Citations

Abstract It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the ‘synthesis and degradation of ketone bodies’ pathway. Our results also support the potential involvement of the ‘neuroactive ligand–receptor interaction’ pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.

SummaryPreviously, we reported increased risk of heavy‐chain (HC) monoclonal gammopathy of undetermined significance (MGUS) among first‐degree (1°) relatives of multiple myeloma (MM) or HC‐MGUS probands. This study investigated whether there was comparable risk for light‐chain (LC) MGUS among 911 relatives of the same HC‐MGUS/MM probands versus a reference population of 21 463. Seventeen 1° relatives had LC‐MGUS (adjusted prevalence = 1·7%, 95% CI = 0·9–2·6%). There was increased risk of LC‐MGUS in relatives of MM probands (RR = 3·4, 95% CI = 2·0–5·5). We saw no increased risk in relatives of HC‐MGUS probands. We conclude that the prevalence of LC‐MGUS is significantly higher among 1° relatives of MM probands compared to the reference population.

Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. Patients and Methods We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. Results We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β 2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. Conclusion Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

Context Perioperative antibiotics are widely used to improve the outcomes of endoscopic sinus surgery. Objective The aim of this study was to summarize the evidence on the effect of perioperative antibiotic prophylaxis on outcomes of endoscopic sinus surgery. Data Sources and Review Methods We searched electronic databases from inception through May 2011 for any relevant clinical trials or observational studies. Two reviewers working independently extracted study characteristics, quality, and the outcomes of interest. Random‐effects meta‐analysis was used to pool the relative risks (RRs) and the standardized mean differences (SMDs) across trials. Results We found 4 eligible trials with varying quality, of which 3 were included in the quantitative analysis. Antibiotic prophylaxis was associated with a nonsignificant reduction in the incidence of infections (relative risk, 0.76; 95% confidence interval [CI], 0.64 to 1.09), symptoms scores (SMD, −0.04; 95% CI, −0.46 to 0.38), and endoscopic scores (SMD, −0.09; 95% CI, 0.30 to 0.13). The heterogeneity associated with the analysis was significant only for the outcome of change in symptoms score (I‐squared values, 0%, 70%, and 0% for the 3 outcomes, respectively). Conclusions Trial data available to date are unable to demonstrate a statistically significant reduction in infection, symptom scores, or endoscopic scores to support the routine use of postoperative prophylactic antibiotics following endoscopic sinus surgery. Our analysis was limited by the number of published trials related to this topic.

Abstract Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15–49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P &lt; 5 × 10−8), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10−7) and rs1986743 (in ARL6IP6; P = 2.7 × 10−7), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.