherence'. Using longitudinal data, we show that decoherent metabolites are better predictors of whether someone will develop metabolic syndrome than metabolites commonly used as biomarkers of this disease. Finally, we demonstrate that correlation itself is under genetic control by mapping hundreds of 'correlation quantitative trait loci (QTLs)'. Together, this work furthers our understanding of how and why coordinated biological processes break down, and points to a potential role for decoherence in disease.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.40538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400502PMC
March 2019

Home Healthcare Nurses' Attitudes, Confidence, and Engagement in Evidence-Based Practice.

Home Healthc Now 2019 Mar/Apr;37(2):79-87

Linda M. Thiel, OP, PhD, RN, is an Associate Professor, McAuley School of Nursing, University of Detroit Mercy, Grand Rapids, Michigan. Arthur Ko, PhD, is Faculty, Graduate School, College of Health Professions, University of Detroit Mercy, Detroit, Michigan. Jill A. Turner, BSN, MLIS, is an Associate Librarian, University of Detroit Mercy, Detroit, Michigan.

Evidence-based practice (EBP) is becoming standard in today's healthcare arena and home care organizations are not exempt from integrating evidence into practice to improve patient outcomes. There is a scarcity of research literature that examines the behaviors and attitudes of home healthcare nurses (HHNs) regarding EBP. In this study, a descriptive survey design was used to investigate HHNs' a) information-seeking behaviors when providing nursing care, b) administrative support for EBP (as perceived by HHNs), c) attitudes toward EBP, and d) EBP engagement and confidence in providing EBP nursing care. Self-reported data were collected by internet and paper survey. The survey consisted of a 65-item questionnaire that included the Nurses' Attitudes Toward Evidence-Based Practice Scale, which has previously established validity and reliability. A convenience sample of 95 HHNs participated in the study. Results suggest HHNs' EBP attitudes are positive. A positive and significant relationship was found between attitudes and hours worked (r = 0.21, p = 0.047) and educational level (r = 0.45, p = 0.0001); 95% confidence level. Confidence levels in providing EBP care were moderate, and HHNs did not perceive EBP as an agency priority. HHNs need to be supported and encouraged in the facilitation of EBP, a task made easier when they are knowledgeable about EBP, have confidence in their EBP skills, and have the support of their organizations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NHH.0000000000000723DOI Listing
June 2019

Advanced nursing practice roles: Closing the knowledge gap.

Nurs Manage 2019 03;50(3):26-36

In Detroit, Mich., Arthur Ko is graduate school faculty in the College of Health Professions and Rosanne Burson is an associate professor in the College of Health Professions and McAuley School of Nursing at University of Detroit Mercy; Therese Mianecki is a nurse researcher at Henry Ford Hospital.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.NUMA.0000553494.24977.2dDOI Listing
March 2019

Author Correction: Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

Nat Commun 2018 08 22;9(1):3472. Epub 2018 Aug 22.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05849-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105720PMC
August 2018

Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

Nat Commun 2018 04 17;9(1):1512. Epub 2018 Apr 17.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-03554-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904163PMC
April 2018

Online Resources to Support Clinical Practice.

Home Healthc Now 2018 Mar/Apr;36(2):114-122

Arthur Ko, PhD, is a Faculty, Graduate School, College of Health Professions, University of Detroit Mercy, Detroit, Michigan. Jill Turner, BSN, MLIS, is an Associate Librarian, University of Detroit Mercy, Detroit, Michigan.

Evidence-based practice requires access to practice guidelines, research articles, and other resources; however, home healthcare clinicians can face barriers when seeking health information. The purpose of this article is to provide home care clinicians with: a) free resources available on the internet, b) suggestions for searching and evaluating health information found on the internet, and c) opportunities for free continuing education for home healthcare clinicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NHH.0000000000000646DOI Listing
September 2018

ASElux: an ultra-fast and accurate allelic reads counter.

Bioinformatics 2018 04;34(8):1313-1320

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA.

Motivation: Mapping bias causes preferential alignment to the reference allele, forming a major obstacle in allele-specific expression (ASE) analysis. The existing methods, such as simulation and SNP-aware alignment, are either inaccurate or relatively slow. To fast and accurately count allelic reads for ASE analysis, we developed a novel approach, ASElux, which utilizes the personal SNP information and counts allelic reads directly from unmapped RNA-sequence (RNA-seq) data. ASElux significantly reduces runtime by disregarding reads outside single nucleotide polymorphisms (SNPs) during the alignment.

Results: When compared to other tools on simulated and experimental data, ASElux achieves a higher accuracy on ASE estimation than non-SNP-aware aligners and requires a much shorter time than the benchmark SNP-aware aligner, GSNAP with just a slight loss in performance. ASElux can process 40 million read-pairs from an RNA-sequence (RNA-seq) sample and count allelic reads within 10 min, which is comparable to directly counting the allelic reads from alignments based on other tools. Furthermore, processing an RNA-seq sample using ASElux in conjunction with a general aligner, such as STAR, is more accurate and still ∼4× faster than STAR + WASP, and ∼33× faster than the lead SNP-aware aligner, GSNAP, making ASElux ideal for ASE analysis of large-scale transcriptomic studies. We applied ASElux to 273 lung RNA-seq samples from GTEx and identified a splice-QTL rs11078928 in lung which explains the mechanism underlying an asthma GWAS SNP rs11078927. Thus, our analysis demonstrated ASE as a highly powerful complementary tool to cis-expression quantitative trait locus (eQTL) analysis.

Availability And Implementation: The software can be downloaded from https://github.com/abl0719/ASElux.

Contact: [email protected] or [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btx762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905663PMC
April 2018

Culturally Sensitive Care for Asian Immigrants: Home Healthcare Perspectives.

Home Healthc Now 2017 Oct;35(9):507-513

Arthur Ko, PhD, is Faculty, Graduate School, University of Detroit Mercy, Detroit, Michigan. Jill Turner, BSN, MLIS, is an Associate Librarian, University of Detroit Mercy, Detroit, Michigan.

The number of Asian immigrants has risen dramatically in recent decades, making them the fastest growing immigrant group in the United States. Home healthcare clinicians are expected to meet the healthcare needs of patients regardless of their ethnic or cultural background, but this can be challenging without a basic understanding of the patient's culture. This article is intended to provide information about the cultural traditions and health conditions clinicians may encounter when caring for patients and families who have immigrated to the United States from the top five Asian countries as determined by the U.S. Census, and concludes with resources that home healthcare clinicians can utilize when engaging in patient education.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NHH.0000000000000608DOI Listing
October 2017

Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family.

Atherosclerosis 2017 Sep 22;264:58-66. Epub 2017 Jul 22.

Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Molecular Biology Institute at UCLA, Los Angeles, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA. Electronic address:

Background And Aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH).

Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)).

Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220.

Conclusions: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2017.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698088PMC
September 2017

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits.

Am J Hum Genet 2017 Mar;100(3):428-443

Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339333PMC
March 2017
-->