Dan L Nicolae

Chang Gung Memorial Hospital, T’ai-pei, Taipei, Taiwan

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Publications (102)1073.56 Total impact

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    ABSTRACT: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
    BMC Medical Genomics 08/2014; 7:48. · 3.91 Impact Factor
  • Matthew Reimherr, Xiao-Li Meng, Dan L. Nicolae
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    ABSTRACT: Dramatically expanded routine adoption of the Bayesian approach has substantially increased the need to assess both the confirmatory and contradictory information in our prior distribution with regard to the information provided by our likelihood function. We propose a diagnostic approach that starts with the familiar posterior matching method. For a given likelihood model, we identify the difference in information needed to form two likelihood functions that, when combined respectively with a given prior and a baseline prior, will lead to the same posterior uncertainty. In cases with independent, identically distributed samples, sample size is the natural measure of information, and this difference can be viewed as the prior data size $M(k)$, with regard to a likelihood function based on $k$ observations. When there is no detectable prior-likelihood conflict relative to the baseline, $M(k)$ is roughly constant over $k$, a constant that captures the confirmatory information. Otherwise $M(k)$ tends to decrease with $k$ because the contradictory prior detracts information from the likelihood function. In the case of extreme contradiction, $M(k)/k$ will approach its lower bound $-1$, representing a complete cancelation of prior and likelihood information due to conflict. We also report an intriguing super-informative phenomenon where the prior effectively gains an extra $(1+r)^{-1}$ percent of prior data size relative to its nominal size when the prior mean coincides with the truth, where $r$ is the percentage of the nominal prior data size relative to the total data size underlying the posterior. We demonstrate our method via several examples, including an application exploring the effect of immunoglobulin levels on lupus nephritis. We also provide a theoretical foundation of our method for virtually all likelihood-prior pairs that possess asymptotic conjugacy.
    06/2014;
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    ABSTRACT: Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies (GWAS) in 2653 male asthma cases, 2566 female asthma cases, and 3830 non-asthma controls from European American, African American, African Caribbean, and Latino populations. Association tests were conducted in each study sample and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had p-values <1x10(-6), of which two were male-specific and four were female-specific; all were ancestry-specific. The most significant sex-specific association in European Americans was at the IRF1 locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single nucleotide polymorphisms (SNPs) that are known expression quantitative trait loci (eQTLs) and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways, and prior reports of sex-specific differences in interferon responses.
    Human Molecular Genetics 05/2014; · 7.69 Impact Factor
  • Matthew Reimherr, Dan Nicolae
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    ABSTRACT: We present a new method based on Functional Data Analysis (FDA) for detecting associations between one or more scalar covariates and a longitudinal response, while correcting for other variables. Our methods exploit the temporal structure of longitudinal data in ways that are otherwise difficult with a multivariate approach. Our procedure, from an FDA perspective, is a departure from more established methods in two key aspects. First, the raw longitudinal phenotypes are assembled into functional trajectories prior to analysis. Second, we explore an association test that is not directly based on principal components. We instead focus on quantifying the reduction in $L^2$ variability as a means of detecting associations. Our procedure is motivated by longitudinal genome wide association studies and, in particular, the childhood asthma management program (CAMP) which explores the long term effects of daily asthma treatments. We conduct a simulation study to better understand the advantages (and/or disadvantages) of an FDA approach compared to a traditional multivariate one. We then apply our methodology to data coming from CAMP. We find a potentially new association with a SNP negatively affecting lung function. Furthermore, this SNP seems to have an interaction effect with one of the treatments.
    The Annals of Applied Statistics 04/2014; 8(1). · 2.24 Impact Factor
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    ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
    Nature Genetics 03/2014; · 35.21 Impact Factor
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    ABSTRACT: Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years. The SNPs with smallest P-values were examined in a replication set of 3,470 EOBC case and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P-values to obtain a gene-based P-value. We examined the gene with smallest P-value for replication in 1,145 breast cancer case and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P<4x10-8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P<6x10-4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P<0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genomewide gene-based threshold of 2.5x10-In conclusion, EOBC and LOBC appear to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
    Cancer Epidemiology Biomarkers &amp Prevention 02/2014; · 4.56 Impact Factor
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    Christopher Ryan King, Dan L Nicolae
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    ABSTRACT: The success of genome-wide association studies (GWAS) in uncovering genetic risk factors for complex traits has generated great promise for the complete data generated by sequencing. The bumpy transition from GWAS to whole-exome or whole-genome association studies (WGAS) based on sequencing investigations has highlighted important differences in analysis and interpretation. We show how the loss in power due to the allele frequency spectrum targeted by sequencing is difficult to compensate for with realistic effect sizes and point to study designs that may help. We discuss several issues in interpreting the results, including a special case of the winner's curse. Extrapolation and prediction using rare SNPs is complex, because of the selective ascertainment of SNPs in case-control studies and the low amount of information at each SNP, and naive procedures are biased under the alternative. We also discuss the challenges in tuning gene-based tests and accounting for multiple testing when genes have very different sets of SNPs. The examples we emphasize in this paper highlight the difficult road we must travel for a two-letter switch.
    Genes. 01/2014; 5(2):460-476.
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    C Ryan King, Paul J Rathouz, Dan L Nicolae
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    ABSTRACT: Investigators interrogating the genetic basis of complex traits using case-control sequencing studies will want to draw conclusions about collections of variants as well as specific variants. We discuss two easy ways to err on estimates of average effects of SNPs and contrasts between groups of SNPs, such as rare versus common. Both of these errors look like interesting findings, so readers should understand and anticipate them. First, we show that when analyzing only SNPs polymorphic in the sample, on average rare variants increase risk even if they are just as likely to decrease risk. Studies of moderate size are unlikely to observe all the variation in a gene which exists in the source population, and the ascertained SNPs are not representative of the larger set. A rare SNP is more likely to be discovered if it increases risk and is enriched in cases; enrichment of protective alleles among controls is negligible. Common alleles are ascertained regardless of their effect on phenotype, creating a rare variant specific bias. Nuisance parameters change the size of the bias, meaning that studies of the same trait could reach inconsistent conclusions about the impact of rare SNPs. The bias applies more broadly than just rare versus common. Our second note is technical, and reflects well-known results. Ubiquitous methods which directly compare quantities like allele-counts or rare-SNP-burdens to phenotype do not describe the distribution of SNP odds ratios, though it is tempting to interpret them in this way. Our leading example is that the same data can lead to two seemingly different conclusions: 1) possessing more minor alleles is associated with higher risk of disease 2) minor alleles are as likely to decrease risk as increase it. Pure association test calibration is unaffected by either error.
    12/2013;
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    ABSTRACT: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
    Nature 12/2013; · 38.60 Impact Factor
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    ABSTRACT: Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.
    Cell 09/2013; 155(1):70-80. · 31.96 Impact Factor
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    ABSTRACT: Using a derivation cohort (N=349), we developed the first warfarin dosing algorithm that includes recently discovered polymorphisms in VKORC1 and CYP2C9 associated with warfarin dose requirement in African Americans (AAs). We tested our novel algorithm in an independent cohort of 129 AAs and compared the dose prediction to the International Warfarin Pharmacogenetics Consortium (IWPC) dosing algorithms. Our algorithm explains more of the phenotypic variation (R(2)=0.27) than the IWPC pharmacogenomics (R(2)=0.15) or clinical (R(2)=0.16) algorithms. Among high-dose patients, our algorithm predicted a higher proportion of patients within 20% of stable warfarin dose (45% vs 29% and 2% in the IWPC pharmacogenomics and clinical algorithms, respectively). In contrast to our novel algorithm, a significant inverse correlation between predicted dose and percent West African ancestry was observed for the IWPC pharmacogenomics algorithm among patients requiring 60 mg per week (β=-2.04, P=0.02).The Pharmacogenomics Journal advance online publication, 10 September 2013; doi:10.1038/tpj.2013.34.
    The Pharmacogenomics Journal 09/2013; · 5.13 Impact Factor
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    ABSTRACT: Lung function is a long-term predictor of mortality and morbidity. We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10(-8) to 3.4 × 10(-9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of β-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.
    The Journal of allergy and clinical immunology 08/2013; · 12.05 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF. First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10(-8)) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes. In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r(2)=0·07], rs5743894 [r(2)=0·16], and rs5743890 [r(2)=0·01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1·72 [95% CI 1·24-2·38]; p=0·0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0·097), 40% in those with the minor allele of rs111521887 (p=3·0 × 10(-4)), and 50% in those with the minor allele of rs5743894 (p=2·93 × 10(-5)) compared with homozygous carriers of common alleles for these SNPs. Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease. National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.
    The lancet. Respiratory medicine. 06/2013; 1(4):309-17.
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    ABSTRACT: Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.
    Nature Genetics 05/2013; · 35.21 Impact Factor
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    Nature Genetics 05/2013; 45(6):580-585. · 35.21 Impact Factor
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    ABSTRACT: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
    Clinical & Experimental Allergy 04/2013; 43(4):463-74. · 4.79 Impact Factor
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    ABSTRACT: Background Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. Methods We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). Results The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific. Conclusions Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).
    New England Journal of Medicine 03/2013; · 54.42 Impact Factor

Publication Stats

9k Citations
1,073.56 Total Impact Points

Institutions

  • 2013
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2006–2013
    • University of Illinois at Chicago
      • Section of General Internal Medicine
      Chicago, Illinois, United States
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, GA, United States
  • 1998–2012
    • University of Chicago
      • • Specialty of Ophthalmology and Visual Sciences
      • • Department of Human Genetics
      • • Department of Medicine
      • • Department of Statistics
      Chicago, IL, United States
    • The University of Chicago Medical Center
      • Department of Medicine
      Chicago, IL, United States
  • 2007
    • Montreal Heart Institute
      • Research Centre
      Montréal, Quebec, Canada
    • University of Pittsburgh
      • School of Medicine
      Pittsburgh, PA, United States
  • 1999
    • deCODE genetics, Inc.
      Reikiavik, Capital Region, Iceland