Background
Crohn’s disease (CD) is highly heritable. NOD2 has emerged as the main susceptibility gene among individuals of European ancestry; however, NOD2 does not appear to contribute to CD susceptibility among many non-European populations. Today’s African American (AA) population represents an admixture of West African (80%) and European (20%) ancestry. Since genotype-based tools are becoming increasingly available for CD, it is important that we validate the risk variants in different populations, such as admixed AAs.
Methods
We analyzed the NOD2 variants among admixed AAs (n=321, 240 with CD and 111 healthy controls) and non-admixed West Africans (n=40) by genotyping for 4 known disease-causing NOD variants. We extracted the publically available 1000 Genomes data on NOD2 variants from 500 subjects of West African origin. Association with disease was evaluated by logistic regression.
Results
An association with CD was found for the classical SNP 1007fs (2.6% CD, 0% HC, p=0.012); there was no association when the genotypic and allelic frequencies of the risk alleles were compared for SNPs R702W and G908R. No known NOD2 risk alleles were seen in either the West African cohort or in subjects of African ancestry from the 1000 Genomes project.
Conclusions
The NOD2 gene is a risk for CD in AAs, although the allele frequencies and the attributable risk are much lower compared to Caucasians. The risk alleles are not seen in the West African population suggesting the risk for CD contributed by NOD2 among AAs is due exclusively to recent European admixture
by
David J Cutler;
Michael Zwick;
David T. Okou;
Sampath Prahalad;
Thomas Walters;
Stephen L. Guthery;
Marla Dubinsky;
Robert Baldassano;
Wallace V. Crandall;
Joel Rosh ;
James Markowitz;
Michael Stephens;
Richard Kellermayer;
Marian Pfefferkon;
Melvin B. Heyman;
Neal LeLeiko;
David Mack;
Dedrick Moulton;
Michael D. Kappelman;
Archana Kumar;
Jarod Prince;
Promita Bose;
Kajari Mondal;
Dhanya Ramchandran;
John F. Bohnsack;
Anne M. Griffiths ;
Yael Haberman;
Jonah Essers;
Susan D. Thompson;
Bruce Aronow;
David J. Keljo;
Jeffrey S. Hyams;
Lee A. Denson;
Subra Kugathasan
The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
Objectives
Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS).
Methods
155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA.
Results
CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males.
Conclusions
TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA.
by
Peter E. Chen;
Kristin M. Willner;
Amy Butani;
Shakia Dorsey;
Matroner George;
Andrew Stewart;
Shannon M. Lentz;
Christopher E. Cook;
Arya Akmal;
Lance B. Price;
Paul S. Keim;
Alfred Mateczun;
Trupti N. Brahmbhatt;
Kimberly A. Bishop-Lilly;
Michael Zwick;
Timothy Read;
Shanmuga Sozhamannan
Background: The anthrax letter attacks of 2001 highlighted the need for rapid identification of biothreat agents not only for epidemiological surveillance of the intentional outbreak but also for implementing appropriate countermeasures, such as antibiotic treatment, in a timely manner to prevent further casualties. It is clear from the 2001 cases that survival may be markedly improved by administration of antimicrobial therapy during the early symptomatic phase of the illness; i.e., within 3 days of appearance of symptoms. Microbiological detection methods are feasible only for organisms that can be cultured in vitro and cannot detect all genetic modifications with the exception of antibiotic resistance. Currently available immuno or nucleic acid-based rapid detection assays utilize known, organism-specific proteins or genomic DNA signatures respectively. Hence, these assays lack the ability to detect novel natural variations or intentional genetic modifications that circumvent the targets of the detection assays or in the case of a biological attack using an antibiotic resistant or virulence enhanced Bacillus anthracis, to advise on therapeutic treatments. Methodology/Principal Findings: We show here that the Roche 454-based pyrosequencing can generate whole genome draft sequences of deep and broad enough coverage of a bacterial genome in less than 24 hours. Furthermore, using the unfinished draft sequences, we demonstrate that unbiased identification of known as well as heretofore-unreported genetic modifications that include indels and single nucleotide polymorphisms conferring antibiotic and phage resistances is feasible within the next 12 hours. Conclusions/Significance: Second generation sequencing technologies have paved the way for sequence-based rapid identification of both known and previously undocumented genetic modifications in cultured, conventional and newly emerging biothreat agents. Our findings have significant implications in the context of whole genome sequencing-based routine clinical diagnostics as well as epidemiological surveillance of natural disease outbreaks caused by bacterial and viral agents.
by
Peter E. Chen;
Christopher Cook;
Andrew C. Stewart;
Niranjan Nagarajan;
Dan D. Sommer;
Mihai Pop;
Brendan Thomason;
Maureen P. Kiley Thomason;
Shannon Lentz;
Nichole Nolan;
Shanmuga Sozhamannan;
Alexander Sulakvelidze;
Alfred Mateczun;
Lei Du;
Michael Zwick;
Timothy D Read
Background
New DNA sequencing technologies have enabled detailed comparative genomic analyses of entire genera of bacterial pathogens. Prior to this study, three species of the enterobacterial genus Yersinia that cause invasive human diseases (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) had been sequenced. However, there were no genomic data on the Yersinia species with more limited virulence potential, frequently found in soil and water environments.
Results
We used high-throughput sequencing-by-synthesis instruments to obtain 25- to 42-fold average redundancy, whole-genome shotgun data from the type strains of eight species: Y. aldovae, Y. bercovieri, Y. frederiksenii, Y. kristensenii, Y. intermedia, Y. mollaretii, Y. rohdei, and Y. ruckeri. The deepest branching species in the genus, Y. ruckeri, causative agent of red mouth disease in fish, has the smallest genome (3.7 Mb), although it shares the same core set of approximately 2,500 genes as the other members of the species, whose genomes range in size from 4.3 to 4.8 Mb. Yersinia genomes had a similar global partition of protein functions, as measured by the distribution of Cluster of Orthologous Groups families. Genome to genome variation in islands with genes encoding functions such as ureases, hydrogeneases and B-12 cofactor metabolite reactions may reflect adaptations to colonizing specific host habitats.
Conclusions
Rapid high-quality draft sequencing was used successfully to compare pathogenic and non-pathogenic members of the Yersinia genus. This work underscores the importance of the acquisition of horizontally transferred genes in the evolution of Y. pestis and points to virulence determinants that have been gained and lost on multiple occasions in the history of the genus.
Background
Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract.
Methodology/Principal Findings
To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations.
Conclusions/Significance
These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.