Perianal disease combined with NOD2 genotype predicts need for IBD-related surgery in Crohn’s Disease patients from a population-based cohort

Background: Patients with Crohn’s disease (CD) often require surgery at some stage of disease course. Prediction of CD outcome is influenced by clinical, environmental, serological, and genetic factors (eg, NOD2). Being able to identify CD patients at high risk of surgical intervention should assist clinicians to decide whether or not to prescribe early aggressive treatment with immunomodulators. Methods: We performed a retrospective analysis of selected clinical (age at diagnosis, perianal disease, active smoking) and genetic (NOD2 genotype) data obtained for a population-based CD cohort from the Canterbury Inflammatory Bowel Disease study. Logistic regression was used to identify predictors of complicated outcome in these CD patients (ie, need for inflammatory bowel disease-related surgery). Results: Perianal disease and the NOD2 genotype were the only independent factors associated with the need for surgery in this patient group (odds ratio=2.84 and 1.60, respectively). By combining the associated NOD2 genotype with perianal disease we generated a single “clinicogenetic” variable. This was strongly associated with increased risk of surgery (odds ratio=3.84, P=0.00, confidence interval, 2.28-6.46) and offered moderate predictive accuracy (positive predictive value=0.62). Approximately 1/3 of surgical outcomes in this population are attributable to the NOD2+PA variable (attributable risk=0.32). Conclusions: Knowledge of perianal disease and NOD2 genotype in patients presenting with CD may offer clinicians some decision-making utility for early diagnosis of complicated CD progression and initiating intensive treatment to avoid surgical intervention. Future studies should investigate combination effects of other genetic, clinical, and environmental factors when attempting to identify predictors of complicated CD outcomes.

Investigation of the [−/A]8 and C1236T genetic variations within the human toll-like receptor 3 gene for association with multiple sclerosis

Multiple sclerosis (MS) is a serious cause of neurological disability among young adults. The clinical course remains difficult to predict, and the pathogenesis of the disease is still modestly understood. Autoimmunity is thought to be a key aspect of the disease, with autoreactive T cells thought to mediate central nervous system (CNS) inflammation to some extent. Toll-like receptors are known to mediate cellular recognition of pathogens by way of patterns of molecular presentation. Toll-like receptor 3 is coded by the gene TLR3 and is recognized as an important factor in virus recognition and is known to be involved in the expression of neuroprotective mediators. We set out to investigate two variations within the TLR3 gene, an 8 bp insertion-deletion \[-/A](8) and a single base-pair variation C1236T, in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We used capillary gel electrophoresis and TaqMan genotyping assay techniques to resolve genotypes for each marker, respectively. Our work found no significant difference between frequencies for TLR3 \[-/A](8) by genotype (chi(2)=1.03, p=0.60) or allele (chi(2)=1.09, p=0.30). Similarly, we found no evidence for the association of TLR3 C1236T by genotype (chi(2)=0.35, p=0.84) or allele frequency (chi(2)=0.31, p=0.58). This work reveals no evidence to suggest that these markers are associated with MS in the tested population. Although the role of TLR3 and the wider toll-like receptor family remain significant in neurological and CNS inflammatory disorders, our current work does not support a role for the two tested variants in this gene with regard to MS susceptibility.

The GSTM1 null genotype confers an increased risk for Solar Keratosis Development in an Australian Caucasian Population

Solar keratoses affect approximately 50% of Australian Caucasians aged over 40 y. Solar keratoses can undergo malignant transformation into squamous cell carcinoma followed by possible metastasis and are risk factors for basal cell carcinoma, melanoma, and squamous cell carcinoma. The glutathione-S-transferase genes play a part in detoxification of carcinogens and mutagens, including some produced by ultraviolet radiation. This study examined the role of glutathione-S-transferase M1, T1, P1, and Z1 gene polymorphisms in susceptibility to solar keratoses development. Using DNA samples from volunteers involved in the Nambour Skin Cancer Prevention Trial, allele and genotype frequencies were determined using polymerase chain reaction and restriction enzyme digestion. No significant differences were detected in glutathione-S-transferase P1 and glutathione-S-transferase Z1 allele or genotype frequencies; however, a significant association between glutathione-S-transferase M1 genotypes and solar keratoses development was detected (p=0.003) with null individuals having an approximate 2-fold increase in risk for solar keratoses development (odds ratio: 2.1; confidence interval: 1.3-3.5) and a significantly higher increase in risk in conjunction with high outdoor exposure (odds ratio: 3.4; confidence interval: 1.9-6.3). Also, a difference in glutathione-S-transferase T1 genotype frequencies was detected (p=0.039), although considering that multiple testing was undertaken, this was found not to be significant. Fair skin and inability to tan were found to be highly significant risk factors for solar keratoses development with odds ratios of 18.5 (confidence interval: 5.7-59.9) and 7.4 (confidence interval: 2.6-21.0), respectively. Overall, glutathione-S-transferase M1 conferred a significant increase in risk of solar keratoses development, particularly in the presence of high outdoor exposure and synergistically with known phenotypic risk factors of fair skin and inability to tan.

Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma

MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype.

G-protein β3 subunit gene (GNB3) variant in causation of essential hypertension

Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein β3 subunit gene (GNB3) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (χ2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC, CT, and 7T, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein β3 subunit gene in the causation of essential hypertension.

Bayesian refinement of association signals for 14 loci in 3 common diseases

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Potential antioxidant response to coffee - A matter of genotype?

In a human intervention trial, a coffee, combining nature green coffee bean constituents and dark roast products was studied towards its potential to activate the Nrf2/ARE-pathway in PBLs. The study coffee was identified as a strong inducer of Nrf2 and downstream GST1A1 and UGT1A1 gene transcription. However, the response of the participants was found to depend on the respective genotype. The -651 SNP in the Nrf2 gene as well as the heterozygote 6/7 sequence in the UGT1A1 gene significantly down-regulated the susceptibility to respond to coffee, proposing the existing genotype to be critical for the response to the coffee.

A new low temperature synthesis route of fraipontite (Zn,Al)3(Si,Al)2O5(OH)4

A low temperature synthesis method based on the decomposition of urea at 90°C in water has been developed to synthesise fraipontite. This material is characterised by a basal reflection 001 at 7.44 Å. The trioctahedral nature of the fraipontite is shown by the presence of a 06l band around 1.54 Å, while a minor band around 1.51 Å indicates some cation ordering between Zn and Al resulting in Al-rich areas with a more dioctahedral nature. TEM and IR indicate that no separate kaolinite phase is present. An increase in the Al content however, did result in the formation of some SiO2 in the form of quartz. Minor impurities of carbonate salts were observed during the synthesis caused by to the formation of CO32- during the decomposition of urea.

No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer

Background There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study. Methods The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression. Results The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age. Conclusion The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women.