Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1-4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOe4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOe2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond e2 and e4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus

Purpose. Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. Methods. Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. Results. The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10 ). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10 ) and rs17501108 (P = 9.9 × 10 ). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). Conclusions. Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Do psychosocial factors moderate the association of fixed-term employment with work interference with family and sleeping problems in registered nurses: A cross-sectional questionnaire survey

Background: The use affixed-term employment has increased lately, particularly in Europe and in the health care sector. Previous studies have shown that especially among the health care sector employee's organizational justice perceptions and job control are important factors that are directly related to the welfare and attitudes of employees and may also help to buffer the negative impacts of many detrimental factors.

The Association of Distress and Sleeping Problems With Physicians' Intentions To Change Profession: The Moderating Effect of Job Control

The present study examined whether job control moderated the association between stress indicators (distress and sleeping problems) and intentions to change profession among 2,650 Finnish physicians. Ordinal logistic regression analysis was applied. The authors found that high levels of distress and sleeping problems were associated with higher levels of intentions to change profession, whereas high job control was associated with lower levels of intentions to change profession even after adjusting for the effects of gender, age, and employment sector. In addition, high job control was able to mitigate the positive association that distress and sleeping problems had with intentions to change profession. Our findings highlight the importance of offering more job control to physicians to prevent unnecessary physician turnover.

Association of impulsivity with sleep duration and insomnia in an employee population

Clinical studies have linked impulsivity and insomnia in patients, but little is known about this association in non-clinical settings. This study examined whether impulsive temperament is associated with sleep duration and insomnia complaints in a large cohort of hospital employees (535 men and 4014 women). Linear regression models were related to prospective data from two surveys conducted in 1998 and 2000. Adjustments were made for age, marital status, education, shift work, smoking, alcohol consumption, body mass index, physical activity, minor psychiatric morbidity, social support, somatic disease, depression and other psychiatric disease in 1998. In men, higher impulsivity predicted shorter sleep duration and waking up several times per night independent of baseline characteristics. In women, higher impulsivity predicted having difficulty falling asleep and waking up feeling tired after the usual amount of sleep after adjustment for most of covariates. However, these associations turned out to be non-significant after adjustment for somatic and psychiatric disease. These results support the hypothesis that impulsive temperament could be a risk factor for insomnia in men. (c) 2007 Elsevier Ltd. All rights reserved.

On the association of ULXs with young superclusters: M82 X-1 and a new candidate in NGC 7479

We investigate the spatial coincidence of ultraluminous X-ray sources (ULXs) with young massive stellar clusters. In particular, we perform astrometry on Chandra and Hubble Space Telescope (HST) data of two ULXs that are possibly associated with such clusters.

The Association of Ownership Type With Job Insecurity and Worry About Job Stability The Moderating Effects of Fair Management, Positive Leadership, and Employment Type

This study examined whether the ownership type is associated with job insecurity and worry about job stability and whether the type of employment contract, positive leadership, and fair management moderated these associations. Survey data from 1249 Finnish female elderly care staff aged 18 to 69 years were used. Job insecurity and worry about job stability were highest in not-for-profit sheltered homes. However, positive leadership and fair management were able to mitigate this insecurity and worry. Job insecurity was highest among fixed-term employees in public sheltered homes or not-for-profit nursing homes. Thus, promoting good leadership and fair management would be of importance.

Association of the G4 rotavirus genotype with gastroenteritis in adults

Rotavirus is the most common etiological cause of acute viral gastroenteritis in infants and young children worldwide, yet its role in the adult population is less well understood. We have recently identified rotavirus as the causative agent of severe diarrhea in adults, specifically in two gastroenteritis outbreaks in separate care for the elderly homes. Strain typing has shown the continued presence of P[8]G1, the emergence of P[8]G9, and the reemergence of P[8]G4. A total of 26 community cases and 6 outbreak cases of rotavirus infection, positive via a molecular screening assay, were subsequently amplified using VP4 and VP7 specific primers (Con2/Con3 and 1A/1B primer sets, respectively). The age range of patients investigated was from

Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP diet and health study

The aim of our study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric noncardia adenocarcinoma. From 1995–1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. The 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric noncardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Although apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null [e.g., EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95% CI) 1.66 (1.27–2.18) p for trend <0.01; EAC multivariate adjusted HR (95% CI) 1.17 (0.84–1.64) p for trend 5 0.58]. Similar patterns were also observed for fat subtypes [e.g., EAC saturated fat, energy adjusted HR (95% CI) 1.79 (1.37–2.33) p for trend <0.01; EAC saturated fat, multivariate adjusted HR (95% CI) 1.27 (0.91–1.78) p for trend 5 0.28]. However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5–<25 kg/m2) [HR (95% CI) 0.76 (0.63–0.92)], that was not present in overweight subjects [HR (95% CI) 1.04 (0.96–1.14)], or in unstratified analysis [HR (95% CI) 0.97 (0.90–1.05)]. p for interaction 5 0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; although a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.

Association of MYH9/APOL1 with chronic kidney disease in a UK population

Following the first report on the association between MYH9 gene variants and glomerular disorders [1], many studies have evaluated MYH9 loci for association with a range of kidney diseases [2]. In 2010, functional mutations in the adjacent APOL1 gene were identified as the primary variants responsible for associations with kidney disease that had previously been attributed to the MHY9 gene [3]. Nevertheless, several loci within MHY9 continue to be independently reported as risk factors for chronic kidney disease (CKD) [2, 4].

Delayed association of the NADPH oxidase complex with macrophage vacuoles containing the opportunistic pathogen Burkholderia cenocepacia

Burkholderia cenocepacia causes chronic lung infections in patients suffering from cystic fibrosis and chronic granulomatous disease. We have previously shown that B. cenocepacia survives intracellularly in macrophages within a membrane vacuole (BcCV) that delays acidification. Here, we report that after macrophage infection with live B. cenocepacia there is a approximately 6 h delay in the association of NADPH oxidase with BcCVs, while heat-inactivated bacteria are normally trafficked into NADPH oxidase-positive vacuoles. BcCVs in macrophages treated with a functional inhibitor of the cystic fibrosis transmembrane conductance regulator exhibited a further delay in the assembly of the NADPH oxidase complex at the BcCV membrane, but the inhibitor did not affect NADPH oxidase complex assembly onto vacuoles containing heat-inactivated B. cenocepacia or live Escherichia coli. Macrophages produced less superoxide following B. cenocepacia infection as compared to heat-inactivated B. cenocepacia and E. coli controls. Reduced superoxide production was associated with delayed deposition of cerium perhydroxide precipitates around BcCVs of macrophages infected with live B. cenocepacia, as visualized by transmission electron microscopy. Together, our results demonstrate that intracellular B. cenocepacia resides in macrophage vacuoles displaying an altered recruitment of the NADPH oxidase complex at the phagosomal membrane. This phenomenon may contribute to preventing the efficient clearance of this opportunistic pathogen from the infected airways of susceptible patients.