Publications by authors named "Gerard Tromp"

151 Publications

A multi-phenotype genome-wide association study of clades causing tuberculosis in a Ghanaian- and South African cohort.

Genomics 2021 Apr 20;113(4):1802-1815. Epub 2021 Apr 20.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Despite decades of research and advancements in diagnostics and treatment, tuberculosis remains a major public health concern. New computational methods are needed to interrogate the intersection of host- and bacterial genomes. Paired host genotype datum and infecting bacterial isolate information were analysed for associations using a multinomial logistic regression framework implemented in SNPTest. A cohort of 853 admixed South African participants and a Ghanaian cohort of 1359 participants were included. Two directly genotyped variants, namely rs529920 and rs41472447, were identified in the Ghanaian cohort as being statistically significantly associated with risk for infection with strains of different members of the MTBC. Thus, a multinomial logistic regression using paired host-pathogen data may prove valuable for investigating the complex relationships driving infectious disease.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.024DOI Listing
April 2021

Editorial: FDA-Approved Drug Repositioning for P-Glycoprotein Overexpressing Resistant Cancer.

Front Oncol 2021 17;11:632657. Epub 2021 Mar 17.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Tygerberg, South Africa.

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http://dx.doi.org/10.3389/fonc.2021.632657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018233PMC
March 2021

Inflammatory Determinants of Differential Tuberculosis Risk in Pre-Adolescent Children and Young Adults.

Front Immunol 2021 25;12:639965. Epub 2021 Feb 25.

South African Tuberculosis Vaccine Initiative (SATVI), Department of Pathology, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, University of Cape Town, Cape Town, South Africa.

The risk of progression from ( infection to active tuberculosis (TB) disease varies markedly with age. TB disease is significantly less likely in pre-adolescent children above 4 years of age than in very young children or post-pubescent adolescents and young adults. We hypothesized that pro-inflammatory responses to in pre-adolescent children are either less pronounced or more regulated, than in young adults. Inflammatory and antimicrobial mediators, measured by microfluidic RT-qPCR and protein bead arrays, or by analyzing published microarray data from TB patients and controls, were compared in pre-adolescent children and adults. Multivariate analysis revealed that -uninfected 8-year-old children had lower levels of myeloid-associated pro-inflammatory mediators than uninfected 18-year-old young adults. Relative to uninfected children, those with -infection had higher levels of similar myeloid inflammatory responses. These inflammatory mediators were also expressed after stimulation of whole blood from uninfected children with live . Our findings suggest that myeloid inflammation is intrinsically lower in pre-pubescent children than in young adults. The lower or more regulated pro-inflammatory responses may play a role in the lower risk of TB disease in this age group.
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http://dx.doi.org/10.3389/fimmu.2021.639965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947716PMC
February 2021

The Peripheral Blood Transcriptome Is Correlated With PET Measures of Lung Inflammation During Successful Tuberculosis Treatment.

Front Immunol 2020 10;11:596173. Epub 2021 Feb 10.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.
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http://dx.doi.org/10.3389/fimmu.2020.596173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902901PMC
February 2021

Higher SARS-CoV-2 seroprevalence in workers with lower socioeconomic status in Cape Town, South Africa.

PLoS One 2021 25;16(2):e0247852. Epub 2021 Feb 25.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Department of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: Inequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known.

Methods: We tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population.

Results: Of the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls.

Conclusions: There is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247852PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906413PMC
March 2021

Distinct host-immune response toward species related intracellular mycobacterial killing: A transcriptomic study.

Virulence 2020 12;11(1):170-182

NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

The comparison of the host immune response when challenged with pathogenic and nonpathogenic species of mycobacteria can provide answers to the unresolved question of how pathogens subvert or inhibit an effective response. We infected human monocyte derived macrophages (hMDMs) with different species of mycobacteria, in increasing order of pathogenicity, i.e. BCG, and R179 that had been cultured in the absence of detergents. RNA was isolated post-infection and transcriptomic analysis using amplicons (Ampliseq) revealed 274 differentially expressed genes (DEGs) across three species, out of which we selected 19 DEGs for further validation. We used qRT-PCR to confirm the differential expression of 19 DEGs. We studied biological network through Ingenuity Pathway Analysis® (IPA) which revealed up-regulated pathways of the interferon and interleukin family related to the killing of . Apart from interferon and interleukin family, we found one up-regulated ( and two down-regulated ( and ) genes as unique potential targets found by Ampliseq and qRT-PCR which may be involved in the intracellular mycobacterial killing. The roles of these genes have not previously been described in tuberculosis. Multiplex ELISA of culture supernatants showed increased host immune response toward as compared to BCG and R179. These results enhance our understanding of host immune response against infection.
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http://dx.doi.org/10.1080/21505594.2020.1726561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051142PMC
December 2020

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response.

EJNMMI Res 2020 Feb 10;10(1). Epub 2020 Feb 10.

Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes.

Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions.

Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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http://dx.doi.org/10.1186/s13550-020-0591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010890PMC
February 2020

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson's disease in Black South African and Nigerian patients.

BMC Med Genet 2020 02 4;21(1):23. Epub 2020 Feb 4.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.

Background: The prevalence of Parkinson's disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients.

Methods: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2's protein structure was investigated by molecular modelling.

Results: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein.

Conclusions: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.
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http://dx.doi.org/10.1186/s12881-020-0953-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001245PMC
February 2020

Distinct serum biosignatures are associated with different tuberculosis treatment outcomes.

Tuberculosis (Edinb) 2019 09 12;118:101859. Epub 2019 Aug 12.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-β, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts.
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http://dx.doi.org/10.1016/j.tube.2019.101859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839616PMC
September 2019

Systematic Review of Genetic Factors in the Etiology of Esophageal Squamous Cell Carcinoma in African Populations.

Front Genet 2019 2;10:642. Epub 2019 Aug 2.

African Cancer Institute, Division of Health Systems and Public Health, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most divergence in cancer incidence globally, with high prevalence reported in East Asia, Southern Europe, and in East and Southern Africa. Its etiology is multifactorial, with lifestyle, environmental, and genetic risk factors. Very little is known about the role of genetic factors in ESCC development and progression among African populations. The study aimed to systematically assess the evidence on genetic variants associated with ESCC in African populations. We carried out a comprehensive search of all African published studies up to April 2019, using PubMed, Embase, Scopus, and African Index Medicus databases. Quality assessment and data extraction were carried out by two investigators. The strength of the associations was measured by odds ratios and 95% confidence intervals. Twenty-three genetic studies on ESCC in African populations were included in the systematic review. They were carried out on Black and admixed South African populations, as well as on Malawian, Sudanese, and Kenyan populations. Most studies were candidate gene studies and included DNA sequence variants in 58 different genes. Only one study carried out whole-exome sequencing of 59 ESCC patients. Sample sizes varied from 18 to 880 cases and 88 to 939 controls. Altogether, over 100 variants in 37 genes were part of 17 case-control genetic association studies to identify susceptibility loci for ESCC. In these studies, 25 variants in 20 genes were reported to have a statistically significant association. In addition, eight studies investigated changes in cancer tissues and identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. Two genes were assessed for both genetic association and somatic mutation. Comprehensive large-scale studies on the genetic basis of ESCC are still lacking in Africa. Sample sizes in existing studies are too small to draw definitive conclusions about ESCC etiology. Only a small number of African populations have been analyzed, and replication and validation studies are missing. The genetic etiology of ESCC in Africa is, therefore, still poorly defined.
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http://dx.doi.org/10.3389/fgene.2019.00642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687768PMC
August 2019

Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy.

Front Microbiol 2019 26;10:1441. Epub 2019 Jun 26.

South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology and Department of Pathology, University of Cape Town, Cape Town, South Africa.

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58-0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.
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http://dx.doi.org/10.3389/fmicb.2019.01441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608601PMC
June 2019

A -Ethnic Genome-Wide Association Study of Uterine Fibroids.

Front Genet 2019 12;10:511. Epub 2019 Jun 12.

Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, United States.

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS ( < 1 × 10) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; = 4.7 × 10), chromosome 16q12.1 (sentinel-SNP rs4785384; = 1.5 × 10) and chromosome 20q13.1 (sentinel-SNP rs6094982; = 2.6 × 10). Our statistically significant findings further support previously reported loci including SNPs near , and /. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the / locus ( = 1.76 × 10). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including in vagina ( = 4.6 × 10), in esophageal mucosa ( = 8.7 × 10), in multiple tissues including subcutaneous adipose tissue ( = 3.3 × 10), and in skeletal muscle tissue ( = 5.8 × 10) were associated with fibroids. The finding for was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.
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http://dx.doi.org/10.3389/fgene.2019.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582231PMC
June 2019

Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases.

Gene 2019 Jul 7;707:151-171. Epub 2019 May 7.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa; Bioinformatics Unit, South African Tuberculosis Bioinformatics Initiative, Stellenbosch University, Cape Town, South Africa; DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa; Centre for Bioinformatics and Computational Biology, Stellenbosch University, Stellenbosch, South Africa.

Collagen alpha-1(III) chain, also known as the alpha 1 chain of type III collagen, is a protein that in humans is encoded by the COL3A1 gene. Three alpha 1 chains are required to form the type III collagen molecule which has a long triple-helical domain. Type III collagen, an extracellular matrix protein, is synthesized by cells as a pre-procollagen. It is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. Other functions of type III collagen include interaction with platelets in the blood clotting cascade and it is also an important signaling molecule in wound healing. Mutations in the COL3A1 gene cause the vascular type of Ehlers-Danlos syndrome (vEDS; OMIM 130050). It is the most serious form of EDS, since patients often die suddenly due to a rupture of large arteries. Inactivation of the murine Col3a1 gene leads to a shorter life span in homozygous mutant mice. The mice die prematurely from a rupture of major arteries mimicking the human vEDS phenotype. The biochemical and cellular effects of COL3A1 mutations have been studied extensively. Most of the glycine mutations lead to the synthesis of type III collagen with reduced thermal stability, which is more susceptible for proteinases. Intracellular accumulation of this normally secreted protein is also found. Ultrastructural analyses have demonstrated dilated rough endoplasmic reticulum and changes in the diameter of collagen fibers. Other clinical conditions associated with type III collagen are several types of fibroses in which increased amounts of type III collagen accumulate in the target organs.
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http://dx.doi.org/10.1016/j.gene.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579750PMC
July 2019

Immunometabolic Signatures Predict Risk of Progression to Active Tuberculosis and Disease Outcome.

Front Immunol 2019 22;10:527. Epub 2019 Mar 22.

Center for Infectious Disease Research, Seattle, WA, United States.

There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcriptional profiling with serum metabolomic profiling can provide new understanding of disease processes and enable improved prediction of TB progression. Compared to either alone, the combined application of pre-existing transcriptome- and metabolome-based signatures more accurately predicted TB progression in the HHC cohorts and more accurately predicted disease severity in the NHPs. Pathway and data-driven correlation analyses of the integrated transcriptional and metabolomic datasets further identified novel immunometabolomic signatures significantly associated with TB progression in HHCs and NHPs, implicating cortisol, tryptophan, glutathione, and tRNA acylation networks. These results demonstrate the power of multi-omics analysis to provide new insights into complex disease processes.
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http://dx.doi.org/10.3389/fimmu.2019.00527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440524PMC
August 2020

Evaluating the Accuracy of Imputation Methods in a Five-Way Admixed Population.

Front Genet 2019 5;10:34. Epub 2019 Feb 5.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Genotype imputation is a powerful tool for increasing statistical power in an association analysis. Meta-analysis of multiple study datasets also requires a substantial overlap of SNPs for a successful association analysis, which can be achieved by imputation. Quality of imputed datasets is largely dependent on the software used, as well as the reference populations chosen. The accuracy of imputation of available reference populations has not been tested for the five-way admixed South African Colored (SAC) population. In this study, imputation results obtained using three freely-accessible methods were evaluated for accuracy and quality. We show that the African Genome Resource is the best reference panel for imputation of missing genotypes in samples from the SAC population, implemented via the freely accessible Sanger Imputation Server.
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http://dx.doi.org/10.3389/fgene.2019.00034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370942PMC
February 2019

A Sex-Stratified Genome-Wide Association Study of Tuberculosis Using a Multi-Ethnic Genotyping Array.

Front Genet 2018 18;9:678. Epub 2019 Jan 18.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Tuberculosis (TB), caused by , is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males than in females. While socio-economic status, behavior and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. A total of 810 individuals (410 cases and 405 controls) from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome (8,27,386 variants) and X chromosome (20,939 variants) in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.
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http://dx.doi.org/10.3389/fgene.2018.00678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346682PMC
January 2019

The X chromosome and sex-specific effects in infectious disease susceptibility.

Hum Genomics 2019 01 8;13(1). Epub 2019 Jan 8.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.
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http://dx.doi.org/10.1186/s40246-018-0185-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325731PMC
January 2019

Viruses as indicators of contemporary host dispersal and phylogeography: an example of feline immunodeficiency virus (FIV ) in free-ranging African lion (Panthera leo).

J Evol Biol 2018 10 25;31(10):1529-1543. Epub 2018 Jul 25.

Evolutionary Genomics Group, Department of Botany and Zoology, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.

Measuring contemporary dispersal in highly mobile terrestrial species is challenging, especially when species are characterized by low levels of population differentiation. Directly transmitted viruses can be used as a surrogate for traditional methods of tracking host movement. Feline immunodeficiency virus (FIV) is a species-specific lentivirus, which has an exceptionally high mutation rate and circulates naturally in wild felids. Using samples derived from 35 lion (Panthera leo) prides, we tested the prediction that FIV in lions (FIV ) can be used to track the dispersal of individuals between prides. As FIV subtypes are geographically structured throughout Africa, we predicted that this marker could be used to detect phylogeographic structure of lions at smaller spatial scales. Phylogenetic analyses of FIV pol-RT sequences showed that core pride members (females and subadults) shared evolutionary close viral lineages which differed from neighbouring core prides, whereas sequences from sexually mature males associated with the same pride were always the most divergent. In six instances, natal pride associations of divergent male lions could be inferred, on the assumption that FIV infections are acquired during early life stages. Congruence between the genetic pattern of FIV and pride structure suggests that vertical transmission plays an important role in lion FIV dynamics. At a fine spatial scale, significant viral geographic structuring was also detected between lions occurring north of the Olifants River within the Kruger National Park (KNP) and those occupying the southern and central regions. This pattern was further supported by phylogenetic analyses and the confinement of FIV subtype E to the northern region of KNP. The study provides new insights into the use of retroviral sequences to predict host dispersal and fine-scale contemporary geographic structure in a social felid species.
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http://dx.doi.org/10.1111/jeb.13348DOI Listing
October 2018

Appetitive and reactive aggression are differentially associated with the STin2 genetic variant in the serotonin transporter gene.

Sci Rep 2018 04 30;8(1):6714. Epub 2018 Apr 30.

Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 × 10). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression.
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http://dx.doi.org/10.1038/s41598-018-25066-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928100PMC
April 2018

A Serum Circulating miRNA Signature for Short-Term Risk of Progression to Active Tuberculosis Among Household Contacts.

Front Immunol 2018 13;9:661. Epub 2018 Apr 13.

DST/NRF Centre of Excellence for Biomedical TB Research and MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Biomarkers that predict who among recently (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk.
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http://dx.doi.org/10.3389/fimmu.2018.00661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908968PMC
June 2019

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

Am J Respir Crit Care Med 2018 May;197(9):1198-1208

South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and.

Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with and progression to disease. We investigated biosignatures with predictive ability for incident TB. In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. meta-analysis identified a single gene pair, / (complement C1q C-chain / T-cell receptor-α variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.
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http://dx.doi.org/10.1164/rccm.201711-2340OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019933PMC
May 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

JAMA Cardiol 2018 01;3(1):26-33

Department of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, England.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.

Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.

Design, Setting, And Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.

Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).

Main Outcomes And Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.

Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28).

Conclusions And Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
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http://dx.doi.org/10.1001/jamacardio.2017.4293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833524PMC
January 2018

Host blood RNA signatures predict the outcome of tuberculosis treatment.

Tuberculosis (Edinb) 2017 12 12;107:48-58. Epub 2017 Aug 12.

The Center for Infectious Disease Research, Seattle, WA, USA. Electronic address:

Biomarkers for tuberculosis treatment outcome will assist in guiding individualized treatment and evaluation of new therapies. To identify candidate biomarkers, RNA sequencing of whole blood from a well-characterized TB treatment cohort was performed. Application of a validated transcriptional correlate of risk for TB revealed symmetry in host gene expression during progression from latent TB infection to active TB disease and resolution of disease during treatment, including return to control levels after drug therapy. The symmetry was also seen in a TB disease signature, constructed from the TB treatment cohort, that also functioned as a strong correlate of risk. Both signatures identified patients at risk of treatment failure 1-4 weeks after start of therapy. Further mining of the transcriptomes revealed an association between treatment failure and suppressed expression of mitochondrial genes before treatment initiation, leading to development of a novel baseline (pre-treatment) signature of treatment failure. These novel host responses to TB treatment were integrated into a five-gene real-time PCR-based signature that captures the clinically relevant responses to TB treatment and provides a convenient platform for stratifying patients according to their risk of treatment failure. Furthermore, this 5-gene signature is shown to correlate with the pulmonary inflammatory state (as measured by PET-CT) and can complement sputum-based Gene Xpert for patient stratification, providing a rapid and accurate alternative to current methods.
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http://dx.doi.org/10.1016/j.tube.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658513PMC
December 2017

Prototype Development: Context-Driven Dynamic XML Ophthalmologic Data Capture Application.

JMIR Med Inform 2017 Sep 13;5(3):e27. Epub 2017 Sep 13.

Marshfield Clinic Research Foundation, Human Genetics, Marshfield, WI, United States.

Background: The capture and integration of structured ophthalmologic data into electronic health records (EHRs) has historically been a challenge. However, the importance of this activity for patient care and research is critical.

Objective: The purpose of this study was to develop a prototype of a context-driven dynamic extensible markup language (XML) ophthalmologic data capture application for research and clinical care that could be easily integrated into an EHR system.

Methods: Stakeholders in the medical, research, and informatics fields were interviewed and surveyed to determine data and system requirements for ophthalmologic data capture. On the basis of these requirements, an ophthalmology data capture application was developed to collect and store discrete data elements with important graphical information.

Results: The context-driven data entry application supports several features, including ink-over drawing capability for documenting eye abnormalities, context-based Web controls that guide data entry based on preestablished dependencies, and an adaptable database or XML schema that stores Web form specifications and allows for immediate changes in form layout or content. The application utilizes Web services to enable data integration with a variety of EHRs for retrieval and storage of patient data.

Conclusions: This paper describes the development process used to create a context-driven dynamic XML data capture application for optometry and ophthalmology. The list of ophthalmologic data elements identified as important for care and research can be used as a baseline list for future ophthalmologic data collection activities.
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http://dx.doi.org/10.2196/medinform.7465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617903PMC
September 2017

Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.

BioData Min 2017 24;10:25. Epub 2017 Jul 24.

Department of Population Health Sciences, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI USA.

Background: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

Results: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts ( = 12,853 to  = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of  < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of  < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

Conclusions: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
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http://dx.doi.org/10.1186/s13040-017-0145-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525436PMC
July 2017