Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort

Background: Irritable bowel syndrome (IBS) is a common disorder that affects 10–15% of the population. Although characterised by a lack of reliable biological markers, the disease state is increasingly viewed as a disorder of the brain-gut axis. In particular, accumulating evidence points to the involvement of both the central and peripheral serotonergic systems in disease symptomatology. Furthermore, altered tryptophan metabolism and indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many stress-related disorders. The kynurenine pathway of tryptophan degradation may serve to link these findings to the low level immune activation recently described in IBS. In this study, we investigated tryptophan degradation in a male IBS cohort (n = 10) and control subjects (n = 26). Methods: Plasma samples were obtained from patients and healthy controls. Tryptophan and its metabolites were measured by high performance liquid chromatography (HPLC) and neopterin, a sensitive marker of immune activation, was measured using a commercially available ELISA assay. Results: Both kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls. Neopterin was also increased in the IBS subjects and the concentration of the neuroprotective metabolite kynurenic acid was decreased, as was the kynurenic acid:kynurenine ratio. Conclusion: These findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls. This study provides novel evidence for an immune-mediated degradation of tryptophan in a male IBS population and identifies the kynurenine pathway as a potential source of biomarkers in this debilitating condition.

Mapping the gene for autosomal dominant restless legs syndrome in an Irish family

Restless Legs Syndrome (RLS) is a common neurological disorder affecting nearly 15% of the general population. Ironically, RLS can be described as the most common condition one has never heard of. It is usually characterised by uncomfortable, unpleasant sensations in the lower limbs inducing an uncontrollable desire to move the legs. RLS exhibits a circadian pattern with symptoms present predominantly in the evening or at night, thus leading to sleep disruption and daytime somnolence. RLS is generally classified into primary (idiopathic) and secondary (symptomatic) forms. Primary RLS includes sporadic and familial cases of which the age of onset is usually less than 45 years and progresses slowly with a female to male ratio of 2:1. Secondary forms often occur as a complication of another health condition, such as iron deficiency or thyroid dysfunction. The age of onset is usually over 45 years, with an equal male to female ratio and more rapid progression. Ekbom described the familial component of the disorder in 1945 and since then many studies have been published on the familial forms of the disorder. Molecular genetic studies have so far identified ten loci (5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p). No specific gene within these loci has been identified thus far. Association mapping has highlighted a further five areas of interest. RLS6 has been found to be associated with SNPs in the BTBD9 gene. Four other variants were found within intronic and intergenic regions of MEIS1, MAP2K5/LBXCOR1, PTPRD and NOS1. The pathophysiology of RLS is complex and remains to be fully elucidated. Conditions associated with secondary RLS, such as pregnancy or end-stage renal disease, are characterised by iron deficiency, which suggests that disturbed iron homeostasis plays a role. Dopaminergic dysfunction in subcortical systems also appears to play a central role. An ongoing study within the Department of Pathology (University College Cork) is investigating the genetic characteristics of RLS in Irish families. A three generation RLS pedigree RLS3002 consisting of 11 affected and 7 unaffected living family members was recruited. The family had been examined for four of the known loci (5q, 12q, 14p and 9p) (Abdulrahim 2008). The aim of this study was to continue examining this Irish RLS pedigree for possible linkage to the previously described loci and associated regions. Using informative microsatellite markers linkage was excluded to the loci on 5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p and also within the regions reported to be associated with RLS. This suggested the presence of a new unidentified locus. A genome-wide scan was performed using two microsatellite marker screening sets (Research Genetics Inc. Mapping set and the Applied Biosystems Linkage mapping set version 2.5). Linkage analysis was conducted under an autosomal dominant model with a penetrance of 95% and an allele frequency of 0.01. A maximum LOD score of 3.59 at θ=0.00 for marker D19S878 indicated significant linkage on chromosome 19p. Haplotype analysis defined a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to 2.5 Mb. There are approximately 100 genes annotated within the critical region. Sequencing of two candidate genes, KLF16 and GAMT, selected on the assumed pathophysiology of RLS, did not identify any sequence variant. This study provides evidence of a novel RLS locus in an Irish pedigree, thus supporting the picture of RLS as a genetically heterogeneous trait.

Alcohol income and health: a complicated but desirable mix

The aim of this thesis is to examine if a difference exists in income for different categories of drinkers in Ireland using the 2007 Slán data set. The possible impact of alcohol consumption on health status and health care utilisation is also examined. Potential endogeneity and selection bias is accounted for throughout. Endogeneity is where an independent variable included in the model is determined within the context of the model (Chenhall and Moers, 2007). An endogenous relationship between income and alcohol and between health and alcohol is accounted for by the use of separate income equations and separate health status equations for each category of drinker similar to what was done in previous studies into the effects of alcohol on earnings (Hamilton and Hamilton, 1997; Barrett, 2002). Sample selection bias arises when a sector selection is non-random due to individuals choosing a particular sector because of their personal characteristics (Heckman, 1979; Zhang, 2004). In relation to alcohol consumption, selection bias may arise as people may select into a particular drinker group due to the fact that they know that by doing so it will not have a negative effect on their income or health (Hamilton and Hamilton, 1997; Di Pietro and Pedace, 2008; Barrett, 2002). Selection bias of alcohol consumption is accounted for by using the Multinomial Logit OLS Two Step Estimate as proposed by Lee (1982), which is an extension of the Heckman Probit OLS Two Step Estimate. Alcohol status as an ordered variable is examined and possible methods of estimation accounting for this ordinality while also accounting for selection bias are looked at. Limited Information Methods and Full Information Methods of estimation of simultaneous equations are assessed and compared. Findings show that in Ireland moderate drinkers have a higher income compared with abstainers or heavy drinkers. Some studies such as Barrett (2002) argue that this is as a consequence of alcohol improving ones health, which in turn can influence ones productivity which may ultimately be reflected in earnings, due to the fact that previous studies have found that moderate levels of alcohol consumption are beneficial towards ones health status. This study goes on to examine the relationship between health status and alcohol consumption and whether the correlation between income and the consumption of alcohol is similar in terms of sign and magnitude to the correlation between health status and the consumption of alcohol. Results indicate that moderate drinkers have a higher income than non or heavy drinkers, with the weekly household income of moderate drinkers being €660.10, non drinkers being €546.75 and heavy drinkers being €449.99. Moderate Drinkers also report having a better health status than non drinkers and a slightly better health status than heavy drinkers. More non-drinkers report poor health than either moderate or heavy drinkers. As part of the analysis into the effect of alcohol consumption on income and on health status, the relationship between other socio economic variables such as gender, age, education among others, with income, health and alcohol status is examined.