Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

Germline predictors of androgen deprivation therapy response in advanced prostate cancer.

OBJECTIVE: To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response. PATIENTS AND METHODS: In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing. RESULTS: At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less. CONCLUSION: Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.

Association of TNFSF8 polymorphisms with peripheral neutrophil count.

OBJECTIVE: To investigate the association between 347 single-nucleotide polymorphisms within candidate genes of the tumor necrosis factor, interleukin 1 and interleukin 6 families with neutrophil count. PATIENTS AND METHODS: Four hundred cases with heart failure after myocardial infarction (MI) were matched by age, sex, and date of incident MI to 694 controls (MI without post-MI heart failure). Both genotypes and neutrophil count at admission for incident MI were available in 314 cases and 515 controls. RESULTS: We found significant associations between the TNFSF8 poly morphisms rs927374 (P=5.1 x 10(-5)) and rs2295800 (P=1.3 x 10(-4)) and neutrophil count; these single-nucleotide polymorphisms are in high linkage disequilibrium (r(2)=0.97). Associations persisted after controlling for clinical characteristics and were unchanged after adjusting for case-control status. For rs927374, the neutrophil count of GG homozygotes (7.6±5.1) was 16% lower than that of CC homozygotes (9.0±5.2). CONCLUSION: The TNFSF8 polymorphisms rs927374 and rs2295800 were associated with neutrophil count. This finding suggests that post-MI inflammatory response is genetically modulated.

Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis.

OBJECTIVES: Existing efficacy trials of Omega-3 (omega-3) fatty acids in mood disorders have yielded inconsistent results. The current paper is an effort to provide a systematic review and meta-analysis to evaluate efficacy of omega-3 fatty acids in treatment of mood disorders. DESIGN: We searched Medline, Embase, PsychInfo, and the Cochrane Controlled Trials registry up to June 2008 for randomized trials investigating efficacy of omega-3 fatty acids in mood disorders.We conducted random effects meta-analyses.We used the I2 statistic to quantify between-study inconsistency, and conducted pre-specified subgroup analyses to explore potential explanations for inconsistency. OBSERVATIONS: We included 21 trials in our systematic review and found 13 trials to be eligible for meta-analysis. The pooled standardized mean difference in depressed mood states (n = 554 in 12 trials) was -0.47 (95% CI:-0.92,-0.02; I2 = 82.7; p = 0.07) and in manic mood states (n = 126 in 4 trials) was 0.22 (95% CI: -0.21, 0.65; I2 = 40.5; p = 0.31).We did not identify any treatment- subgroup interaction across forms of omega-3 fatty acids preparations (P = 0.99) or patient diagnosis (bipolar vs. unipolar depressive disorder; P = 0.96); there was a significant correlation between omega-3 fatty acids dose and treatment effect on depressive symptoms (r = 0.5, p = 0.04), but not on manic symptoms (P = 0.3). CONCLUSIONS: The available evidence suggests that omega-3 fatty acids are a potential treatment of depressive disorders, but not mania. The unexplained between-study inconsistency and imprecision of the pooled estimates mitigate this suggestion. Large randomized placebo-controlled trials are needed to better estimate the value of this intervention for patients with depression.