Quantifying the effects of sleep on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment.

BACKGROUND: Despite the promise of wearable sensors for both rehabilitation research and clinical care, these technologies pose significant burden on data collectors and analysts. Investigations of factors that may influence the wearable sensor data processing pipeline are needed to support continued use of these technologies in rehabilitation research and integration into clinical care settings. The purpose of this study was to investigate the effect of one such factor, sleep, on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment and across a two-day wearing period. METHODS: This was a secondary analysis of data collected during a prospective, longitudinal cohort study (n = 127 individuals, 62 with upper limb impairment and 65 without). Participants wore a wearable sensor on each wrist for 48 h. Five upper limb sensor variables were calculated over the full wear period (sleep included) and with sleep time removed (sleep excluded): preferred time, non-preferred time, use ratio, non-preferred magnitude and its standard deviation. Linear mixed effects regression was used to quantify the effect of sleep on each sensor variable and determine if the effect differed between people with and without upper limb impairment and across a two-day wearing period. RESULTS: There were significant differences between sleep included and excluded for the variables preferred time (p < 0.001), non-preferred time (p < 0.001), and non-preferred magnitude standard deviation (p = 0.001). The effect of sleep was significantly different between people with and without upper limb impairment for one variable, non-preferred magnitude (p = 0.02). The effect of sleep was not substantially different across wearing days for any of the variables. CONCLUSIONS: Overall, the effects of sleep on sensor-derived variables of upper limb accelerometry are small, similar between people with and without upper limb impairment and across a two-day wearing period, and can likely be ignored in most contexts. Ignoring the effect of sleep would simplify the data processing pipeline, facilitating the use of wearable sensors in both research and clinical practice.

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

Computed tomography of suppurative and neoplastic diseases involving the canine omenta and omental bursa.

The greater and lesser omenta are fused peritoneal folds that largely delimit the omental bursa (lesser peritoneal cavity). The omental bursa is a potential space within the abdominal cavity that communicates with the greater peritoneal cavity via the omental (epiploic) foramen: it is subdivided into the omental vestibule, caudal omental recess, and splenic recess. Aims of this retrospective case series study were to describe the frequencies of CT findings of dogs with confirmed inflammatory or neoplastic disease of the omenta, omental bursa, or both. The sample included seven adult, medium-to-large breed dogs. All had fluid in the greater peritoneal cavity and 5/7 (71%) dogs also had fluid in the omental bursa. Primary suppurative inflammatory disease was present in three dogs, each dog had a large abscess with central gas in either the omental vestibule (two dogs) or caudal omental recess (one dog). Both abscesses in the omental vestibule arose from the papillary process of the caudate liver lobe and were surgically removed without complication. Neoplasia was present in four dogs and either arose from omentum (hemangiosarcoma, carcinoma) or infiltrated the omentum from an adjacent organ (splenic leiomyosarcoma, gastric adenocarcinoma). Neoplasms created mass-like tumors, infiltrative tumors, or both and had variable distribution (focal, multifocal, or locally extensive). All dogs with neoplasia were euthanized. CT signs of inflammatory and neoplastic disease overlapped, but the presence of gas might prioritize abscessation. CT signs helped decide feasibility of surgery based on extent of local invasion, especially involvement of structures passing through the porta hepatis.

Comparison of Work Relative Value Units for Outpatient Pediatric and Adult Dermatology Encounters.

Importance: Dermatologists with specialty training in pediatric dermatology are scarce, which can mean extended wait times and reduced access to care for patients. Lower compensation for pediatric dermatology visits compared with adult visits may affect physician career choice and contribute to workforce shortages. Objective: To evaluate differences in work relative value units (wRVUs) generated by pediatric and adult outpatient dermatology encounters. Design, Setting, and Participants: This cross-sectional study used data from outpatient dermatology encounters at a single-site academic center in Atlanta, Georgia, from September 1, 2016, to March 31, 2020. Encounters with patients younger than 18 years were classified as pediatric, and encounters with those 18 years or older were classified as adult. Encounters with missing data were excluded as were those generating 0 wRVUs, inpatient visits, nursing visits, postoperative encounters, cosmetic procedures, phototherapy visits, and Mohs surgery encounters. Main Outcomes and Measures: Work relative value units generated per encounter type were assessed through multivariable linear regression models adjusted for the potential confounder of sex. Results: The study included 12 989 pediatric dermatology encounters (mean [SD] age, 7.3 [5.2] years; 7586 [58.4%] girls) and 78 057 adult dermatology encounters (mean [SD] age, 54.9 [18.9] years; 45 724 [58.6%] women). Pediatric encounters were associated with 0.23 (95% CI, 0.21-0.25; P < .001) fewer wRVUs than adult encounters after adjusting for sex. In a mediation analysis, biopsies and destruction of premalignant lesions explained 74.1% (95% CI, 69.6%-77.9%; P < .001) of the wRVU difference between pediatric and adult encounters. Conclusions and Relevance: This cross-sectional study found significant differences in wRVUs generated between adult and pediatric dermatology encounters that were largely attributable to biopsies and destruction of premalignant lesions. Policies that increase the value of cognitive services to be on par with procedural care may mitigate wRVU differences and improve reimbursement for pediatric dermatologists.

Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells.

BACKGROUND: Environmental factors, such as oxidative stress, have the potential to modify the epigenetic landscape of cells. We have previously shown that DNA methyltransferase (DNMT) activity can be inhibited by sublethal doses of hydrogen peroxide (H2O2). However, site-specific changes in DNA methylation and the reversibility of any changes have not been explored. Using bead chip array technology, differential methylation was assessed in Jurkat T-lymphoma cells following exposure to H2O2. RESULTS: Sublethal H2O2 exposure was associated with an initial genome-wide decrease in DNA methylation in replicating cells, which was largely corrected 72 h later. However, some alterations were conserved through subsequent cycles of cell division. Significant changes to the variability of DNA methylation were also observed both globally and at the site-specific level. CONCLUSIONS: This research indicates that increased exposure to H2O2 can result in long-term alterations to DNA methylation patterns, providing a mechanism for environmental factors to have prolonged impact on gene expression.

MinION Sequencing of colorectal cancer tumour microbiomes-A comparison with amplicon-based and RNA-Sequencing.

BACKGROUND: Recent evidence suggests a role for the gut microbiome in the development and progression of many diseases and many studies have been carried out to analyse the microbiome using a variety of methods. In this study, we compare MinION sequencing with meta-transcriptomics and amplicon-based sequencing for microbiome analysis of colorectal tumour tissue samples. METHODS: DNA and RNA were extracted from 11 colorectal tumour samples. 16S rRNA amplicon sequencing and MinION sequencing was carried out using genomic DNA, and RNA-Sequencing for meta-transcriptomic analysis. Non-human MinION and RNA-Sequencing reads, and 16S rRNA amplicon sequencing reads were taxonomically classified using a database built from available RefSeq bacterial and archaeal genomes and a k-mer based algorithm in Kraken2. Concordance between the three platforms at different taxonomic levels was tested on a per-sample basis using Spearman's rank correlation. RESULTS: The average number of reads per sample using RNA-Sequencing was greater than 129 times that generated using MinION sequencing. However, the average read length of MinION sequences was more than 13 times that of RNA or 16S rRNA amplicon sequencing. Taxonomic assignment using 16S sequencing was less reliable beyond the genus level, and both RNA-Sequencing and MinION sequencing could detect greater numbers of phyla and genera in the same samples, compared to 16S sequencing. Bacterial species associated with colorectal cancer, Fusobacterium nucleatum, Parvimonas micra, Bacteroides fragilis and Porphyromonas gingivalis, were detectable using MinION, RNA-Sequencing and 16S rRNA amplicon sequencing data. CONCLUSIONS: Long-read sequences generated using MinION sequencing can compensate for low numbers of reads for bacterial classification. MinION sequencing can discriminate between bacterial strains and plasmids and shows potential as a cost-effective tool for rapid microbiome sequencing in a clinical setting.

T Cell Repertoire Maturation Induced by Persistent and Latent Viral Infection Is Insufficient to Induce Costimulation Blockade Resistant Organ Allograft Rejection in Mice.

CD28:CD80/86 pathway costimulation blockade (CoB) with the CD80/86-specific fusion protein CTLA4-Ig prevents T cell-mediated allograft rejection in mice. However, in humans, transplantation with CoB has been hampered by CoB-resistant rejection (CoBRR). CoBRR has been attributed in part to pathogen-driven T cell repertoire maturation and resultant heterologous alloreactive memory. This has been demonstrated experimentally in mice. However, prior murine models have used viral pathogens, CoB regimens, graft types, and/or antigen systems atypically encountered clinically. We therefore sought to explore whether CoBRR would emerge in a model of virus-induced memory differentiation designed to more closely mimic clinical conditions. Specifically, we examined mouse homologs of clinically prevalent viruses including murine polyomavirus, cytomegalovirus, and gammaherpesvirus 68 in the presence of clinically relevant maintenance CoB regimens using a fully MHC-mismatched, vascularized allograft model. Infected mice developed a significant, sustained increase in effector memory T cells consistent with that seen in humans, but neither developed heterologous alloreactivity nor rejected primarily vascularized heterotopic heart transplants at an increased rate compared with uninfected mice. These results indicate that memory acquisition alone is insufficient to provoke CoBRR and suggest that knowledge of prior latent or persistent viral infection may have limited utility in anticipating heterologous CoB-resistant alloimmunity.

Nanopore sequencing of full-length BRCA1 mRNA transcripts reveals co-occurrence of known exon skipping events.

BACKGROUND: Laboratory assays evaluating the effect of DNA sequence variants on BRCA1 mRNA splicing may contribute to classification by providing molecular evidence. However, our knowledge of normal and aberrant BRCA1 splicing events to date has been limited to data derived from assays targeting partial transcript sequences. This study explored the utility of nanopore sequencing to examine whole BRCA1 mRNA transcripts and to provide accurate categorisation of in-frame and out-of-frame splicing events. METHODS: The exon structure of BRCA1 transcripts from a previously studied control lymphoblastoid cell line were assessed using MinION nanopore sequencing of long-range reverse transcriptase-PCR amplicons. RESULTS: Our study identified and characterised 32 complete BRCA1 isoforms, including 18 novel isoforms which showed skipping of multiple contiguous and/or non-contiguous exons. Furthermore, we show that known BRCA1 exon skipping events, such as Δ(9,10) and Δ21, can co-occur in a single transcript, with some isoforms containing four or more alternative splice junctions. Fourteen novel isoforms were formed entirely from a combination of previously identified alternative splice junctions, suggesting that the total number of BRCA1 isoforms might be lower than the number of splicing events reported previously. CONCLUSIONS: Our results highlight complexity in BRCA1 transcript structure that has not been described previously. This finding has key implications for predicting the translation frame of splicing transcripts, important for interpreting the clinical significance of spliceogenic variants. Future research is warranted to quantitatively assess full-length BRCA1 transcript levels, and to assess the application of nanopore sequencing for routine evaluation of potential spliceogenic variants.

Effect of 7,8-dihydroneopterin mediated CD36 down regulation and oxidant scavenging on oxidised low-density lipoprotein induced cell death in human macrophages.

The role of CD36 in oxidised low-density lipoprotein (oxLDL) mediated cell death was examined by down regulating the receptor level with the macrophage generated antioxidant 7,8-dihydroneopterin. Down regulation of CD36 protein levels in human monocyte derived macrophages by 7,8-dihydroneopterin corresponded to a decrease in CD36-mRNA. The oxidation products of 7,8-dihydroneopterin, dihydroxanthopterin and neopterin did not significantly down regulate CD36. The CD36 down regulation resulted in a decrease in oxLDL uptake measured as 7-ketocholesterol accumulation. Though less oxLDL was taken up by the macrophages as a result of the 7,8-dihydroneopterin induced down regulation in CD36 levels, the cytotoxicity of the oxLDL was not decreased. Addition of 7,8-dihydroneopterin to oxLDL treated macrophages decreased the concentration of intracellular oxidants. In the presence of oxLDL, 7,8-dihydroneopterin was oxidised to neopterin showing that the 7,8-dihydroneopterin was scavenging intracellular oxidants generated in response to the oxLDL. The results show CD36 down regulation does not protect human macrophages form oxLDL cytotoxicity but 7,8-dihydroneopterin intracellular oxidant scavenging is protective.

Single nucleotide polymorphism discovery via genotyping by sequencing to assess population genetic structure and recurrent polyploidization in Andropogon gerardii.

PREMISE OF THE STUDY: Autopolyploidy, genome duplication within a single lineage, can result in multiple cytotypes within a species. Geographic distributions of cytotypes may reflect the evolutionary history of autopolyploid formation and subsequent population dynamics including stochastic (drift) and deterministic (differential selection among cytotypes) processes. Here, we used a population genomic approach to investigate whether autopolyploidy occurred once or multiple times in Andropogon gerardii, a widespread, North American grass with two predominant cytotypes. METHODS: Genotyping by sequencing was used to identify single nucleotide polymorphisms (SNPs) in individuals collected from across the geographic range of A. gerardii. Two independent approaches to SNP calling were used: the reference-free UNEAK pipeline and a reference-guided approach based on the sequenced Sorghum bicolor genome. SNPs generated using these pipelines were analyzed independently with genetic distance and clustering. KEY RESULTS: Analyses of the two SNP data sets showed very similar patterns of population-level clustering of A. gerardii individuals: a cluster of A. gerardii individuals from the southern Plains, a northern Plains cluster, and a western cluster. Groupings of individuals corresponded to geographic localities regardless of cytotype: 6x and 9x individuals from the same geographic area clustered together. CONCLUSIONS: SNPs generated using reference-guided and reference-free pipelines in A. gerardii yielded unique subsets of genomic data. Both data sets suggest that the 9x cytotype in A. gerardii likely evolved multiple times from 6x progenitors across the range of the species. Genomic approaches like GBS and diverse bioinformatics pipelines used here facilitate evolutionary analyses of complex systems with multiple ploidy levels.

S100A9 induced inflammatory responses are mediated by distinct damage associated molecular patterns (DAMP) receptors in vitro and in vivo.

Release of endogenous damage associated molecular patterns (DAMPs), including members of the S100 family, are associated with infection, cellular stress, tissue damage and cancer. The extracellular functions of this family of calcium binding proteins, particularly S100A8, S100A9 and S100A12, are being delineated. They appear to mediate their functions via receptor for advanced glycation endproducts (RAGE) or TLR4, but there remains considerable uncertainty over the relative physiological roles of these DAMPs and their pattern recognition receptors. In this study, we surveyed the capacity of S100 proteins to induce proinflammatory cytokines and cell migration, and the contribution RAGE and TLR4 to mediate these responses in vitro. Using adenoviral delivery of murine S100A9, we also examined the potential for S100A9 homodimers to trigger lung inflammation in vivo. S100A8, S100A9 and S100A12, but not the S100A8/A9 heterodimer, induced modest levels of TLR4-mediated cytokine production from human PBMC. In contrast, for most S100s including S100A9, RAGE blockade inhibited S100-mediated cell migration of THP1 cells and major leukocyte populations, whereas TLR4-blockade had no effect. Intranasal administration of murine S100A9 adenovirus induced a specific, time-dependent predominately macrophage infiltration that coincided with elevated S100A9 levels and proinflammatory cytokines in the BAL fluid. Inflammatory cytokines were markedly ablated in the TLR4-defective mice, but unexpectedly the loss of TLR4 signaling or RAGE-deficiency did not appreciably impact the S100A9-mediated lung pathology or the inflammatory cell infiltrate in the alveolar space. These data demonstrate that physiological levels of S100A9 homodimers can trigger an inflammatory response in vivo, and despite the capacity of RAGE and TLR4 blockade to inhibit responses in vitro, the response is predominately independent of both these receptors.

Environmental correlates of cytotype distribution in Andropogon gerardii (Poaceae).

UNLABELLED: • PREMISE OF THE STUDY: Information about geographic distribution of cytotypes can provide insight into the origin and maintenance of autopolyploid complexes and builds a foundation for understanding cytotype differentiation and the dynamics of mixed-ploidy populations. Here, we investigate environmental correlates of the geographic distributions of 6x and 9x individuals in the ecologically dominant grass Andropogon gerardii to examine the role of climate in shaping patterns of cytotype distribution in this species.• METHODS: Flow cytometry was used to estimate ploidy level in 352 individuals from 32 populations across North America. Ecological differentiation of cytotypes was tested by relating BIOCLIM variables to cytotype distribution using principal components analysis and partial linear regression.• KEY RESULTS: Broad geographic sampling confirmed two primary cytotypes-6x (hexaploid) and 9x (enneaploid)-and revealed that 9x plants are more common than previously thought. Enneaploids occur frequently in the southern portions of the range, with hexaploids dominating in northern regions. Mixed-ploidy populations were common (46.9%). Principal components analysis and partial linear regression indicated that reduced summer precipitation and increased variation in diurnal and seasonal temperature range were significant predictors of the frequency of 9x plants in a population.• CONCLUSIONS: Results indicate that (1) geographic distribution of 6x and 9x individuals is nonrandom; (2) environmental variables are associated with cytotype distribution in A. gerardii; and (3) nearly half of populations surveyed include both 6x and 9x individuals. The persistence of mixed-ploidy populations may reflect a combination of recurrent polyploid formation and the prevalence of clonal reproduction.

Toxicity of Deepwater Horizon source oil and the chemical dispersant, Corexit® 9500, to coral larvae.

Acute catastrophic events can cause significant damage to marine environments in a short time period and may have devastating long-term impacts. In April 2010 the BP-operated Deepwater Horizon (DWH) offshore oil rig exploded, releasing an estimated 760 million liters of crude oil into the Gulf of Mexico. This study examines the potential effects of oil spill exposure on coral larvae of the Florida Keys. Larvae of the brooding coral, Porites astreoides, and the broadcast spawning coral, Montastraea faveolata, were exposed to multiple concentrations of BP Horizon source oil (crude, weathered and WAF), oil in combination with the dispersant Corexit® 9500 (CEWAF), and dispersant alone, and analyzed for behavior, settlement, and survival. Settlement and survival of P. astreoides and M. faveolata larvae decreased with increasing concentrations of WAF, CEWAF and Corexit® 9500, however the degree of the response varied by species and solution. P. astreoides larvae experienced decreased settlement and survival following exposure to 0.62 ppm source oil, while M. faveolata larvae were negatively impacted by 0.65, 1.34 and 1.5 ppm, suggesting that P. astreoides larvae may be more tolerant to WAF exposure than M. faveolata larvae. Exposure to medium and high concentrations of CEWAF (4.28/18.56 and 30.99/35.76 ppm) and dispersant Corexit® 9500 (50 and 100 ppm), significantly decreased larval settlement and survival for both species. Furthermore, exposure to Corexit® 9500 resulted in settlement failure and complete larval mortality after exposure to 50 and 100 ppm for M. faveolata and 100 ppm for P. astreoides. These results indicate that exposure of coral larvae to oil spill related contaminants, particularly the dispersant Corexit® 9500, has the potential to negatively impact coral settlement and survival, thereby affecting the resilience and recovery of coral reefs following exposure to oil and dispersants.

Moderating role of the MAOA genotype in antisocial behaviour.

BACKGROUND: Recent studies have examined gene×environment (G×E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between exposure to adversity and antisocial behaviour. The present study examined a novel method for assessing interactions between a single gene and multiple risk factors related to environmental and personal adversity. AIMS: To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to a series of risk factors. METHOD: Participants were 399 males from the Christchurch Health and Development Study who had complete data on: (a) MAOA promoter region variable number tandem repeat genotype; (b) antisocial behaviour (criminal offending) to age 30 and convictions to age 21; and (c) maternal smoking during pregnancy, IQ, childhood maltreatment and school failure. RESULTS: Poisson regression models were fitted to three antisocial behaviour outcomes (property/violent offending ages 15-30; and convictions ages 17-21), using measures of exposure to adverse childhood circumstances. The analyses revealed consistent evidence of G x E interactions, such that those with the low-activity MAOA variant who were exposed to adversity in childhood were significantly more likely to report offending in late adolescence and early adulthood. CONCLUSIONS: The present findings add to the evidence suggesting that there is a stable G x E interaction involving MAOA, a range of adverse environmental and personal factors, and antisocial behaviour across the life course. These analyses also demonstrate the utility of using multiple environmental/personal exposures to test G×E interactions.

Glomus tumor of the ovary masquerading as granulosa cell tumor: case report.

A solid right adnexal mass in a 73-year-old woman bled profusely with mobilization mimicking a granulosa cell tumor. There was almost complete replacement of the ovary by a circumscribed, 4.0 cm tumor with a hemorrhagic, solid cut surface. Morphologic and phenotypic correlation supported a diagnosis of glomus tumor. Large gaping vessels and small sinusoidal-type vessels formed an anastomotic vascular network with an inner endothelial lining (CD31+/CD34+) and an outer layer of glomocytes (actin+/desmin-/inhibin-). The hemangiopericytoma-like vasculature accounted for bleeding during surgery.

Feasibility of ex vivo FDG PET of the colon.

To facilitate future direct correlations between fluorine 18 fluorodeoxyglucose (FDG)-avid colonic lesions and immunohistochemical assay findings, the authors tested the feasibility of ex vivo FDG positron emission tomography (PET) of the colon resected from humans. In this institutional review board-approved, HIPAA-compliant study, the authors, after obtaining informed patient consent, injected FDG intraoperatively in five patients with neoplasms and imaged their resected colons approximately 3 hours later. The colon could be imaged during this fairly limited time interval, and polyps and cancers could be identified. No biologic tissue degradation occurred. The authors concluded that ex vivo FDG PET of the colon is feasible and, when combined with careful histologic and immunohistochemical analyses, may serve as a research tool to determine the mechanisms of the normal colonic uptake of FDG and the localization of FDG in polyps and cancers.

Generation of a novel system for studying spleen tyrosine kinase function in macrophages and B cells.

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is expressed primarily in hematopoietic cells. Because this protein has been implicated in processes such as Fc-mediated phagocytosis, BCR signaling, oxidative burst, degranulation, cytokine secretion, and integrin-mediated outside-in signaling, it is hypothesized that Syk may be a viable target in the treatment of a variety of autoimmune and inflammatory diseases. Because efforts to design a small-molecule therapeutic that specifically inhibits Syk have been largely unsuccessful, and genetic studies of Syk have been hampered by the fact that syk-/- mice die in utero, we have taken a chemical genetic approach to study the function of Syk. Specifically, we have created a mutant form of Syk that retains its wild-type function, but is susceptible to inhibition by enlarged derivatives of the tyrosine kinase inhibitor, PP1. We report in this study that Syk M442A S505A reconstituted wild-type function when introduced into murine syk-/- bone marrow-derived macrophages and syk-/- DT40 chicken B cells, as determined by functional and biochemical assays. Furthermore, after screening a series of PP1 derivatives, we identified one compound, namely 2,3-DMB-PP1, that specifically inhibited Syk M442A S505A, but not wild-type Syk. This system provides us with the power to characterize immune functions that are Syk specific, and furthermore, it provides us with a tool to assess how inhibition of Syk may alter an immune response and influence disease pathogenesis and/or progression.

IL23R R381Q and ATG16L1 T300A are strongly associated with Crohn's disease in a study of New Zealand Caucasians with inflammatory bowel disease.

OBJECTIVE: Recently, separate genome-wide association analyses have identified nonsynonymous SNPs in IL23R and ATG16L1 (rs11209026; c1142G>A, R381Q, and rs2241880; c1338A>G, T300A, respectively) as strong candidate susceptibility factors for Crohn's disease (CD) in whites. The aim of our study was to test whether these SNPs are associated with CD in a population-based cohort of New Zealand Caucasian inflammatory bowel disease (IBD) patients. METHODS: Allele frequencies of rs11209026 and rs2241880 were determined in 496 CD patients, 466 ulcerative colitis (UC) patients, and 591 controls. Distribution of the relevant alleles was compared between controls and IBD patients. rs11209026 and rs2241880 genotype distributions were examined both within IBD clinical subphenotypes and CARD15 genotypes. RESULTS: rs11209026 and rs2241880 were both associated with CD (P valuers11209026=0.0026, OR 0.54, 95% CI 0.36-0.81; P valuers2241880=0.0001, OR 1.41, 95% CI 1.18-1.67). In addition, there was evidence for association of rs11209026 with UC (P value=0.037, OR 0.66, 95% CI 0.45-0.98). No significant association was observed between IL23R genotype or ATG16L1 genotype and IBD subphenotypes. IL23R was associated with CD and UC only in the absence of CARD15 mutations, whereas ATG16L1 was associated with CD in the presence and absence of CARD15 mutations. CONCLUSIONS: We replicated the previously reported associations between CD and rs11209026 and rs2241880, confirming that IL23R and ATG16L1 are susceptibility loci for CD in the New Zealand population. We also provide further evidence for association of rs11209026 with UC and a report of an additive effect between IL23R and CARD15 genotypes in CD.