Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Ascaris lumbricoides Infection and Its Relation to Environmental Factors in the Mbeya Region of Tanzania, a Cross-Sectional, Population-Based Study

Background: With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics. Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems. To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection. Methodology: Cross-sectional survey data of 6, 366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection. Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders. Principal Findings: The overall prevalence of A. lumbricoides infection was 6.8%. Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall. Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78-0.97). Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years),socio-economic status (OR = 0.82, CI = 0.68-0.97),and latrine coverage around the house (OR = 0.80, CI = 0.67-0.96) remained in the final model. Conclusions: A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni-and multivariable analysis. Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas. However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

The amount of dysfunctional but viable myocardium predicts long-term survival in patients with ischemic cardiomyopathy and left ventricular dysfunction

To evaluate the prognostic significance of combined myocardial perfusion SPECT and [18F]FDG PET viability scanning for the prediction of survival in patients with ischemic cardiomyopathy (iCMP) and left ventricular dysfunction. 244 patients (64.0 ± 10.6 years, 86 % men) with iCMP and LVEF ≤45 % underwent SPECT/PET. Percent scar tissue and SPECT/PET-mismatch (%-mismatch) were calculated and correlated with event-free survival according to the type of therapy (medical therapy with/out revascularization) provided after imaging. Death from any cause was defined as the primary endpoint. Early revascularization (ER) was performed in 113/244 (46 %) patients within 32 ± 52 days (26 bypass surgeries and 87 percutaneous coronary interventions). 65 patients died during follow-up for a median of 33 months. Kaplan–Meier analysis showed that those patients with ≥5 % mismatch not undergoing ER had significantly higher mortality than did the group with similar mismatch who did receive ER. Cox analysis identified both SPECT/PET-mismatch and the interaction of SPECT/PET-mismatch with ER as independent predictors for death due to all causes. A threshold of ≥5 % SPECT/PET-mismatch predicted best which patients with iCMP and LV dysfunction would benefit from ER in terms of long-term survival

<i>A. lumbricoides</i> prevalence in the study sites.

<p>Color coding indicates household prevalence, labels indicate site name and site prevalence. <i>A. lumbricoides</i> infection is strongly clustered both between and within sites.</p

Multivariable association of environmental and socio-demographic factors with <i>A. lumbricoides</i> infection using logistic regression with fractional polynomials (n = 6,363).

<p>β =  beta coefficient; OR  =  odds ratio; 95% CI  =  confidence interval; LST  =  land surface temperature; EVI  =  enhanced vegetation index; SES  =  socio economic score, AIC  =  Akaike information criterion; BIC  =  Bayesian information criterion.</p>a)<p>Adjusted for household clustering using Huber/White/Sandwich variance estimates and for study sites.</p>b)<p>Fractional polynomial transformation with two degrees and powers p = 3: β₁x^p+β₂x^p*ln x.</p>c)<p>Fractional polynomial transformation with two degrees and powers p = −0.5: β₁x^p+β₂x^p*ln x.</p>d)<p>Percentage of households with a latrine within one kilometer around the participant's household.</p

Description of variables.

<p>N =  number of observations; Std. Dev.  =  standard deviation; EPG  =  eggs per gram of feces; LST  =  land surface temperature; EVI  =  enhanced vegetation index; SES  =  socio-economic score.</p>a)<p>Mean for continuous and % for categorical variables.</p>b)<p>According to Montresor, 1998 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092032#pone.0092032-Montresor1" target="_blank">[35]</a>.</p>c)<p>Percentage of households with a latrine within one kilometer around the participant's household.</p

Location and altitude of the EMINI study sites.

<p>The large altitude range results in very diverse environmental conditions regarding temperature, vegetation, slope etc.</p

Non-linear partial prediction of the log odds of <i>A. lumbricoides</i> infection by annual rainfall.

<p>The partial predicted curve is adjusted for LST-day, slope, SES, age, latrine coverage and the nine study sites. The maximum is at 1740 mm of mean annual rainfall. Grey shadings indicate 95% confidence band.</p