Association of candidate genes with phenotypic traits relevant to anorexia nervosa.

This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein, we investigate alternative phenotypes associated with AN. In 1762 females, using regression analyses, we examined the following: (i) lowest illness-related attained body mass index; (ii) age at menarche; (iii) drive for thinness; (iv) body dissatisfaction; (v) trait anxiety; (vi) concern over mistakes; and (vii) the anticipatory worry and pessimism versus uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes. Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.

Ability for self-care and its association with sociodemographic factors of people with spinal cord injury

This study aimed to verify the association between self-care ability and sociodemographic factors of people with spinal cord injury (SCI). It was a cross-sectional study, conducted in 2012, in all 58 Basic Health Units of Natal/RN, Brazil. Seventy-three subjects completed a sociodemographic form andSelf-Care Agency Scale. Statistical analyses were performed using SPSS,including Cronbach’s Alpha, Chi-square, Fisher’s and contingency coefficient tests. The Cronbach's alpha was 0.788. The result verified that sex (p = 0.028), religion (p <0.001), education (p = 0.046), current age (p = 0.027), SCI time (p = 0.020) and the SCI type (p = 0.012) were variables associated with self-care ability of the subjects. It was concluded that sociodemographic factors may interfere with the self-care ability of persons with SCI, and nurses should consider this aspect during the execution of the nursing process.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel diseases (IBDs), Crohn's disease, and ulcerative colitis (UC), are multifactorial disorders, characterized by chronic inflammation of the intestine. A number of genetic components have been proposed to contribute to IBD pathogenesis. In this case-control study, we investigated the association between two common vitamin D-binding protein (DBP) genetic variants and IBD susceptibility. These two single nucleotide polymorphisms (SNPs) in exon 11 of the DBP gene, at codons 416 (GAT>GAG; Asp>Glu) and 420 (ACG>AAG; Thr>Lys), have been previously suggested to play roles in the etiology of other autoimmune diseases. METHODS: Using TaqMan SNP technology, we have genotyped 884 individuals (636 IBD cases and 248 non-IBD controls) for the two DBP variants. RESULTS: On statistical analysis, we observed that the DBP 420 variant Lys is less frequent in IBD cases than in non-IBD controls (allele frequencies, P=0.034; homozygous carrier genotype frequencies, P=0.006). This inverse association between the DBP 420 Lys and the disease remained significant, when non-IBD participants were compared with UC (homozygous carrier genotype frequencies, P=0.022) or Crohn's disease (homozygous carrier genotype frequencies, P=0.016) patients separately. Although the DBP position 416 alone was not found to be significantly associated with IBD, the haplotype DBP_2, consisting of 416 Asp and 420 Lys, was more frequent in the non-IBD population, particularly notably when compared with the UC group (Odds ratio, 4.390). CONCLUSION: Our study adds DBP to the list of potential genes that contribute to the complex genetic etiology of IBD, and further emphasizes the association between vitamin D homeostasis and intestinal inflammation.

Association of socioeconomic position with health behaviors and mortality

CONTEXT: Previous studies may have underestimated the contribution of health behaviors to social inequalities in mortality because health behaviors were assessed only at the baseline of the study. OBJECTIVE: To examine the role of health behaviors in the association between socioeconomic position and mortality and compare whether their contribution differs when assessed at only 1 point in time with that assessed longitudinally through the follow-up period. DESIGN, SETTING, AND PARTICIPANTS: Established in 1985, the British Whitehall II longitudinal cohort study includes 10 308 civil servants, aged 35 to 55 years, living in London, England. Analyses are based on 9590 men and women followed up for mortality until April 30, 2009. Socioeconomic position was derived from civil service employment grade (high, intermediate, and low) at baseline. Smoking, alcohol consumption, diet, and physical activity were assessed 4 times during the follow-up period. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality. RESULTS: A total of 654 participants died during the follow-up period. In the analyses adjusted for sex and year of birth, those with the lowest socioeconomic position had 1.60 times higher risk of death from all causes than those with the highest socioeconomic position (a rate difference of 1.94/1000 person-years). This association was attenuated by 42% (95% confidence interval [CI], 21%-94%) when health behaviors assessed at baseline were entered into the model and by 72% (95% CI, 42%-154%) when they were entered as time-dependent covariates. The corresponding attenuations were 29% (95% CI, 11%-54%) and 45% (95% CI, 24%-79%) for cardiovascular mortality and 61% (95% CI, 16%-425%) and 94% (95% CI, 35%-595%) for noncancer and noncardiovascular mortality. The difference between the baseline only and repeated assessments of health behaviors was mostly due to an increased explanatory power of diet (from 7% to 17% for all-cause mortality, respectively), physical activity (from 5% to 21% for all-cause mortality), and alcohol consumption (from 3% to 12% for all-cause mortality). The role of smoking, the strongest mediator in these analyses, did not change when using baseline or repeat assessments (from 32% to 35% for all-cause mortality). CONCLUSION: In a civil service population in London, England, there was an association between socioeconomic position and mortality that was substantially accounted for by adjustment for health behaviors, particularly when the behaviors were assessed repeatedly.

Association of nuclear matrix proteins with granular and threaded nuclear bodies in cell lines undergoing apoptosis.

The granules which appear in the nucleolar area in apoptotic HL-60 cells after camptothecin administration (Zweyer et al., Exp. Cell Res. 221,27-40, 1995) were detected also in several other cell lines induced to undergo apoptosis by different stimuli, such as MOLT-4 treated with staurosporine, K-562 incubated with actinomycin D, P-815 exposed to temperature causing heat shock, Jurkat cells treated with EGTA, U-937 growing in the presence of cycloheximide and tumor necrosis factor-alpha, and HeLa cells treated with etoposide. Using immunoelectron microscopy techniques, we demonstrate that, besides the already described nuclear matrix proteins p125 and p160, these granules contain other nucleoskeletal polypeptides such as proliferating cell nuclear antigen, a component of ribonucleoprotein particles, a 105-kDa constituent of nuclear spliceosomes, and the 240-kDa nuclear mitotic apparatus-associated protein referred to as NuMA. Moreover, we also found in the granules SAF-A/hn-RNP-U and SATB1 proteins, two polypeptides that have been reported to bind scaffold-associated regions DNA sequences in vitro, thus mediating the formation of looped DNA structures in vivo. Fibrillarin and coilin are not present in these granules or the PML protein. Thus, the granules seen during the apoptotic process apparently are different from coiled bodies or other types of nuclear bodies. Furthermore, these granules do not contain chromatin components such as histones and DNA. Last, Western blotting analysis revealed that nuclear matrix proteins present in the granules are not proteolytically degraded except for the NuMA polypeptide. We propose that these granules might represent aggregates of nuclear matrix proteins forming during the apoptotic process. Moreover, since the granules are present in several cell lines undergoing apoptosis, they could be considered a previously unrecognized morphological hallmark of the apoptotic process.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.

BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.¦METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.¦RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.¦CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

Association of brain spectrin isoforms with microtubules.

The relationship of rat brain spectrin isoforms to microtubules of newborn and adult animals was studied. Spectrins were minor components in microtubule preparations. The microtubule-associated spectrin is a major calmodulin-binding protein. Radiolabelled brain spectrin(240/235) revealed specific microtubule binding activity in vitro, possibly via a tubulin.

Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.

BACKGROUND: Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. METHODS: A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. RESULTS: During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). CONCLUSIONS: Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.

Association of ischaemic stroke subtype with long-term cardiovascular events.

BACKGROUND AND PURPOSE: There is no strong evidence that all ischaemic stroke types are associated with high cardiovascular risk. Our aim was to investigate whether all ischaemic stroke types are associated with high cardiovascular risk. METHODS: All consecutive patients with ischaemic stroke registered in the Athens Stroke Registry between 1 January 1993 and 31 December 2010 were categorized according to the TOAST classification and were followed up for up to 10 years. Outcomes assessed were cardiovascular and all-cause mortality, myocardial infarction, stroke recurrence, and a composite cardiovascular outcome consisting of myocardial infarction, angina pectoris, acute heart failure, sudden cardiac death, stroke recurrence and aortic aneurysm rupture. The Kaplan-Meier product limit method was used to estimate the probability of each end-point in each patient group. Cox proportional hazards models were used to determine the independent covariates of each end-point. RESULTS: Two thousand seven hundred and thirty patients were followed up for 48.1 ± 41.9 months. The cumulative probabilities of 10-year cardiovascular mortality in patients with cardioembolic stroke [46.6%, 95% confidence interval (CI) 40.6-52.8], lacunar stroke (22.1%, 95% CI 16.2-28.0) or undetermined stroke (35.2%, 95% CI 27.8-42.6) were either similar to or higher than those of patients with large-artery atherosclerotic stroke (LAA) (28.7%, 95% CI 22.4-35.0). Compared with LAA, all other TOAST types had a higher probability of 10-year stroke recurrence. In Cox proportional hazards analysis, compared with patients with LAA, patients with any other stroke type were associated with similar or higher risk for the outcomes of overall mortality, cardiovascular mortality, stroke recurrence and composite cardiovascular outcome. CONCLUSIONS: Large-artery atherosclerotic stroke and cardioembolic stroke are associated with the highest risk for future cardiovascular events, with the latter carrying at least as high a risk as LAA stroke.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans.

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node-like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin(+) T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell-rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter-CXCL13-transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell-rich zone.

Unusual association of diseases/symptoms: Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome?

We report on a 70-year-old woman with partial complex status epilepticus who was initially diagnosed with herpes simplex-2 (HSV-2) encephalitis, based on brain magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) lymphocytic pleocytosis and HSV-2 DNA detection by polymerase chain reaction (PCR) in the CSF, but without improvement on intravenous acyclovir. Anti-Ri antibodies were positive and computed tomography (CT) investigations revealed a small cell carcinoma at biopsy suggesting paraneoplastic encephalitis. The outcome was unfavourable and the autopsy showed typical features of paraneoplastic encephalitis but no evidence of viral inclusions. This case report is interesting because: (1) it is the first report of an autopsy proven paraneoplastic widespread encephalitis with anti-Ri antibodies; (2) despite a positive HSV-2 PCR in the CSF, there was no sign of herpetic infections of the nervous system; and (3) it illustrates the fact that if paraneoplastic antibodies are usually good markers of the underlying tumour, they are not always predictive of neurological deficits.