Publications by authors named "Kenneth B Beckman"

39 Publications

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

Commun Biol 2021 May 3;4(1):519. Epub 2021 May 3.

Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore, Singapore.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-6.94×10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR = 1.544 (1.173, 2.032), P = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR = 1.123 (1.051, 1.201), P = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.
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http://dx.doi.org/10.1038/s42003-021-02056-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093266PMC
May 2021

Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants.

J Gerontol A Biol Sci Med Sci 2021 Mar 4. Epub 2021 Mar 4.

Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.

Background: Age and disease prevalence are the two biggest risk factors for COVID-19 symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.

Methods: Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of two COVID-19 severity outcomes (inpatient test positivity and COVID-19 related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and pre-existing diseases/conditions.

Results: 613 participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19 related mortality (ORMortality=1.63 per 5 years, 95% CI: 1.43-1.86, p=4.7×10 -13) adjusting for demographics including age at the pandemic. Further adjustment for pre-existing disease s/conditions at baseline (ORM=1.50, 95% CI: 1.30-1.73 per 5 years, p=3.1×10 -8) and at the early pandemic (ORM=1.21, 95% CI: 1.04-1.40 per 5 years, p=0.011) decreased the association.

Conclusions: PhenoAge measured in 2006-2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.
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http://dx.doi.org/10.1093/gerona/glab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989601PMC
March 2021

Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.

Int J Cancer 2021 Jan 5;148(2):352-362. Epub 2020 Aug 5.

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (P < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.
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http://dx.doi.org/10.1002/ijc.33211DOI Listing
January 2021

A rapid, cost-effective tailed amplicon method for sequencing SARS-CoV-2.

BMC Genomics 2020 Dec 4;21(1):863. Epub 2020 Dec 4.

University of Minnesota Genomics Center, Minneapolis, MN, 55455, USA.

Background: The global COVID-19 pandemic has led to an urgent need for scalable methods for clinical diagnostics and viral tracking. Next generation sequencing technologies have enabled large-scale genomic surveillance of SARS-CoV-2 as thousands of isolates are being sequenced around the world and deposited in public data repositories. A number of methods using both short- and long-read technologies are currently being applied for SARS-CoV-2 sequencing, including amplicon approaches, metagenomic methods, and sequence capture or enrichment methods. Given the small genome size, the ability to sequence SARS-CoV-2 at scale is limited by the cost and labor associated with making sequencing libraries.

Results: Here we describe a low-cost, streamlined, all amplicon-based method for sequencing SARS-CoV-2, which bypasses costly and time-consuming library preparation steps. We benchmark this tailed amplicon method against both the ARTIC amplicon protocol and sequence capture approaches and show that an optimized tailed amplicon approach achieves comparable amplicon balance, coverage metrics, and variant calls to the ARTIC v3 approach.

Conclusions: The tailed amplicon method we describe represents a cost-effective and highly scalable method for SARS-CoV-2 sequencing.
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http://dx.doi.org/10.1186/s12864-020-07283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716288PMC
December 2020

Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma.

Bone 2020 Oct 27:115716. Epub 2020 Oct 27.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul 55108, USA; Institute of Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, UDS Institute for Engineering in Medicine, Minneapolis, MN 55455, USA.

Osteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor protein p53 (TP53) is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples. SIGNIFICANCE: Genome wide comparison of DNA methylation patterns in osteosarcoma across two species lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of varied mutational landscapes.
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http://dx.doi.org/10.1016/j.bone.2020.115716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076342PMC
October 2020

COVID-19 severity is predicted by earlier evidence of accelerated aging.

medRxiv 2020 Jul 11. Epub 2020 Jul 11.

With no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020). Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2x10-6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.
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http://dx.doi.org/10.1101/2020.07.10.20147777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359549PMC
July 2020

Association between mitochondrial genetic variation and breast cancer risk: The Multiethnic Cohort.

PLoS One 2019 2;14(10):e0222284. Epub 2019 Oct 2.

Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America.

Background: The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species.

Methods: To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study.

Results: We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk.

Conclusions: In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774509PMC
March 2020

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Nat Commun 2019 06 6;10(1):2491. Epub 2019 Jun 6.

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.
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http://dx.doi.org/10.1038/s41467-019-10443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554354PMC
June 2019

Measuring sequencer size bias using REcount: a novel method for highly accurate Illumina sequencing-based quantification.

Genome Biol 2019 04 29;20(1):85. Epub 2019 Apr 29.

University of Minnesota Genomics Center, Minneapolis, MN, 55455, USA.

Quantification of DNA sequence tags from engineered constructs such as plasmids, transposons, or other transgenes underlies many functional genomics measurements. Typically, such measurements rely on PCR followed by next-generation sequencing. However, PCR amplification can introduce significant quantitative error. We describe REcount, a novel PCR-free direct counting method. Comparing measurements of defined plasmid pools to droplet digital PCR data demonstrates that REcount is highly accurate and reproducible. We use REcount to provide new insights into clustering biases due to molecule length across different Illumina sequencers and illustrate the impacts on interpretation of next-generation sequencing data and the economics of data generation.
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http://dx.doi.org/10.1186/s13059-019-1691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489363PMC
April 2019

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 07;200(2):199-208

7 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. We performed deep targeted resequencing (3.69 Mb of DNA) in cases ( = 3,624) and control subjects ( = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and ) individual common variants via logistic regression and ) groups of rare variants via sequence kernel association tests. Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele ( = 9.60 × 10). In addition to identifying for the first time that rare variation in is associated with disease, we confirmed the role of rare variation in the and gene regions in the risk of IPF, and found that the and regions have independent common and rare variant signals. A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
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http://dx.doi.org/10.1164/rccm.201810-1891OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635791PMC
July 2019

Evaluating the Information Content of Shallow Shotgun Metagenomics.

mSystems 2018 Nov-Dec;3(6). Epub 2018 Nov 13.

Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, USA.

Although microbial communities are associated with human, environmental, plant, and animal health, there exists no cost-effective method for precisely characterizing species and genes in such communities. While deep whole-metagenome shotgun (WMS) sequencing provides high taxonomic and functional resolution, it is often prohibitively expensive for large-scale studies. The prevailing alternative, 16S rRNA gene amplicon (16S) sequencing, often does not resolve taxonomy past the genus level and provides only moderately accurate predictions of the functional profile; thus, there is currently no widely accepted approach to affordable, high-resolution, taxonomic, and functional microbiome analysis. To address this technology gap, we evaluated the information content of shallow shotgun sequencing with as low as 0.5 million sequences per sample as an alternative to 16S sequencing for large human microbiome studies. We describe a library preparation protocol enabling shallow shotgun sequencing at approximately the same per-sample cost as 16S sequencing. We analyzed multiple real and simulated biological data sets, including two novel human stool samples with ultradeep sequencing of 2.5 billion sequences per sample, and found that shallow shotgun sequencing recovers more-accurate species-level taxonomic and functional profiles of the human microbiome than 16S sequencing. We discuss the inherent limitations of shallow shotgun sequencing and note that 16S sequencing remains a valuable and important method for taxonomic profiling of novel environments. Although deep WMS sequencing remains the gold standard for high-resolution microbiome analysis, we recommend that researchers consider shallow shotgun sequencing as a useful alternative to 16S sequencing for large-scale human microbiome research studies where WMS sequencing may be cost-prohibitive. A common refrain in recent microbiome-related academic meetings is that the field needs to move away from broad taxonomic surveys using 16S sequencing and toward more powerful longitudinal studies using shotgun sequencing. However, performing deep shotgun sequencing in large longitudinal studies remains prohibitively expensive for all but the most well-funded research labs and consortia, which leads many researchers to choose 16S sequencing for large studies, followed by deep shotgun sequencing on a subset of targeted samples. Here, we show that shallow- or moderate-depth shotgun sequencing may be used by researchers to obtain species-level taxonomic and functional data at approximately the same cost as amplicon sequencing. While shallow shotgun sequencing is not intended to replace deep shotgun sequencing for strain-level characterization, we recommend that microbiome scientists consider using shallow shotgun sequencing instead of 16S sequencing for large-scale human microbiome studies.
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http://dx.doi.org/10.1128/mSystems.00069-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234283PMC
November 2018

Comprehensive Functional Analysis of the Enterococcus faecalis Core Genome Using an Ordered, Sequence-Defined Collection of Insertional Mutations in Strain OG1RF.

mSystems 2018 Sep-Oct;3(5). Epub 2018 Sep 11.

Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

Enterococcus faecalis is a common commensal bacterium in animal gastrointestinal (GI) tracts and a leading cause of opportunistic infections of humans in the modern health care setting. E. faecalis OG1RF is a plasmid-free strain that contains few mobile elements yet retains the robust survival characteristics, intrinsic antibiotic resistance, and virulence traits characteristic of most E. faecalis genotypes. To facilitate interrogation of the core enterococcal genetic determinants for competitive fitness in the GI tract, biofilm formation, intrinsic antimicrobial resistance, and survival in the environment, we generated an arrayed, sequence-defined set of chromosomal transposon insertions in OG1RF. We used an orthogonal pooling strategy in conjunction with Illumina sequencing to identify a set of mutants with unique, single -based transposon insertions. The mutants contained insertions in 1,926 of 2,651 (72.6%) annotated open reading frames and in the majority of hypothetical protein-encoding genes and intergenic regions greater than 100 bp in length, which could encode small RNAs. As proof of principle of the usefulness of this arrayed transposon library, we created a minimal input pool containing 6,829 mutants chosen for maximal genomic coverage and used an approach that we term SMarT (sequence-defined technology) transposon sequencing (TnSeq) to identify numerous genetic determinants of bile resistance in E. faecalis OG1RF. These included several genes previously associated with bile acid resistance as well as new loci. Our arrayed library allows functional screening of a large percentage of the genome with a relatively small number of mutants, reducing potential effects of bottlenecking, and enables immediate recovery of mutants following competitions. The robust ability of Enterococcus faecalis to survive outside the host and to spread via oral-fecal transmission and its high degree of intrinsic and acquired antimicrobial resistance all complicate the treatment of hospital-acquired enterococcal infections. The conserved E. faecalis core genome serves as an important genetic scaffold for evolution of this bacterium in the modern health care setting and also provides interesting vaccine and drug targets. We used an innovative pooling/sequencing strategy to map a large collection of arrayed transposon insertions in E. faecalis OG1RF and generated an arrayed library of defined mutants covering approximately 70% of the OG1RF genome. Then, we performed high-throughput transposon sequencing experiments using this library to determine core genomic determinants of bile resistance in OG1RF. This collection is a valuable resource for comprehensive, functional enterococcal genomics using both traditional and high-throughput approaches and enables immediate recovery of mutants of interest.
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http://dx.doi.org/10.1128/mSystems.00062-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134198PMC
September 2018

Leukocyte telomere length in relation to risk of lung adenocarcinoma incidence: Findings from the Singapore Chinese Health Study.

Int J Cancer 2018 06 25;142(11):2234-2243. Epub 2018 Jan 25.

Duke-NUS Medical School Singapore, Singapore, Singapore.

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow-up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94-4.14, p  < 0.0001). This positive association was present in never smokers (p  < 0.0001), ever smokers (p  = 0.0010), men (p  = 0.0003), women (p  < 0.0001), and in shorter (p  = 0.0002) and longer (p  = 0.0001) duration of follow-up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.
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http://dx.doi.org/10.1002/ijc.31251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893405PMC
June 2018

Single-Strand Consensus Sequencing Reveals that HIV Type but not Subtype Significantly Impacts Viral Mutation Frequencies and Spectra.

J Mol Biol 2017 07 11;429(15):2290-2307. Epub 2017 May 11.

Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA; Institute for Molecular Virology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA; Division of Basic Sciences, School of Dentistry, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA; Department of Microbiology & Immunology, University of Minnesota-Twin Cities, Minneapolis, MN, 55455, USA. Electronic address:

A long-standing question of human immunodeficiency virus (HIV) genetic variation and evolution has been whether differences exist in mutation rate and/or mutation spectra among HIV types (i.e., HIV-1 versus HIV-2) and among HIV groups (i.e., HIV-1 groups M-P and HIV-2 groups A-H) and HIV-1 Group M subtypes (i.e., subtypes A-D, F-H, and J-K). To address this, we developed a new single-strand consensus sequencing assay for the determination of HIV mutation frequencies and spectra using the Illumina sequencing platform. This assay enables parallel and standardized comparison of HIV mutagenesis among various viral vectors with lower background error than traditional methods of Illumina library preparation. We found significant differences in viral mutagenesis between HIV types but intriguingly no significant differences among HIV-1 Group M subtypes. More specifically, HIV-1 exhibited higher transition frequencies than HIV-2, due mostly to single G-to-A mutations and (to a lesser extent) G-to-A hypermutation. These data suggest that HIV-2 RT exhibits higher fidelity during viral replication, and taken together, these findings demonstrate that HIV type but not subtype significantly affects viral mutation frequencies and spectra. These differences may inform antiviral and vaccine strategies.
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http://dx.doi.org/10.1016/j.jmb.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557043PMC
July 2017

Systematic improvement of amplicon marker gene methods for increased accuracy in microbiome studies.

Nat Biotechnol 2016 09 25;34(9):942-9. Epub 2016 Jul 25.

University of Minnesota Genomics Center, Minneapolis, Minnesota, USA.

Amplicon-based marker gene surveys form the basis of most microbiome and other microbial community studies. Such PCR-based methods have multiple steps, each of which is susceptible to error and bias. Variance in results has also arisen through the use of multiple methods of next-generation sequencing (NGS) amplicon library preparation. Here we formally characterized errors and biases by comparing different methods of amplicon-based NGS library preparation. Using mock community standards, we analyzed the amplification process to reveal insights into sources of experimental error and bias in amplicon-based microbial community and microbiome experiments. We present a method that improves on the current best practices and enables the detection of taxonomic groups that often go undetected with existing methods.
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http://dx.doi.org/10.1038/nbt.3601DOI Listing
September 2016

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

BMC Genet 2016 06 7;17(1):74. Epub 2016 Jun 7.

National Heart and Lung Institute, Imperial College, London, UK.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.

Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).

Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
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http://dx.doi.org/10.1186/s12863-016-0377-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895966PMC
June 2016

No Association between the Mitochondrial Genome and Prostate Cancer Risk: The Multiethnic Cohort.

Cancer Epidemiol Biomarkers Prev 2016 06 28;25(6):1001-3. Epub 2016 Mar 28.

Cancer Prevention Institute of California, Fremont, California. Stanford Cancer Institute, Palo Alto, California.

Background: Mitochondria are involved in many processes that are central to the life and death of a cell. Oxidative phosphorylation (OXPHOS), in particular, is known to be altered in carcinogenesis, leading to an increase in the production of reactive oxidative species and glycolysis, one of the hallmarks of cancer cells. Because of this, genetic variation in the mitochondrial genome, which encodes for part of the OXPHOS pathway, has been suggested to play a role in many cancers, including prostate cancer.

Methods: We comprehensively examined the role of the mitochondrial genome and prostate cancer risk in 4,086 prostate cancer cases and 3,698 controls from the Multiethnic Cohort (MEC), testing 350 mitochondrial SNPs (mtSNPs) in five racial/ethnic populations-Africans, Asian Americans, Europeans, Latinos, and Native Hawaiians. Logistic regression was conducted to examine single mitochondrial SNP and haplogroup associations. The sequence kernel association test was conducted for gene and pathway analysis.

Results: Eleven mtSNPs and haplogroup N were nominally associated with overall prostate cancer risk at P < 0.05. The mitochondrial DNA-encoded OXPHOS pathway, complexes, and genes were not associated with prostate cancer risk. No significant associations were identified after multiple testing corrections (all FDR q > 0.20).

Conclusions: The mitochondrial genome was not associated with prostate cancer risk in our study of 7,784 subjects from the MEC.

Impact: Our comprehensive study does not support the role of the mitochondrial genome in the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 1001-3. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891274PMC
June 2016

Toward clinical genomics in everyday medicine: perspectives and recommendations.

Expert Rev Mol Diagn 2016 24;16(5):521-32. Epub 2016 Feb 24.

y Stanford Center for Biomedical Ethics , Stanford School of Medicine , Stanford , CA , USA.

Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.
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http://dx.doi.org/10.1586/14737159.2016.1146593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841021PMC
December 2016

Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery.

PeerJ 2015 26;3:e1398. Epub 2015 Nov 26.

Department of Surgical Research, Mayo Clinic, Rochester, MN, USA.

Background. Preterm Premature Rupture of Membranes (PPROM) is a major leading cause of preterm births. While the cause for PPROM remains unidentified, it is anticipated to be due to subclinical infection, since a large proportion of PPROM patients display signs of chorioamnionitis. Since subclinical infections can be facilitated by dysbiosis, our goal was to characterize the vaginal microbiome and amniotic fluid discharge upon PPROM, through latency antibiotic treatment, and until delivery, to detect the presence of pathogens, microbiota alteration, and microbial response to treatment. Methods. Enrolled subjects (15) underwent routine institutional antenatal care for PPROM, including the administration of latency antibiotics. Serial vaginal swabs were obtained from diagnosis of PPROM through delivery and the sequencing of the V3-V5 region of the 16S rRNA gene was performed for all collected samples. Results. The results show that Lactobacilli species were markedly decreased when compared to vaginal swabs collected from uncomplicated pregnancy subjects with a matched gestational time. Prevotella and Peptoniphilus were the most prevalent taxa in PPROM subjects at presentation. The vaginal microbiome of the PPROM subjects varied substantially intra- and inter-subjects. Several taxa were found to be significantly reduced during and after the antibiotic treatment: Weeksella, Lachnospira, Achromobacter, and Pediococcus. In contrast, Peptostreptococcus and Tissierellaceae ph2 displayed a significant increase after the antibiotic treatment. However, the relative abundance of Lactobacillus, Prevotella, and Peptoniphilus was not substantially impacted during the hospitalization of the PPROM subjects. The deficiency of Lactobacillus, and constancy of known pathogenic species, such as Prevotella and Peptoniphilus during and after antibiotics, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches. Discussion. PPROM is responsible for one third of all preterm births. It is thought that subclinical infection is a crucial factor in the pathophysiology of PPROM because 25-40% of patients present signs of chorioamnionitis on amniocentesis. Here we sought to directly assess the bacterial content of the vagina and leaking amniotic fluid of subjects at presentation, throughout treatment and up until delivery, in order to search for common pathogens, microbiota changes, and microbial response to latency antibiotic treatment. We have found that the vaginal microbiome of PPROM subjects is highly variable and displays significant changes to treatment. However, the unchanging deficiency of Lactobacillus, and persistence of known pathogenic species, such as Prevotella and Peptoniphilus from presentation, through antibiotic treatment and up until delivery, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches.
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http://dx.doi.org/10.7717/peerj.1398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671185PMC
December 2015

Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.

PLoS One 2015 4;10(9):e0136796. Epub 2015 Sep 4.

Cancer Prevention Institute of California, Fremont, California, United States of America; Stanford Cancer Institute, Palo Alto, California, United States of America.

The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19-2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups--African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560485PMC
May 2016

Next generation sequencing in endocrine practice.

Mol Genet Metab 2015 Jun-Jul;115(2-3):61-71. Epub 2015 May 3.

Department of Pediatrics, Division of Pediatric Endocrinology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN 55454, USA. Electronic address:

With the completion of the Human Genome Project and advances in genomic sequencing technologies, the use of clinical molecular diagnostics has grown tremendously over the last decade. Next-generation sequencing (NGS) has overcome many of the practical roadblocks that had slowed the adoption of molecular testing for routine clinical diagnosis. In endocrinology, targeted NGS now complements biochemical testing and imaging studies. The goal of this review is to provide clinicians with a guide to the application of NGS to genetic testing for endocrine conditions, by compiling a list of established gene mutations detectable by NGS, and highlighting key phenotypic features of these disorders. As we outline in this review, the clinical utility of NGS-based molecular testing for endocrine disorders is very high. Identifying an exact genetic etiology improves understanding of the disease, provides clear explanation to families about the cause, and guides decisions about screening, prevention and/or treatment. To illustrate this approach, a case of hypophosphatasia with a pathogenic mutation in the ALPL gene detected by NGS is presented.
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http://dx.doi.org/10.1016/j.ymgme.2015.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818590PMC
March 2016

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.

Nat Commun 2014 Oct 20;5:5260. Epub 2014 Oct 20.

Division of General Internal Medicine, Department of Medicine, Institute of Human Genetics, University of California San Fancisco, San Francisco, California 94158, USA.

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
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http://dx.doi.org/10.1038/ncomms6260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204111PMC
October 2014

Implementation of Cloud based next generation sequencing data analysis in a clinical laboratory.

BMC Res Notes 2014 May 23;7:314. Epub 2014 May 23.

Research Informatics Support Systems, Minnesota Supercomputing Institute, University of Minnesota, Room 599 Walter Library 117 Pleasant St SE, Minneapolis, MN 55455, USA.

Background: The introduction of next generation sequencing (NGS) has revolutionized molecular diagnostics, though several challenges remain limiting the widespread adoption of NGS testing into clinical practice. One such difficulty includes the development of a robust bioinformatics pipeline that can handle the volume of data generated by high-throughput sequencing in a cost-effective manner. Analysis of sequencing data typically requires a substantial level of computing power that is often cost-prohibitive to most clinical diagnostics laboratories.

Findings: To address this challenge, our institution has developed a Galaxy-based data analysis pipeline which relies on a web-based, cloud-computing infrastructure to process NGS data and identify genetic variants. It provides additional flexibility, needed to control storage costs, resulting in a pipeline that is cost-effective on a per-sample basis. It does not require the usage of EBS disk to run a sample.

Conclusions: We demonstrate the validation and feasibility of implementing this bioinformatics pipeline in a molecular diagnostics laboratory. Four samples were analyzed in duplicate pairs and showed 100% concordance in mutations identified. This pipeline is currently being used in the clinic and all identified pathogenic variants confirmed using Sanger sequencing further validating the software.
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http://dx.doi.org/10.1186/1756-0500-7-314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036707PMC
May 2014

Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals.

Genome Res 2014 Jan 3;24(1):14-24. Epub 2013 Oct 3.

Department of Computer Science, Stanford University, Stanford, California 94305, USA;

Understanding the consequences of regulatory variation in the human genome remains a major challenge, with important implications for understanding gene regulation and interpreting the many disease-risk variants that fall outside of protein-coding regions. Here, we provide a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals. We present a comprehensive description of the distribution of regulatory variation--by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants. We detect variants influencing expression of over ten thousand genes, and through the enhanced resolution offered by RNA-sequencing, for the first time we identify thousands of variants associated with specific phenotypes including splicing and allelic expression. Evaluating the effects of both long-range intra-chromosomal and trans (cross-chromosomal) regulation, we observe modularity in the regulatory network, with three-dimensional chromosomal configuration playing a particular role in regulatory modules within each chromosome. We also observe a significant depletion of regulatory variants affecting central and critical genes, along with a trend of reduced effect sizes as variant frequency increases, providing evidence that purifying selection and buffering have limited the deleterious impact of regulatory variation on the cell. Further, generalizing beyond observed variants, we have analyzed the genomic properties of variants associated with expression and splicing and developed a Bayesian model to predict regulatory consequences of genetic variants, applicable to the interpretation of individual genomes and disease studies. Together, these results represent a critical step toward characterizing the complete landscape of human regulatory variation.
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http://dx.doi.org/10.1101/gr.155192.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875855PMC
January 2014

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

Nat Genet 2013 Jun 14;45(6):613-20. Epub 2013 Apr 14.

University of Colorado Denver, School of Public Health, Denver, Colorado, USA.

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.
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http://dx.doi.org/10.1038/ng.2609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677861PMC
June 2013

Association between celiac disease and iron deficiency in Caucasians, but not non-Caucasians.

Clin Gastroenterol Hepatol 2013 Jul 13;11(7):808-14. Epub 2013 Feb 13.

Division of Gastroenterology/Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905, USA.

Background & Aims: Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron-deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening study to identify individuals with iron deficiency and to assess the frequency of celiac disease.

Methods: We analyzed serum samples from white men (≥25 y) and women (≥50 y) who participated in the Hemochromatosis and Iron Overload Screening study; cases were defined as individuals with iron deficiency (serum ferritin level, ≤12 μg/L) and controls were those without (serum ferritin level, >100 μg/L in men and >50 μg/L in women). All samples also were analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency.

Results: Celiac disease occurred in 14 of 567 cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher exact test, P = 1.92 × 10(-6)). Celiac disease was more common in Caucasian cases (14 of 363; 4%) than non-Caucasian cases (0 of 204; P = .003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7-212.8) that of controls; 13 of 14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype.

Conclusions: Celiac disease is associated with iron deficiency in Caucasians. Celiac disease is rare among non-Caucasians-even among individuals with features of celiac disease, such as iron deficiency. Celiac disease also is rare among individuals without iron deficiency. Men and postmenopausal women with iron deficiency should be tested for celiac disease.
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http://dx.doi.org/10.1016/j.cgh.2013.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843318PMC
July 2013

Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore.

Br J Nutr 2013 Feb 15;109(3):493-502. Epub 2012 May 15.

University of Pittsburgh Cancer Institute, UPMC Cancer Pavillion, Suite 4C-464, 5150 Center Avenue, Pittsburgh, PA 15232, USA.

Vitamin D is known for maintaining Ca homeostasis and bone structure, and may also decrease susceptibility to chronic and infectious diseases. However, data on vitamin D status and its predictors among Southeast Asian populations are limited. We evaluated the distribution and determinants (genetic and environmental) of serum 25-hydroxyvitamin D (25(OH)D) concentrations among 504 middle-aged and elderly participants (aged 45-74 years) in the Singapore Chinese Health Study. Data on dietary and other lifestyle factors were collected by trained interviewers. Serum 25(OH)D concentrations and genetic polymorphisms in vitamin D metabolism pathway enzymes (cytochrome P450 (CYP) 2R1, 3A4, 27B1, 24A1; vitamin D binding protein (also known as group-specific component, GC); and vitamin D receptor) were measured using stored biospecimens. Mean 25(OH)D concentration was 68·8 nmol/l. Serum 25(OH)D concentrations were positively associated with dietary vitamin D intake, and inversely associated with hours spent sitting at work. BMI was not associated with 25(OH)D concentrations. CYP2R1 rs10741657, rs12794714, rs1993116; CYP3A4 rs2242480; and GC rs4588, rs7041, rs16847015, rs2298849 were statistically significantly associated with 25(OH)D concentrations. Individuals with the Gc2-2 haplotype (rs4588AA/rs7041TT) had statistically significantly lower 25(OH)D concentrations compared to all other Gc haplotypes (P-trend < 0·001). The majority of participants (86 %) had 25(OH)D concentrations ≥ 50 nmol/l, which is consistent with the 2011 Institute of Medicine (US) recommendation for bone health, and 32 % had concentrations of ≥ 75 nmol/l that are thought to be required for broader health effects. Dietary vitamin D intake, hours spent indoors at work and genetic variation in CYP2R1, CYP3A4 and GC are significant predictors of 25(OH)D concentrations among Singapore Chinese.
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http://dx.doi.org/10.1017/S0007114512001675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442149PMC
February 2013

Development and initial characterization of a HAPPY panel for mapping the X. tropicalis genome.

Int J Biol Sci 2011 24;7(7):1037-44. Epub 2011 Aug 24.

Department of Animal Sciences, Washington State University, Pullman, WA 99164-6351, USA.

HAPPY mapping was designed to pursue the analysis of approximately random HAPloid DNA breakage samples using the PolYmerase chain reaction for mapping genomes. In the present study, we improved the method and integrated two other molecular techniques into the process: whole genome amplification and the Sequenom SNP (single nucleotide polymorphism) genotyping assay in order to facilitate whole genome mapping of X. tropicalis. The former technique amplified enough DNA materials to genotype a large number of markers, while the latter allowed for relatively high throughput marker genotyping with multiplex assays on the HAPPY lines. A total of 58 X. tropicalis genes were genotyped on an initial panel of 383 HAPPY lines, which contributed to formation of a working panel of 146 lines. Further genotyping of 29 markers on the working panel led to construction of a HAPPY map for the X. tropicalis genome. We believe that our improved HAPPY method described in the present study has paved the way for the community to map different genomes with a simple, but powerful approach.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164153PMC
http://dx.doi.org/10.7150/ijbs.7.1037DOI Listing
January 2012

Genome-wide association study identifies genetic loci associated with iron deficiency.

PLoS One 2011 Mar 31;6(3):e17390. Epub 2011 Mar 31.

Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF)≤12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7) for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9), corrected P=0.012) was replicated within the VA samples (observed P=0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017390PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069025PMC
March 2011

European ancestry is positively associated with breast cancer risk in Mexican women.

Cancer Epidemiol Biomarkers Prev 2010 Apr 23;19(4):1074-82. Epub 2010 Mar 23.

Division of General Internal Medicine, Department of Medicine, Institute for Human Genetics, University of California, San Francisco, California, USA.

The incidence of breast cancer is 35% lower in Hispanic women living in the San Francisco Bay Area than in non-Hispanic White women. We have previously described a significant association between genetic ancestry and risk for breast cancer in a sample of U.S. Hispanics/Latinas. We retested the association in women residing in Mexico because of the possibility that the original finding may be confounded by U.S. specific unmeasured environmental exposures. We genotyped a set of 106 ancestry informative markers in 846 Mexican women with breast cancer and 1,035 unaffected controls and estimated genetic ancestry using a maximum likelihood method. Odds ratios and 95% confidence intervals (95% CI) for ancestry modeled as a categorical and continuous variable were estimated using logistic regression and adjusted for reproductive and other known risk factors. Greater European ancestry was associated with increased breast cancer risk in this new and independent sample of Mexican women residing in Mexico. Compared with women with 0% to 25% European ancestry, the risk was increased for women with 51% to 75% and 76% to 100% European ancestry [odds ratios, 1.35 (95% CI, 0.96-1.91) and 2.44 (95% CI, 0.94-6.35), respectively; P for trend = 0.044]. For every 25% increase in European ancestry (modeled as a continuous variable), there was a 20% increase in risk for breast cancer (95% CI, 1.03-1.41; P = 0.019). These results suggest that nongenetic factors play a crucial role in explaining the difference in breast cancer incidence between Latinas and non-Latina White women, and it also points out to the possibility of a genetic component to this difference.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852491PMC
April 2010