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Dan L Nicolae

Publications and source records attributed to Dan L Nicolae.

13 recordsLinked to original sources
PubMed2006

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Alleles↗
PubMed2006

GEL: a novel genotype calling algorithm using empirical likelihood.

MOTIVATION: Preliminary results on the data produced using the Affymetrix large-scale genotyping platforms show that it is necessary to construct improved genotype calling algorithms. There is evidence that some of the existing algorithms lead to an increased error rate in heterozygous genotypes, and a disproportionately large rate of heterozygotes with missing genotypes. Non-random errors and missing data can lead to an increase in the number of false discoveries in genetic association studies. Therefore, the factors that need to be evaluated in assessing the performance of an algorithm are the missing data (call) and error rates, but also the heterozygous proportions in missing data and errors. RESULTS: We introduce a novel genotype calling algorithm (GEL) for the Affymetrix GeneChip arrays. The algorithm uses likelihood calculations that are based on distributions inferred from the observed data. A key ingredient in accurate genotype calling is weighting the information that comes from each probe quartet according to the quality/reliability of the data in the quartet, and prior information on the performance of the quartet. AVAILABILITY: The GEL software is implemented in R and is available by request from the corresponding author at nicolae@galton.uchicago.edu.

Algorithms↗
PubMed2006

Coverage and characteristics of the Affymetrix GeneChip Human Mapping 100K SNP set.

Improvements in technology have made it possible to conduct genome-wide association mapping at costs within reach of academic investigators, and experiments are currently being conducted with a variety of high-throughput platforms. To provide an appropriate context for interpreting results of such studies, we summarize here results of an investigation of one of the first of these technologies to be publicly available, the Affymetrix GeneChip Human Mapping 100K set of single nucleotide polymorphisms (SNPs). In a systematic analysis of the pattern and distribution of SNPs in the Mapping 100K set, we find that SNPs in this set are undersampled from coding regions (both nonsynonymous and synonymous) and oversampled from regions outside genes, relative to SNPs in the overall HapMap database. In addition, we utilize a novel multilocus linkage disequilibrium (LD) coefficient based on information content (analogous to the information content scores commonly used for linkage mapping) that is equivalent to the familiar measure r2 in the special case of two loci. Using this approach, we are able to summarize for any subset of markers, such as the Affymetrix Mapping 100K set, the information available for association mapping in that subset, relative to the information available in the full set of markers included in the HapMap, and highlight circumstances in which this multilocus measure of LD provides substantial additional insight about the haplotype structure in a region over pairwise measures of LD.

Chromosome Mapping↗
PubMed2006

Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease.

Crohn's disease (CD) is associated with elevated adaptive immunity to commensal microbes, with flagellin being a dominant antigen. In light of heightened awareness of the importance of innate immunity in regulating adaptive immunity and ambiguity as to the role of CD-associated immune responses in CD pathophysiology, we sought to determine whether natural acquisition of immune responses to flagellin were regulated by the innate immune flagellin receptor toll-like receptor 5 (TLR5) and determine whether persons carrying a recently defined common dominant-negative TLR5 polymorphism (TLR5-stop) might be protected from developing CD. Carriage rates of a recently defined dominant-negative TLR5 polymorphism (TLR5-stop) and levels of serum immunoreactivity to bacterial products were measured in inflammatory bowel disease patients, first-degree relatives, and unrelated controls. We observed that, in healthy subjects, persons carrying TLR5-stop had significantly lower levels of flagellin-specific IgG and IgA but had similar levels of total and LPS-specific Ig. Moreover, we observed that, among Jewish subjects, the carriage rate of TLR5-stop (in heterozygous state) was significantly less in CD patients, but not ulcerative colitis (UC) patients, compared with unaffected relatives and unrelated controls (5.4, 0.9, 6.0, and 6.5% for unaffected relatives, CD, UC, and unrelated Jewish controls, respectively, n = 296, 215, 185, and 416, respectively; P = 0.037 by likelihood calculation for CD vs. controls), indicating that TLR5-stop can protect persons of Jewish ethnicity against CD. We did not observe a significant association of TLR5-stop with CD in a non-Jewish cohort (11.1, 10.4, and 11.7% for unaffected relatives, CD, and UC, respectively; n = 841, 543, and 300 for unaffected relatives, respectively). These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather promote the pathogenic response.

Adaptation, Physiological↗
PubMed2006

Quantifying the amount of missing information in genetic association studies.

Many genetic analyses are done with incomplete information; for example, unknown phase in haplotype-based association studies. Measures of the amount of available information can be used for efficient planning of studies and/or analyses. In particular, the linkage disequilibrium (LD) between two sets of markers can be interpreted as the amount of information one set of markers contains for testing allele frequency differences in the second set, and measuring LD can be viewed as quantifying information in a missing data problem. We introduce a framework for measuring the association between two sets of variables; for example, genotype data for two distinct groups of markers, or haplotype and genotype data for a given set of polymorphisms. The goal is to quantify how much information is in one data set, e.g. genotype data for a set of SNPs, for estimating parameters that are functions of frequencies in the second data set, e.g. haplotype frequencies, relative to the ideal case of actually observing the complete data, e.g. haplotypes. In the case of genotype data on two mutually exclusive sets of markers, the measure determines the amount of multi-locus LD, and is equal to the classical measure r(2), if the sets consist each of one bi-allelic marker. In general, the measures are interpreted as the asymptotic ratio of sample sizes necessary to achieve the same power in case-control testing. The focus of this paper is on case-control allele/haplotype tests, but the framework can be extended easily to other settings like regressing quantitative traits on allele/haplotype counts, or tests on genotypes or diplotypes. We highlight applications of the approach, including tools for navigating the HapMap database [The International HapMap Consortium, 2003], and genotyping strategies for positional cloning studies.

Alleles↗
PubMed2006

Testing untyped alleles (TUNA)-applications to genome-wide association studies.

The large number of tests performed in analyzing data from genome-wide association studies has a large impact on the power of detecting risk variants, and analytic strategies specifying the optimal set of hypotheses to be tested are necessary. We propose a genome-wide strategy that is based on one degree of freedom tests for all the genotyped variants, and for all the untyped variants for which there is sufficient information in the observed data. The set of untyped variants to be tested is found using multi-locus measures of linkage disequilibrium and haplotype frequencies from a reference database such as HapMap (The International HapMap Consortium [2003] Nature 426:789-796). We introduce a novel statistic for testing differences in allele frequencies for untyped variation that is based on linear combinations of estimable haplotype frequencies. Algorithms for finding the sets of genotyped markers to be used in testing an untyped allele, and ways of incorporating haplotypes observed in the study data but not in the reference database are also described. The proposed testing strategy can be used as the first step in the analysis of genome-wide association data, and, because every performed test is directed to a marker, it can be used to specify the set of polymorphisms to genotype in follow-up studies. The described methodology provides also a tool for joint analysis of data from studies done on different platforms.

Algorithms↗
PubMed2006

Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus.

OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations.

Crohn's disease (CD) is a chronic inflammation affecting the gastrointestinal tract. Three mutations (Arg702Trp, Gly908Arg and Leu1007fsinsC) within the NOD2/CARD15 gene increase CD susceptibility. Here, we define cytokine regulation in primary human mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. By microarray, MDP induces a broad array of transcripts, including interleukin 1beta (IL-1beta) and interleukin 8 (IL-8). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Electromobility shift assay demonstrated that MDP-induced NF-kappaB activation is mediated via p50 and p65 subunits, but not RelB or c-Rel. In wild-type individuals, MDP-induced IL-8 protein expression with a greater response to high dose (1 micro g/ml) compared with low-dose (10 ng/ml) MDP. At low MDP doses, in all homozygotes, we observed no induction of IL-8 protein. With high doses of MDP, Leu1007fsinsC homozygotes showed no induction. Modest induction of IL-8 protein was observed in Gly908Arg and Arg702Trp homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. In wild-type healthy control, CD and ulcerative colitis individuals, low-dose MDP and TNFalpha alone results in only modest IL-1beta protein induction. With MDP plus TNFalpha, there is a synergistic induction of IL-1beta secretion. In Leu1007fsinsC homozygotes, there is a profound defect in IL-1beta secretion, despite marked induction of IL-1beta mRNA. These findings demonstrate post-transcriptional dependency on the NOD2/CARD15 pathway for IL-1beta secretion with MDP and TNFalpha treatment. Taken together, these studies suggest that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

A genome scan in 260 inflammatory bowel disease-affected relative pairs.

We report the results of a new genome scan in 260 IBD-affected relative pairs from 139 families that we have recruited since our previous IBD genome scans were performed. The goal of our study was to determine whether we could extend the linkage evidence in any of the more than 20 regions with nominal evidence for linkage to IBD in previous individual genome scans in order to prioritize regions for further study.

Colitis, Ulcerative↗
PubMed2004

A genome scan in 260 inflammatory bowel disease-affected relative pairs.

We report genome-wide linkage results using model-free linkage analysis (Allegro) of 358 autosomal microsatellites in 260 new inflammatory bowel disease-affected relative pairs from 139 Caucasian families, including 108 Crohn's disease-affected relative pairs and 72 ulcerative colitis-affected relative pairs. Our results provide confirmatory evidence for linkage between the IBD2 locus and the inflammatory bowel disease phenotype (lod = 2.12 at GATA91H06) and ulcerative colitis phenotype (lod = 1.44 at GATA91H06), but not the Crohn's disease phenotype. We also find confirmatory evidence for linkage between the IBD3 locus and Crohn's disease (lod = 2.26 at D6S2439) but not ulcerative colitis or inflammatory bowel disease. We find nominal evidence for linkage of inflammatory bowel disease to loci on chromosome 6q (lod = 2.21 between D6S2436/D6S305), 8q (lod = 1.57 between D8S1113/D8S1136), 15q (lod = 2.02 between D15S652/D15S816), and 22 (lod = 1.50 at D22S689); of Crohn's disease to loci on chromosome 5q approximately 50 centiMorgans centromeric from IBD5 (lod = 1.69 at D5S1501) and 15q (lod = 1.82 at D15S652); and of ulcerative colitis to a locus on chromosome 2q (lod = 2.19 between D2S1776/D2S1391). The inflammatory bowel disease linkage peak on chromosome 6q is located in the same general region that showed nominal evidence for linkage to IBD in a Belgian genome scan, and the ulcerative colitis linkage peak on chromosome 2q is located in the same general region that showed nominal evidence for linkage to the inflammatory bowel disease, Crohn's disease, or ulcerative colitis phenotypes in four other European/North American genome scans.

Adolescent↗
PubMed2004

Measuring the relative information in allele-sharing linkage studies.

In the context of allele-sharing methods, this article investigates ways of measuring the information in the marker data relative to the amount of information that would have been available if the identity-by-descent (IBD) process were known. Such measures are needed to decide whether new markers can substantially modify the evidence for excess sharing. We propose new measures that take advantage of the properties of the exponential model introduced by Kong and Cox (1997, American Journal of Human Genetics61, 1179-1188). These measures are related to Fisher Information and hence are also efficiency measures. Large-sample and small-sample properties of the new and previously proposed measures of information are examined.

Alleles↗
PubMed2003

Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan.

BACKGROUND & AIMS: The NOD2 variants R702W, G908R, and L1007fsinsC are strongly associated with Crohn's disease (CD) in both European and American populations, but whether this susceptibility extends to all ethnic groups remains unknown. Except for the L1007fsinsC mutation, which produces a truncated NOD2 protein, the functional activity of the major CD-associated variants G908R and R702W is unknown. METHODS: Individuals were genotyped for R702W, G908R, and L1007fsinsC. The ability of G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and peptidoglycan (PGN) was determined in HEK293T kidney cells. RESULTS: G908R and L1007fsinsC, but not R702W, were associated with disease susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly higher allele frequency carriage of G908R and lower carriage of R702W compared with non-Jewish whites with CD. Functional studies revealed that the G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S are defective in their ability to respond to bacterial LPS and PGN, whereas P268S alone exhibited wild-type activity. CONCLUSIONS: R702W is not associated with susceptibility to CD in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components, providing evidence for a unifying molecular mechanism whereby NOD2 mutations contribute to disease susceptibility.

Alleles↗