Limited Evidence for Parent-of-Origin Effects in Inflammatory Bowel Disease Associated Loci

Background

Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only ∼23% of the genetic risk. Part of the ‘hidden heritability’ could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients.

Methods

We selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci.

Results

We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03).

Conclusions

Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further.     

Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest

Central aortic pressure gives better insight into ventriculo-arterial coupling and better prognosis of cardiovascular complications than peripheral pressures. Therefore transfer functions (TF), reconstructing aortic pressure from peripheral pressures, are of great interest. Generalized TFs (GTF) give useful results, especially in larger study populations, but detailed information on aortic pressure might be improved by individualization of the TF. We found earlier that the time delay, representing the travel time of the pressure wave between measurement site and aorta is the main determinant of the TF. Therefore, we hypothesized that the TF might be individualized (ITF) using this time delay. In a group of 50 patients at rest, aged 28-66 yr (43 men), undergoing diagnostic angiography, ascending aortic pressure was 119 +/- 20/70 +/- 9 mmHg (systolic/diastolic). Brachial pressure, almost simultaneously measured using catheter pullback, was 131 +/- 18/67 +/- 9 mmHg. We obtained brachial-to-aorta ITFs using time delays optimized for the individual and a GTF using averaged delay. With the use of ITFs, reconstructed aortic pressure was 121 +/- 19/69 +/- 9 mmHg and the root mean square error (RMSE), as measure of difference in wave shape, was 4.1 +/- 2.0 mmHg. With the use of the GTF, reconstructed pressure was 122 +/- 19/69 +/- 9 mmHg and RMSE 4.4 +/- 2.0 mmHg. The augmentation index (AI) of the measured aortic pressure was 26 +/- 13%, and with ITF and GTF the AIs were 28 +/- 12% and 30 +/- 11%, respectively. Details of the wave shape were reproduced slightly better with ITF but not significantly, thus individualization of pressure transfer is not effective in resting patients.     

PML Nuclear Bodies and SATB1 Are Associated with HLA Class I Expression in EBV+ Hodgkin Lymphoma

Tumor cells of classical Hodgkin lymphoma (cHL) are characterized by a general loss of B cell phenotype, whereas antigen presenting properties are commonly retained. HLA class I is expressed in most EBV+ cHL cases, with an even enhanced expression in a proportion of the cases. Promyelocytic leukemia protein (PML) and special AT-rich region binding protein 1 (SATB1) are two global chromatin organizing proteins that have been shown to regulate HLA class I expression in Jurkat cells. We analyzed HLA class I, number of PML nuclear bodies (NBs) and SATB1 expression in tumor cells of 54 EBV+ cHL cases and used 27 EBV− cHL cases as controls. There was a significant difference in presence of HLA class I staining between EBV+ and EBV− cases (p<0.0001). We observed normal HLA class I expression in 35% of the EBV+ and in 19% of the EBV− cases. A stronger than normal HLA class I expression was observed in approximately 40% of EBV+ cHL and not in EBV− cHL cases. 36 EBV+ cHL cases contained less than 10 PML-NBs per tumor cell, whereas 16 cases contained more than 10 PML-NBs. The number of PML-NBs was positively correlated to the level of HLA class I expression (p<0.01). The percentage of SATB1 positive cells varied between 0% to 100% in tumor cells and was inversely correlated with the level of HLA class I expression, but only between normal and strong expression (p<0.05). Multivariable analysis indicated that the number of PML-NBs and the percentage of SATB1+ tumor cells are independent factors affecting HLA class I expression in EBV+ cHL. In conclusion, both PML and SATB1 are correlated to HLA class I expression levels in EBV+ cHL.     

Transient receptor potential channels meet phosphoinositides

Transient receptor potential (TRP) cation channels are unique cellular sensors that are involved in multiple cellular functions, ranging from transduction of sensory signals to the regulation of Ca²⁺ and Mg²⁺ homoeostasis. Malfunctioning of TRP channels is now recognized as the cause of several hereditary and acquired human diseases. At the time of cloning of the first Drosophila TRP channel, a close connection between gating and phosphatidylinositol phosphates (PIPs) was already recognized. In this review, we summarize current knowledge about the mechanisms of interaction between TRP channels and PIPs, and discuss the possible functional implications of TRP–PIP interactions to human physiology and pathophysiology.     

Influence of Some Preservatives on the Quality of Prepacked Cod Fillets in Relation to the Oxygen Permeability of the Film

S ummary : The deterioration of prepacked cod fillets in relation to different concentrations of citric acid (HC) and of potassium sorbate (PS) was studied bacteriologically and chemically. Spoilage of fish treated with PS in relation to the oxygen permeability (OP) of the polyethylene film was also examined. The trimethylamine (TMA) and formalin bound nitrogen compounds (FBN) formation at 0° in prepacked cod fillets is inhibited by the addition of HC and PS. A concentration of 0·4% of PS in the cod fillets is sufficient to inhibit the TMA production completely. The OP of the film determines the keeping quality of the cod fillets containing 0·4% of PS. The film with the lowest OP gives the best results, since the spoilage of PS treated fish during the first 12 days is exclusively caused by an increase of FBN. The formation of this fraction at 0° is related directly to the OP of the packing film. From the experiments with PS treated cod fillets it can be deduced that a film with a low OP gives the best results.     

In Vitro Interaction of the Housekeeping SecA1 with the Accessory SecA2 Protein of Mycobacterium tuberculosis

The majority of proteins that are secreted across the bacterial cytoplasmic membrane leave the cell via the Sec pathway, which in its minimal form consists of the dimeric ATP-driven motor protein SecA that associates with the protein-conducting membrane pore SecYEG. Some Gram-positive bacteria contain two homologues of SecA, termed SecA1 and SecA2. SecA1 is the essential housekeeping protein, whereas SecA2 is not essential but is involved in the translocation of a subset of proteins, including various virulence factors. Some SecA2 containing bacteria also harbor a homologous SecY2 protein that may form a separate translocase. Interestingly, mycobacteria contain only one SecY protein and thus both SecA1 and SecA2 are required to interact with SecYEG, either individually or together as a heterodimer. In order to address whether SecA1 and SecA2 cooperate during secretion of SecA2 dependent proteins, we examined the oligomeric state of SecA1 and SecA2 of Mycobacterium tuberculosis and their interactions with SecA2 and the cognate SecA1, respectively. We conclude that both SecA1 and SecA2 individually form homodimers in solution but when both proteins are present simultaneously, they form dissociable heterodimers.     

TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption

Mg2+ is an essential ion involved in a multitude of physiological and biochemical processes and a major constituent of bone tissue. Mg2+ homeostasis in mammals depends on the equilibrium between intestinal Mg2+ absorption and renal Mg2+ excretion, but little is known about the molecular nature of the proteins involved in the transepithelial transport of Mg2+ in these organs. Recently, it was shown that patients with mutations in TRPM6, a member of the transient receptor potential family of cation channels, suffer from hypomagnesemia with secondary hypocalcemia (HSH) as a result of impaired renal and/or intestinal Mg2+ handling. Here, we show that TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and the brush-border membrane of the small intestine, epithelia particularly associated with active Mg2+ (re)absorption. In kidney, parvalbumin and calbindin-D28K, two divalent-binding proteins, are co-expressed with TRPM6 and might function as intracellular Mg2+ buffers in the distal convoluted tubule. Heterologous expression of wild-type TRPM6 but not TRPM6 mutants identified in HSH patients induces a Mg2+- and Ca2+-permeable cation channel tightly regulated by intracellular Mg2+ levels. The TRPM6-induced channel displays strong outward rectification, has a 5-fold higher affinity for Mg2+ than for Ca2+, and is blocked in a voltage-dependent manner by ruthenium red. Our data indicate that TRPM6 comprises all or part of the apical Mg2+ channel of Mg2+-absorbing epithelia.     

Inheritance mode of multiple sclerosis: the effect of <Emphasis Type="Italic">HLA</Emphasis> class II alleles is stronger than additive

We previously identified on chromosome 6 an interval of 51 kb as the most likely interval in the HLA region for a disease-susceptibility locus for multiple sclerosis (MS). The interval was located between markers G511525 and D6S1666 and identified by the haplotype sharing statistic (HSS). The study comprised 124 patients with ancestry within the northeastern part of the Netherlands. Haplotype clustering indicated that two different ancestral haplotypes likely include a polymorphism involved in susceptibility to MS. To investigate the dominance characteristics of the MS susceptibility locus in the HLA class II region, we reanalyzed our data, performing genotype association analyses for both marker loci separately and for the two-locus haplotype. The two-locus genotype association analysis showed that in individuals who carry only one of the risk haplotypes the risk for MS is moderately increased (odds ratio (OR) 2.82; 95% confidence interval (CI) 1.50–5.31). However, in individuals carrying two risk haplotypes the risk for MS is highly increased compared with individuals who carry no risk haplotypes (OR 37.00; 95% CI 8.31–164.74). This susceptibility locus for MS seems to follow an intermediate mode of inheritance. Fitting additive, multiplicative and third power risk models to the data, the effect appears to be significantly stronger than additive.     

Microbiological and biochemical effects of the application of bitumenous emulsions as soil conditioners

Summary Bitumenous emulsions, used as soil conditioners for various soil textural classes, caused no dramatic short-term or long-term alterations of various soil microbial populations and enzymatic activities. A certain inhibition of the soil microbial populations and enzymes occured at the higher application rates (1.0–1.5 l/m²) of bitumen, especially in the sand and clay soils, while an enhancement was often noted at the lower rates (0.5–0.75 l/m²), particularly in the loam soils. re]19721019