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The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region—two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6–8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.Genes and Immunity (2008) 9, 556–560; doi:10.1038/gene.2008.44; published online 19 June 2008 [ABSTRACT FROM AUTHOR]

The article discusses the lack of association of the pregnane X receptor gene with inflammatory bowel disease determined through a parallel allelic association study and gene wide haplotype analysis. According to sources, dysregulation of this gene may influence intestinal barrier defence and susceptibility to inflammatory bowel disease. Thus, a critical re-evaluation of the allelic variants of the gene as determinants of disease susceptibility and phenotype in the Scottish population.

Focuses on the rise in incidence of Crohn's disease in Scottish children during the period of 1968 and 1983. Database used to identify patients; Conclusion that the incidence of juvenile-onset Crohn's disease continued to rise and is not the result of changing diagnostic patterns.

Background: Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors., Methods: Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case-control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression., Results: Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02-1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11-1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06-1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11-1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03-1.69], P = 0.03, respectively)., Conclusions: COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD., (Copyright © 2010 Crohn's & Crohn's & Colitis Foundation of America, Inc.)

Background: Osteoporosis is a recognized complication of inflammatory bowel disease (IBD). Aim To investigate the role of environmental factors and vitamin D receptor (VDR) variants on the prevalence of osteoporosis., Methods: DEXA scans and case note review were performed on 440 IBD patients from 1997 to 2006. All the IBD patients and 240 healthy controls were genotyped for VDR variants Taq-1 and Apa-1 using PCR-RFLP., Results: Osteoporosis and osteopenia rates were 15% and 18% for IBD, 16% and 18% for Crohn's disease (CD) and 13% and 19% for ulcerative colitis, respectively. On univariate analysis of the CD patients, low body mass index (BMI, <18.5) and smoking status (P = 0.008 and 0.005 respectively) were associated with osteoporosis and osteopenia. Low BMI was also associated with osteoporosis on multivariate analysis in CD (P = 0.021, OR 5.83, CI 1.31-25.94). No difference was observed between Taq-1 and Apa-1 VDR polymorphisms in IBD, CD, ulcerative colitis and healthy controls. However, CD males were more likely to carry the variant Taq-1 polymorphism than healthy controls males (P = 0.0018, OR 1.94, CI 1.28-2.92) and female CD patients (P = 0.0061, OR 1.60, CI 1.17-2.44)., Conclusions: In this well-phenotyped cohort of IBD patients, a relatively low prevalence of osteoporosis was observed. Low BMI was the only independent risk factor identified to be associated with osteoporosis.

Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations., Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD., Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative., Conclusions: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

Background & Aims: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15., Methods: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought., Results: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15., Conclusions: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.

Objective: To assess the contribution of the 113 G-->A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland., Study Design: Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent)., Results: TDT analysis demonstrated a significant association with IBD (P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (>75th centile vs <75th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn's disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A (P = .001, OR = 6.92 [2.24-21.33])., Conclusions: DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.

Introduction: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection., Aims: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population., Patients and Methods: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system., Results: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15., Conclusions: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.

NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of Crohn's disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4) and CD14 genes may also be relevant to disease pathophysiology. We aimed to assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and Irish CD patients. In all, 612 patients with well-characterised inflammatory bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S), TLR4 (A299G) and CD14 (T-159C). Genotype-phenotype analyses were performed. Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In conclusion, we present compelling evidence for genetic heterogeneity within Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and Irish CD patients, consistent with an emerging pattern from Northern Europe.

Objective: A previous study reported a three-fold rise in the incidence of juvenile-onset Crohn's disease in Scottish children and a marginal fall in ulcerative colitis between 1968 and 1983. The present study aimed to document the incidence of juvenile-onset inflammatory bowel disease between 1981 and 1995 and examine temporal trends between 1968 and 1995 in Scotland., Setting: Scotland (latitude 55-60 degrees N) has a total area of 77 837 km2 (30 405 square miles) and includes four urban centres each with a population of over 100,000., Participants: The Scottish hospital discharges linked database was used to identify 1002 patients less than 19 years old who were coded as having inflammatory bowel disease between 1981 and 1997. All case notes were reviewed and diagnoses verified. Incident cases were defined as those with symptom onset before or at 16 years of age between 1 January 1981 and 31 December 1995., Results: During the 15 year period 1981-1995, 438 incident cases of Crohn's disease and 227 of ulcerative colitis were identified, giving standardized incidences of 2.5 cases and 1.3 cases per 100,000 population per year for Crohn's disease and ulcerative colitis respectively. On 31 December 1995 there were 150 children < or = 16 years of age with Crohn's disease and 101 with ulcerative colitis, giving crude prevalences of 13.7 cases per 100,000 population for Crohn's disease and 9.2 for ulcerative colitis. The continuing rise in Crohn's disease incidence between 1981 and 1995 fits that predicted by linear trend analysis of the 1968-1983 data. The incidence of Crohn's disease in the 12-16 age range almost doubled between 1981 and 1995 and was greater for males than females. Ulcerative colitis incidence was thought to show a slight fall in the 1968-1983 data, but this is reversed in the 1981-1995 data., Conclusion: The incidence of juvenile-onset Crohn's disease continues to rise in Scotland and the prevalence has increased by 30% since 1983. Unlike the previous report from Scotland, the incidence of juvenile-onset ulcerative colitis also is apparently rising. Whether this represents a real rise in incidence, or merely the inclusion of milder cases which were not previously hospitalized remains uncertain.