Charles Kooperberg

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (275)1992.84 Total impact

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    ABSTRACT: Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, blacks have longer LTL than whites, but the LTL-CHD relationship in blacks is unknown. We investigated the relationship of LTL with CHD and mortality among blacks. Using a case-cohort design, 1525 postmenopausal women (667 blacks and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas blacks experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in blacks. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in blacks. As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and black postmenopausal women. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2015; DOI:10.1161/ATVBAHA.115.305838 · 5.53 Impact Factor
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    ABSTRACT: Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
    Nature Communications 07/2015; 6:7138. DOI:10.1038/ncomms8138 · 10.74 Impact Factor
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    ABSTRACT: Fibrinogen, coagulation factor VII (FVII), factor VIII (FVIII), and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities and additional variation may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n=2) and rare (n=10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identify new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information to understanding individual variation in hemostasis pathways. Copyright © 2015 American Society of Hematology.
    Blood 06/2015; DOI:10.1182/blood-2015-02-624551 · 10.43 Impact Factor
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    ABSTRACT: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. © 2015 American Heart Association, Inc.
    Stroke 06/2015; DOI:10.1161/STROKEAHA.115.009044 · 6.02 Impact Factor
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    ABSTRACT: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 05/2015; DOI:10.1093/ije/dyv074 · 9.20 Impact Factor
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    ABSTRACT: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10-8) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10-7) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
    05/2015; DOI:10.1001/jamaneurol.2015.0582
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    ABSTRACT: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT - CLPTM1L gene region on chr5p15.33. Since this region is characterized by low linkage disequilibrium (LD), we sought to identify additional SNPs could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia.We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, OR=0.85; 95% CI=0.80-0.90, P=8.3x10(-8) ). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low LD between them (r(2) =0.07, D'=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (P=3.0x10(-5) ), rs4583925 (P=4.0x10(-5) ) and rs2735948 (P=5.0x10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 05/2015; DOI:10.1002/ijc.29590 · 5.01 Impact Factor
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    ABSTRACT: Elucidating the genetic basis of complex traits and diseases in non-European populations is particularly challenging because US minority populations have been under-represented in genetic association studies. We developed an empirical Bayes approach named XPEB (cross-population empirical Bayes), designed to improve the power for mapping complex-trait-associated loci in a minority population by exploiting information from genome-wide association studies (GWASs) from another ethnic population. Taking as input summary statistics from two GWASs-a target GWAS from an ethnic minority population of primary interest and an auxiliary base GWAS (such as a larger GWAS in Europeans)-our XPEB approach reprioritizes SNPs in the target population to compute local false-discovery rates. We demonstrated, through simulations, that whenever the base GWAS harbors relevant information, XPEB gains efficiency. Moreover, XPEB has the ability to discard irrelevant auxiliary information, providing a safeguard against inflated false-discovery rates due to genetic heterogeneity between populations. Applied to a blood-lipids study in African Americans, XPEB more than quadrupled the discoveries from the conventional approach, which used a target GWAS alone, bringing the number of significant loci from 14 to 65. Thus, XPEB offers a flexible framework for mapping complex traits in minority populations. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 04/2015; 96(5). DOI:10.1016/j.ajhg.2015.03.008 · 10.99 Impact Factor
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    ABSTRACT: Results from the Women's Health Initiative (WHI) clinical trials (CT) demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy. We conducted a joint analysis of the WHI observational study data and CT data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk. Reproductive history, oral contraceptive (OC) use, and postmenopausal hormone therapy (HT) was evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2,467 incident lung cancer cases were ascertained, with median follow-up of 14 years. For all lung cancers, women with previous use of estrogen plus progestin of < 5 years (HR=0.84; 95% CI 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend towards decreased risk with increasing age at menopause (ptrend=0.04) and a trend towards increased risk with increasing number of live births (ptrend=0.03). Reduced risk of non-small cell lung cancer was associated with age 20-29 at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy. Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with ER expression in the lung should continue as a role for estrogen can't be ruled out and may hold potential for prevention and treatment strategies.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2015; 10(7). DOI:10.1097/JTO.0000000000000558 · 5.80 Impact Factor
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    ABSTRACT: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.
    PLoS ONE 03/2015; 10(3):e0120491. DOI:10.1371/journal.pone.0120491 · 3.23 Impact Factor
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    ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(3):487-97. DOI:10.1016/j.ajhg.2015.01.011 · 10.99 Impact Factor
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Nature 02/2015; 518(7538). DOI:10.1038/nature14177 · 42.35 Impact Factor
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    ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
    Nature 02/2015; 518(7538-7538):187-96. DOI:10.1038/nature14132 · 42.35 Impact Factor
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    ABSTRACT: The consumption and blood concentrations of lycopene are both positively and inversely associated with the risk of several chronic diseases. The inconsistences in lycopene disease association studies may stem from a lack of knowledge about the genetic variation in the synthesis, metabolism, and deposition of transport and binding proteins, which potentially influence serum lycopene concentrations. We examined the association between variation across the genome and serum concentrations of lycopene in a multiethnic population. Participants included African (n = 914), Hispanic (n = 464), and European (n = 1203) American postmenopausal women from the Women's Health Initiative. We analyzed ∼7 million single nucleotide polymorphisms (SNPs). Linear regression models were used to assess associations between each SNP and serum concentrations (log transformed, continuous) of lycopene; we adjusted for age, body mass index, and population substructure. Models were run separately by ethnicity, and results were combined in a transethnic fixed-effects meta-analysis. In the meta-analysis, the scavenger receptor class B, member 1 (SCARB1) gene, which encodes for a cholesterol membrane transporter, was significantly associated with lycopene concentrations (rs1672879; P < 2.68 × 10(-9)). Each additional G allele resulted in a 12% decrease in lycopene concentrations for African Americans, 20% decrease for Hispanic Americans, and 9% decrease for European Americans. In addition, 2 regions were significantly associated with serum lycopene concentrations in African Americans: the slit homolog 3 gene (SLIT3), which serves as a molecular guidance cue in cellular migration, and the dehydrogenase/reductase (SDR family) member 2 (DHRS2) gene, which codes for an oxidoreductase that mitigates the breakdown of steroids. We found 3 novel loci associated with serum lycopene concentrations, 2 of which were specific to African Americans. Future functional studies looking at these specific genes may provide insight into the metabolism and underlying function of lycopene in humans, which may further elucidate lycopene's influence on disease risk and health. This trial was registered at clinicaltrials.gov as NCT00000611. © 2015 American Society for Nutrition.
    Journal of Nutrition 02/2015; 145(2):187-92. DOI:10.3945/jn.114.202150 · 4.23 Impact Factor
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    ABSTRACT: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10-8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
    PLoS ONE 12/2014; 9(12):e113203. DOI:10.1371/journal.pone.0113203 · 3.23 Impact Factor
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    ABSTRACT: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15, 17 and apolipoprotein C-III. Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
    Nature 12/2014; advance online publication. DOI:10.1038/nature13917 · 42.35 Impact Factor
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    Tobias Ragoczy · Agnes Telling · David Scalzo · Charles Kooperberg · Mark Groudine
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    ABSTRACT: Abstract The eukaryotic nucleus is structurally and functionally organized, as reflected in the distribution of its protein and DNA components. The genome itself is segregated into euchromatin and heterochromatin that replicate in a distinct spatio-temporal manner. We used a combination of fluorescence in situ hybridization (FISH) and DamID to investigate the localization of the early and late replicating components of the genome in a lymphoblastoid cell background. Our analyses revealed that the bulk of late replicating chromatin localizes to the nuclear peripheral heterochromatin (PH) in a chromosome size and gene density dependent manner. Late replicating DNA on small chromosomes exhibits a much lower tendency to localize to PH and tends to associate with alternate repressive subcompartments such as pericentromeric (PCH) and perinucleolar heterochromatin (PNH). Furthermore, multicolor FISH analysis revealed that late replicating loci, particularly on the smaller chromosomes, may associate with any of these three repressive subcompartments, including more than one at the same time. These results suggest a functional equivalence or redundancy among the three subcompartments. Consistent with this notion, disruption of nucleoli resulted in an increased association of late replicating loci with peripheral heterochromatin. Our analysis reveals that rather than considering the morphologically distinct PH, PCH and PNH as individual subcompartments, they should be considered in aggregate as a functional compartment for late replicating chromatin.
    Nucleus (Austin, Texas) 12/2014; 5(6). DOI:10.4161/19491034.2014.990863 · 3.15 Impact Factor
  • Human Molecular Genetics 11/2014; 24(2). DOI:10.1093/hmg/ddu539 · 6.68 Impact Factor

Publication Stats

17k Citations
1,992.84 Total Impact Points

Institutions

  • 1996–2015
    • Fred Hutchinson Cancer Research Center
      • Division of Public Health Sciences
      Seattle, Washington, United States
  • 1992–2014
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Biostatistics
      • • Department of Biochemistry
      • • Department of Statistics
      Seattle, Washington, United States
  • 2013
    • Vanderbilt University
      • Center for Human Genetics Research (CHGR)
      Nashville, MI, United States
  • 2010
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, Pennsylvania, United States
  • 1995
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1990–1991
    • University of California, Berkeley
      • Department of Statistics
      Berkeley, California, United States