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1.
PLoS One ; 17(12): e0275970, 2022.
Article in English | MEDLINE | ID: mdl-36576894

ABSTRACT

BACKGROUND: Surgical site infections (SSI) present a substantial burden to patients and healthcare systems. This study aimed to elucidate the prevalence of SSIs in German hospitals and to quantify their clinical and economic burden based on German hospital reimbursement data (G-DRG). METHODS: This retrospective, cross-sectional study used a 2010-2016 G-DRG dataset to determine the prevalence of SSIs in hospital, using ICD-10-GM codes, after surgical procedures. The captured economic and clinical outcomes were used to quantify and compare resource use, reimbursement and clinical parameters for patients who had or did not have an SSI. FINDINGS: Of the 4,830,083 patients from 79 hospitals, 221,113 were eligible. The overall SSI prevalence for the study period was 4.9%. After propensity-score matching, procedure type, immunosuppression and BMI ≥30 were found to significantly affect the risk of SSI (p<0.001). Mortality and length of stay (LOS) were significantly higher in patients who had an SSI (mortality: 9.3% compared with 4.5% [p<0.001]; LOS (median [interquartile range, IQR]): 28 [27] days compared with 12 [8] days [p<0.001]). Case costs were significantly higher for the SSI group (median [IQR]) €19,008 [25,162] compared with € 9,040 [7,376] [p<0.001]). A median underfunding of SSI was identified at €1,534 per patient. INTERPRETATION: The dataset offers robust information about the "real-world" clinical and economic burden of SSI in hospitals in Germany. The significantly increased mortality of patients with SSI, and their underfunding, calls for a maximization of efforts to prevent SSI through the use of evidence-based SSI-reduction care bundles.


Subject(s)
Financial Stress , Surgical Wound Infection , Humans , Cross-Sectional Studies , Retrospective Studies , Surgical Wound Infection/epidemiology , Inpatients , Length of Stay , Hospitals
2.
Article in English | MEDLINE | ID: mdl-35886468

ABSTRACT

Strategic management is becoming increasingly important for sustainable management in healthcare. The reasons for this can be seen in the increasing complexity, dynamics and uncertainty of the system's regimes and the resulting need for strategic thinking in a long-term period. The scientific discussion of this issue is the aim of the present analytical framework. The starting point is the definition of the term strategic management itself, followed by a reflection on the requirements resulting from the changes in the political, social and economic value systems of our post-industrial society. In this context, Dynaxity Zone III is used to explain the long-term perspective, the high levels of complexity and uncertainty and the responsibility of strategic management as important parameters. For a practical illustration, we demonstrate two selected applications (German hospital financing systems and development process of implants) and how the implementation of strategic management in the health care system shows success.


Subject(s)
Delivery of Health Care , Health Facilities , Uncertainty
3.
Article in English | MEDLINE | ID: mdl-34639328

ABSTRACT

Innovations are the source of all human development and improvement of quality of life. At the same time, they challenge existing standards, solutions and societal patterns. In health care in particular, innovations enable us to treat previously incurable diseases or to make better use of scarce resources. However, they also make existing health care technologies obsolete, force specialists to learn completely new methods and require high investments. Consequently, in this paper we develop a conceptual framework model for the development, adoption and diffusion of innovations in health care. We analyse barriers and promoters of innovations, in particular meta-stability, costs, innovative ability and leadership and apply the framework to three innovations: personalized medicine, digital health, and implants. We conclude that strategic innovation management in healthcare is a prerequisite of the rapid development and adoption of innovations and the improvement of quality of life of the (aging) population.


Subject(s)
Delivery of Health Care , Quality of Life , Health Facilities , Humans , Leadership , Precision Medicine
4.
Pathology ; 49(7): 776-783, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29100713

ABSTRACT

Melanoma patients with BRAF V600E and V600K mutations show complete or partial response to vemurafenib. Detection assays often scan for the common V600E mutation rather than the rare V600K variant, although this mutation can be found in a high proportion of melanoma patients in the South Pacific. Herein, we describe a BRAF high resolution melting (HRM) assay that can differentiate low level of V600E and V600K mutations using formalin fixed, paraffin embedded (FFPE) reference standards for assay validation. The assay is based on the competitive amplification of differentially melting amplicons (CADMA principle) and has a limit of detection of 0.8% mutant allele for V600K and 1.4% mutant allele for V600E. A differentiation between the two mutations based on the melting profile is possible even at low mutation level. Sixty FFPE specimens were scanned and mutations could be scored correctly as confirmed by castPCR. In summary, the developed HRM assay is suitable for detection of V600K and V600E mutations and proved to be reliable and cost effective in a diagnostic environment.


Subject(s)
DNA Mutational Analysis/methods , Melanoma/genetics , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Antineoplastic Agents/therapeutic use , DNA Mutational Analysis/standards , Formaldehyde , Humans , Indoles/therapeutic use , Melanoma/diagnosis , Mutation , Paraffin Embedding , Sensitivity and Specificity , Skin Neoplasms/diagnosis , Sulfonamides/therapeutic use , Tissue Fixation , Vemurafenib
5.
BMJ Open ; 6(2): e008458, 2016 Feb 23.
Article in English | MEDLINE | ID: mdl-26908511

ABSTRACT

OBJECTIVES: Infections and colonisations with multidrug-resistant organisms (MDROs) increasingly affect different types of healthcare facilities worldwide. So far, little is known about additional costs attributable to MDROs outside hospitals. The aim of this study was to analysis the economic burden of multidrug-resistant bacteria in nursing homes in Germany. SETTING: The cost analysis is performed from a microeconomic perspective of the healthcare facilities. Study took place in six long-term care facilities in north-eastern Germany. PARTICIPANTS: Data of 71 residents with a positive MDRO status were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The study analysed MDRO surveillance data from 2011 to 2013. It was supplemented by an empirical analysis to determine the burden on staff capacity and materials consumption. RESULTS: 11,793 days with a positive multidrug-resistant pathogen diagnosis could be included in the analysis. On average, 11.8 (SD ± 6.3) MDRO cases occurred per nursing home. Mean duration per case was 163.3 days (SD ± 97.1). The annual MDRO-related costs varied in nursing homes between €2449.72 and €153,263.74 on an average €12,682.23 per case. Main cost drivers were staff capacity (€43.95 per day and €7177.04 per case) and isolation materials (€24.70 per day and €4033.51 per case). CONCLUSIONS: The importance of MDROs in nursing homes could be confirmed. MDRO-related cost data in this specific healthcare sector were collected for the first time. Knowledge about the burden of MDROs will enable to assess the efficiency of hygiene intervention measures in nursing homes in the future.


Subject(s)
Cost of Illness , Costs and Cost Analysis/economics , Cross Infection/economics , Drug Resistance, Multiple, Bacterial , Homes for the Aged/economics , Nursing Homes/economics , Aged, 80 and over , Costs and Cost Analysis/statistics & numerical data , Female , Germany , Humans , Male
7.
Appl Environ Microbiol ; 77(7): 2541-4, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21317252

ABSTRACT

Increased numbers of adherent invasive Escherichia coli (AIEC) have been found in Crohn's disease (CD) patients. In this report, we investigate the potential of the probiotic Escherichia coli Nissle 1917 (EcN) to reduce features associated with AIEC pathogenicity in an already established infection with AIEC reference strain LF82.


Subject(s)
Antibiosis , Crohn Disease/microbiology , Cytokines/metabolism , Epithelial Cells/microbiology , Escherichia coli/growth & development , Escherichia coli/pathogenicity , Probiotics , Caco-2 Cells , Epithelial Cells/immunology , Escherichia coli Infections/microbiology , Humans
8.
Mutat Res ; 690(1-2): 108-15, 2010 Aug 07.
Article in English | MEDLINE | ID: mdl-20109474

ABSTRACT

The Signal Transducers and Activators of Transcription (STAT)-Janus kinase (JAK) pathway controls signal transduction between cell surface receptors and the nucleus. Two members of that pathway, STAT3 and JAK2, enhanced the risk of Crohn's disease (CD) in recent genome-wide association studies. We replicated these findings in a New Zealand Caucasian case-control cohort, by genotyping two single nucleotide polymorphisms (SNPs) in STAT3 (rs744166(G>A) and rs3816769(C>T)) and rs10758669(A>C) in JAK2, in 302 CD patients and 382 controls. For STAT3, there was a significant decrease in the frequency of the G allele of rs744166 and the C allele of rs3816769 in CD patients as compared with controls (OR=0.76, 95% CI=0.61-0.95, p=0.013; OR=0.71, 95% CI=0.56-0.89, p=0.003). For the JAK2 rs10758669 polymorphism, the homozygous C/C or heterozygous A/C genotypes increased the risk of having CD as compared with the homozygous A/A (OR=1.76, 95% CI=1.26-2.45 and OR=2.36, 95% CI=1.44-3.86, respectively, p=0.0003). Variant alleles in either gene significantly modified the likelihood of inflammatory disease in a colonic location, and of developing extra-intestinal manifestations. The JAK2 variant also strongly enhanced the risk of ileocolonic disease, with stricturing or ileal/stricturing behaviour, requiring a bowel resection. We further studied a subset of our control population, stratified for JAK2 rs10758669 and/or STAT3 rs3816769 genotype. Carrying either the JAK2 or STAT3 IBD risk allele was associated with significantly enhanced susceptibility to DNA damage, as estimated by comet assays in peripheral blood leukocytes, with or without a subsequent oxidative challenge. That is, both risk alleles enhance genomic instability. The JAK2 SNP is part of a haplotype previously associated with enhanced susceptibility to myeloproliferative neoplasms, but functional consequences of the STAT3 variant had not been previously demonstrated. It will be of interest to follow up CD patients carrying either JAK2 or STAT3 risk alleles for development of further secondary effects, including cancer.


Subject(s)
Crohn Disease/genetics , DNA Damage , Genetic Predisposition to Disease , Janus Kinase 2/genetics , Polymorphism, Single Nucleotide , STAT3 Transcription Factor/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genomic Instability , Humans , Infant , Male , New Zealand , Nod2 Signaling Adaptor Protein/genetics , Signal Transduction/genetics
9.
Mutat Res ; 690(1-2): 139-44, 2010 Aug 07.
Article in English | MEDLINE | ID: mdl-20067801

ABSTRACT

The gene-specific modulation of inflammatory cytokines by food bioactives represents a possible approach to the nutritional or pharmaceutical prevention and treatment of inflammatory bowel disease (IBD). There is evidence for a key role of the interleukin-12beta1/23 receptor (IL-12 Rbeta1/23 R) pathway in IBD, and that reduction of the normal expression of the IL-23 R gene may provide a therapeutic target for this disease. The binding of interleukin-23 (IL-23) to its receptor IL-23 R regulates a newly defined effector T-cell subset, Th17 cells, characterised by the production of interleukin-17 (IL-17) and other cytokines, including tumour necrosis factor-alpha (TNF-alpha). In this study we developed an assay that measured IL-17 and TNF-alpha expression after incubation with specific dietary bioactives in the human T-cell Kit 225. It is anticipated that these changes will reflect differences in IL-23 R production, albeit indirectly. The cell line Kit 225 has similarities to Th17 cells, a subset of T cells producing IL-17 and TNF-alpha, and in initial experiments we demonstrated that the cells express both IL-23 receptor subunits, as well as IL-17 and TNF-alpha genes. Upon verification that stimulation of Kit 225 cells with 1ng/mL IL-23 significantly upregulated IL-17 and TNF-alpha gene expression, and IL-17 production, we supplemented cells with selected food bioactives, caffeic acid phenethyl ester (CAPE), epigallocatechin gallate (EGCG), docosahexaenoic acid (DHA), and linoleic acid (LA), and with phorbol myristate acetate (PMA) and sodium salicylate, used as pro-inflammatory and anti-inflammatory controls, respectively. In both unstimulated cells and after IL-23 stimulation, bioactives modulated the pro-inflammatory cytokines involved in IBD, underlining the possible role of foods in this disease. EGCG and DHA, which significantly inhibited both IL-17 and TNF-alpha expression, appeared particularly interesting.


Subject(s)
Caffeic Acids/pharmacology , Catechin/analogs & derivatives , Docosahexaenoic Acids/pharmacology , Interleukin-12/metabolism , Interleukin-23/metabolism , Tumor Necrosis Factor-alpha/metabolism , Catechin/pharmacology , Cell Line, Tumor , Food , Humans , Signal Transduction
10.
Gastroenterol Res Pract ; 2010: 539461, 2010.
Article in English | MEDLINE | ID: mdl-21253534

ABSTRACT

DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17-40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.

11.
Inflamm Bowel Dis ; 16(2): 282-95, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19653290

ABSTRACT

BACKGROUND: The era of genome-wide association studies (GWAS) has led to the identification of many inflammatory bowel disease (IBD)-associated single-nucleotide polymorphisms (SNPs) with unknown function. The next step would be to identify the functional consequences of these polymorphisms in order to target them efficiently for therapeutic purposes. One way to study this type of genetic variation is the use of cell line models. However, to characterize the functional effect of a SNP, it is important to know if the selected cell line model itself carries the studied genetic variation. Here, we genotyped 50 IBD markers across 32 susceptibility genes in 9 commonly used gastrointestinal cell lines. METHODS: We used Sequenom, TaqMan, and DNA sequencing for the genotyping. To determine the expression profile of the selected genes, we conducted real-time RT-PCR. RESULTS: We found variant SNPs in all analyzed cell lines. Almost every minor allele was carried by at least one of the tested cell lines. We analyzed the effect of 4 SNPs in more detail using quantitative real-time RT-PCR (qRT-PCR) comprising genes ATG16L1, CD14, MDR1, and OCTN2. According to our data, only 2 of the commonly studied SNPs in MDR1 and CD14 have an impact on gene expression. CONCLUSIONS: We have identified genotype variants in all analyzed cell lines. Some of them are functional and alter the response to drugs (MDR1) or affect bacterial recognition (TLR4, NOD2). Our results highlight that the genotype should not be neglected in experimental design when using model cell lines.


Subject(s)
Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide/genetics , Alleles , Caco-2 Cells , Cell Line , Chromosome Aberrations , Gene Expression Profiling , Genetic Markers/genetics , Genetic Predisposition to Disease , Genotype , HCT116 Cells , HT29 Cells , Humans , Reverse Transcriptase Polymerase Chain Reaction
12.
Inflamm Bowel Dis ; 15(12): 1784-93, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19685447

ABSTRACT

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the multidrug transporter MDR1 have been associated with inflammatory bowel disease (IBD) in different studies. However, the data are highly controversial. Recently, 6 haplotype tagging SNPs (tSNPs), representing the haplotype variations of the MDR1 gene, were identified. The aims of this study were to genotype these variants and correlate them to disease phenotype in New Zealand IBD patients. MATERIALS AND METHODS: A total of 784 IBD patients and 200 healthy subjects were genotyped for 5 tSNPs and the triallelic MDR1 variant G2677T/A using the Sequenom MassArray platform. Furthermore, the effects of these variants were examined in correlation with phenotypic clinical features. RESULTS: Heterozygous carriers for the variants C1236T, rs2235046 (an SNP in intron 16), and G2677T/A showed a lower risk of developing ulcerative colitis (C1236T: odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.42-0.93, P = 0.03; G2677T/A: OR = 0.59, CI = 0.39-0.89, P = 0.02; and rs2235046: OR = 0.59, 95% CI = 0.38-0.91, P = 0.009) as compared with homozygotes. None of the analyzed markers were associated with Crohn's disease on a genotypic level. Subgroup analysis revealed an association for 2 variants with IBD when stratified for age of onset (C1236T SNP and rs3789243). The MDR1 variant C3435T was associated with disease behavior in CD (OR = 1.45, 95% CI = 1.01-2.08, P = 0.04), whereas the SNP rs3789243 was found to be associated with pancolitis in UC patients (OR = 1.35, CI = 1.00-1.82, P = 0.05). CONCLUSIONS: The results of our study support the role of MDR1 as a candidate gene for ulcerative colitis. Furthermore, our results suggest the possibility of a heterozygous advantage for certain MDR1 variants for this disease.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Genetic Predisposition to Disease , Heterozygote , Inflammatory Bowel Diseases/genetics , Adolescent , Adult , Colitis, Ulcerative/genetics , Female , Genetic Association Studies , Genotype , Haplotypes , Humans , Introns , Male , New Zealand , Polymorphism, Single Nucleotide , Risk , Young Adult
13.
Br J Nutr ; 102(4): 506-8, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19660151

ABSTRACT

Carrying a functional single nucleotide polymorphism (L503F, c. 1672 C>T) in the gene for the Na-dependent organic cation transporter (OCTN1), increases the risk of Crohn's disease (CD) in some, but not all, populations. Case-control data on New Zealand Caucasians show no differences for CD risk between individuals carrying the L503F OCTN1 C-allele when compared with those carrying the variant T-allele. However, more of the New Zealand CD cases report intolerance to maize and mushrooms than those who report beneficial effects or no differences. The OCTN1 gene encodes a transporter for ergothionine, a fungal metabolite at high levels in mushrooms but not widely common in other dietary items. An inability to tolerate mushrooms showed statistically significant associations with the variant OCTN1 genotype. That is, among those individuals reporting adverse effects from mushrooms, there was a higher frequency of the variant T-allele when compared with the general population, or with CD patients overall. We believe that this is a novel gene-diet association, suggesting that individuals carrying the OCTN1 variant single nucleotide polymorphism may have an enhanced risk of adverse symptoms associated with consuming mushrooms. Nutrigenomic approaches to dietary recommendations may be appropriate in this group.


Subject(s)
Agaricales , Alleles , Crohn Disease/genetics , Food Hypersensitivity/genetics , Organic Cation Transport Proteins/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , New Zealand , Regression Analysis , Symporters , White People/genetics , Zea mays
14.
Gastroenterol Res Pract ; 2009: 591704, 2009.
Article in English | MEDLINE | ID: mdl-19421420

ABSTRACT

Inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions with polygenic susceptibility. Interactions between TNF-alpha and TNF-alpha receptor play a fundamental role in inflammatory response. This study investigates the role that selected single nucleotide polymorphisms (SNPs) and haplotypes in the TNF-alpha receptor (TNSFRSF1B) gene play in the risk of IBD in a New Zealand Caucasian population. DNA samples from 388 CD, 405 UC, 27 indeterminate colitis patients, and 293 randomly selected controls, from Canterbury, New Zealand were screened for 3 common SNPs in TNSFRSF1B: rs1061622 (c.676T > C), rs1061624 (c.*1663A > G), and rs3397 (c.*1690T > C), using TaqMan technologies. Carrying the rs1061624 variant decreased the risk of UC in the left colon (OR 0.73, 95% CI = 0.54-1.00) and of being a smoker at diagnosis (OR 0.62; 95% CI = 0.40-0.96). Carrying the rs3397 variant decreased the risk of penetrating CD (OR 0.62, 95% CI = 0.40-0.95). Three marker haplotype analyses revealed highly significant differences between CD patients and control subjects (chi(2) = 29.9, df = 7, P = .0001) and UC cases and controls (chi(2) = 46.3, df = 7, P < .0001). We conclude that carrying a 3-marker haplotype in the TNSFRSF1B gene may increase (e.g., haplotype of GGC was 2.9-fold more in the CD or UCpatients) or decrease (e.g., TGT was 0.47-fold less in UC patients) the risk of IBD in a New Zealand Caucasian population.

15.
Mol Microbiol ; 72(4): 1054-67, 2009 May.
Article in English | MEDLINE | ID: mdl-19400792

ABSTRACT

Two closely related pathogenic species have evolved in the genus Neisseria: N. meningitidis and N. gonorrhoeae, which occupy different host niches and cause different clinical entities. In contrast to the pathogen N. gonorrhoeae, N. meningitidis is a commensal and only rarely becomes invasive. Little is known about the genetic background of the entirely different lifestyles in these closely related species. Meningococcal NMB1843 encodes a transcriptional regulator of the MarR family. The gonococcal homologue FarR regulates expression of farAB, mediating fatty acid resistance. We show that NmFarR also directly interacts with NmfarAB. Yet, by contrast to N. gonorrhoeae, no significant sensitivity to fatty acids was observed in a DeltafarR mutant due to intrinsic resistance of meningococci. Further analyses identified an NmFarR-repressed protein absent from N. gonorrhoeae. This protein is the meningococcus-specific adhesin and vaccine component NadA that has most likely been acquired by horizontal gene transfer. NmFarR binds to a 16 base pair palindromic repeat within the nadA promoter. De-repression of nadA resulted in significantly higher association of a DeltafarR strain with epithelial cells. Hence NmFarR has gained control over a meningococcus-specific gene involved in host colonization and thus contributed to divergent niche adaptation in pathogenic Neisseriae.


Subject(s)
Adhesins, Bacterial/metabolism , DNA-Binding Proteins/metabolism , Neisseria meningitidis/genetics , Transcription Factors/metabolism , Adhesins, Bacterial/genetics , Amino Acid Sequence , Binding Sites , Cell Line , Cloning, Molecular , DNA, Bacterial/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Bacterial , Genes, Bacterial , Humans , Molecular Sequence Data , Mutagenesis, Insertional , Neisseria meningitidis/metabolism , Promoter Regions, Genetic , Sequence Alignment , Sequence Analysis, DNA , Transcription Factors/genetics
16.
Hum Immunol ; 70(6): 440-6, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19275920

ABSTRACT

Bacterial sensing is crucial for appropriate response by the innate and adaptive immune system against invading microorganisms. Single nucleotide polymorphisms (SNPs) in genes involved in bacterial recognition, CARD15 and TLR4, increased the risk of inflammatory bowel disease (IBD) in a New Zealand Caucasian case-control cohort. We now consider the effects of SNPs in CD14, TLR9, and BPI, analyzed individually, in association with one another, and with SNPs in CARD15 or TLR4 in this same population group. SNPs in CD14 (c.-159 C>T), TLR9 (c.-1237T>C) and BPI (c.645A>G) showed no significant allele or genotype frequency differences between IBD cases and controls. Genotype-phenotype mapping reveals an association with BPI and ileocolonic Crohn's disease (CD) as well as an association with CD14 and early-onset ulcerative colitis (UC). Genotype interaction analyses using three different statistical approaches provided significant evidence of interaction for the following combinations: CARD15/TLR4 (CD and UC), CARD15/CD14 (CD and UC), CD14/TLR4 (UC only), and CD14/BPI (UC only). A trend for an association between BPI and TLR4 was observed in UC patients, but failed to reach statistical significance. Our findings support the idea of gene-gene interactions for genes involved in closely related pathways (i.e. bacterial detection). There is evidence that carrying two SNPs in genes may lead to statistical significance for genes and SNPs that do not otherwise confirm as risk alleles for disease aetiology when analysed alone.


Subject(s)
Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Antimicrobial Cationic Peptides/genetics , Blood Proteins/genetics , Case-Control Studies , Child , Child, Preschool , Colitis, Ulcerative/genetics , Colitis, Ulcerative/microbiology , Crohn Disease/genetics , Crohn Disease/microbiology , Female , Host-Pathogen Interactions , Humans , Infant , Infant, Newborn , Inflammatory Bowel Diseases/microbiology , Lipopolysaccharide Receptors/genetics , Male , New Zealand , Toll-Like Receptor 9/genetics , Young Adult
17.
BMC Res Notes ; 2: 52, 2009 Mar 27.
Article in English | MEDLINE | ID: mdl-19327158

ABSTRACT

BACKGROUND: The nucleotide-binding oligomerization domain containing 1 (NOD1) gene encodes a pattern recognition receptor that senses pathogens, leading to downstream responses characteristic of innate immunity. We investigated the role of NOD1 single nucleotide polymorphisms (SNPs) on IBD risk in a New Zealand Caucasian population, and studied Nod1 expression in response to bacterial invasion in the Caco2 cell line. FINDINGS: DNA samples from 388 Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis patients and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common SNPs in NOD1, using the MassARRAY iPLEX Gold assay. Transcriptional activation of the protein produced by NOD1 (Nod1) was studied after infection of Caco2 cells with Escherichia coli LF82. Carrying the rs2075818 G allele decreased the risk of CD (OR = 0.66, 95% CI = 0.50-0.88, p < 0.002) but not UC. There was an increased frequency of the three SNP (rs2075818, rs2075822, rs2907748) haplotype, CTG (p = 0.004) and a decreased frequency of the GTG haplotype (p = 0.02).in CD. The rs2075822 CT or TT genotypes were at an increased frequency (genotype p value = 0.02), while the rs2907748 AA or AG genotypes showed decreased frequencies in UC (p = 0.04), but not in CD. Functional assays showed that Nod1 is produced 6 hours after bacterial invasion of the Caco2 cell line. CONCLUSION: The NOD1 gene is important in signalling invasion of colonic cells by pathogenic bacteria, indicative of its' key role in innate immunity. Carrying specific SNPs in this gene significantly modifies the risk of CD and/or UC in a New Zealand Caucasian population.

18.
World J Gastroenterol ; 14(29): 4652-61, 2008 Aug 07.
Article in English | MEDLINE | ID: mdl-18698679

ABSTRACT

AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-alpha) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies. METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-alpha receptor: -238 G-->A, -308 G-->A and -857C-->T, using a Taqman assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies. RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, c2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, c2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, c2 = 4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, c2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, c2 = 4.86, P = 0.028). CONCLUSION: TNF-alpha is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-alpha promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desirable for individuals with such affected genotypes.


Subject(s)
Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Necrosis Factor-alpha/genetics , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 6 , Colitis, Ulcerative/ethnology , Colitis, Ulcerative/genetics , Crohn Disease/ethnology , Crohn Disease/genetics , Female , Genetic Predisposition to Disease/genetics , Haplotypes/genetics , Humans , Infant , Inflammatory Bowel Diseases/ethnology , Male , New Zealand , Risk Factors , Young Adult
19.
Am J Gastroenterol ; 102(11): 2504-12, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17850411

ABSTRACT

OBJECTIVES: Published association studies of the TLR4 Asp299Gly polymorphism and inflammatory bowel disease (IBD) in caucasian populations have inconsistent results. We tested two TLR4 variants for association with IBD in the New Zealand caucasian population and assessed the cumulative evidence for association of TLR4 Asp299Gly and IBD. METHODS: The TLR4 Asp299Gly and Thr399Ile polymorphisms were genotyped and tested for case-control frequency differences in a New Zealand white cohort of 389 Crohn's disease (CD) patients, 405 ulcerative colitis (UC) patients, and 416 population controls. Meta-analysis using a random effects model was performed to test whether 299Gly carriage was associated with UC, CD, or phenotypes of CD patients. RESULTS: There were no significant allele or genotype frequency differences between cases and controls or between CD phenotypes in our New Zealand data. Meta-analysis did not identify any significant associations between CD phenotypes and 299Gly carriage. However, meta-analysis demonstrated significantly higher 299Gly carrier frequencies in CD patients (odds ratio 1.45, 95% CI 1.11-1.90) and in IBD patients (odds ratio 1.36, 95% CI 1.01-1.84) compared to controls. CONCLUSIONS: The meta-analysis provides evidence that Asp299Gly is associated with CD and IBD in whites. Only the Asp299Gly polymorphism has been consistently genotyped in previous TLR4 studies with IBD patients, therefore other TLR4 variants with stronger associations with IBD may exist. Additional well-powered studies of Asp299Gly and other TLR4 variants are urgently needed.


Subject(s)
Inflammatory Bowel Diseases/genetics , Toll-Like Receptor 4/genetics , White People , Adolescent , Adult , Chi-Square Distribution , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Inflammatory Bowel Diseases/ethnology , Logistic Models , Male , Membrane Glycoproteins/genetics , New Zealand , Phenotype , Polymorphism, Genetic/genetics
20.
Mutat Res ; 622(1-2): 70-83, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17628615

ABSTRACT

Inflammatory bowel disease (IBD) arises in part from a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. A consistent observation across most populations is that any of three polymorphisms of the Caspase-activated recruitment domain (CARD15) gene are more prevalent in IBD patients as compared with unaffected controls. Similar aberrant responses to bacteria are associated with variants in Autophagy-related 16-like 1 (ATG16L1) and human defensin (HBD-2, -3 and -4) genes. The defective bacterial signal in turn leads to an excessive immune response, presenting as chronic gut inflammation in susceptible individuals. Inconsistent population reports implicate the major histocompatability complex (MHC), that encodes a number of human leukocyte antigens (HLA), MHC class I chain-related gene A (MICA) or cytokines, such as tumour necrosis factor-alpha (TNF-alpha). Toll-like receptors encoded by the TLR4 or TLR9 genes may also play a role. Recent whole genome scans suggest that a rare variant in the interleukin-23 receptor (IL23R) gene may actually protect against IBD. Other implicated genes may affect mucosal cell polarity (Drosophila discs large homologue 5, DLG5) or mucosal transporter function (sodium dependent organic cation transporters, SLC22A4 and SLC22A5). A variant in ABCB1 (ATP-binding cassette subfamily B member 1) may be especially associated with increased risk of UC. While pharmacogenetics is increasingly being used to predict and optimise clinical response to therapy, nutrigenetics may have even greater potential. In many cases, IBD can be controlled through prescribing an elemental diet, which appears to act through modulating cytokine response and changing the gut microbiota. More generally, no single group of dietary items is beneficial or detrimental to all patients, and elimination diets have been used to individualise dietary requirements. However, recognising the nature of the genes involved may suggest a more strategic approach. Pro- or prebiotics will directly influence the microbial flora, while immunonutrition, including omega-3 fatty acids and certain polyphenols, may reduce the symptoms of gut inflammation. The expression of gut transporters may be modulated through various herbal remedies including green tea polyphenols. Such approaches would require that the gene of interest is functioning normally, other than its expression being up or down-regulated. However, new approaches are being developed to overcome the effects of polymorphisms that affect the function of a gene. A combination of human correlation studies with experimental models could provide a rational strategy for optimising nutrigenetic approaches to IBD.


Subject(s)
Diet , Genes/physiology , Inflammatory Bowel Diseases/genetics , Humans , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology
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