4 research outputs found
Identification and replication of the interplay of four genetic high risk variants for urinary bladder cancer
Little is known whether genetic variants identified in
genome-wide association studies interact to increase bladder
cancer risk. Recently, we identified two- and three-variant
combinations associated with a particular increase of bladder
cancer risk in a urinary bladder cancer case-control series
(IfADo, 1501 cases, 1565 controls). In an independent
case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468
cases, 1720 controls) we confirmed these two- and three-variant
combinations. Pooled analysis of the two studies as discovery
group (IfADo-NBCS) resulted in sufficient statistical power to
test up to four-variant combinations by a logistic regression
approach. The New England and Spanish Bladder Cancer Studies
(2080 cases and 2167 controls) were used as a replication
series. Twelve previously identified risk variants were
considered.The strongest four-variant combination was obtained
in never smokers. The combination of rs1014971[AA] near APOBEC3A
and CBX6, SLC14A1 exon SNP rs1058396[AG,GG], UGT1A intron SNP
rs11892031[AA], and rs8102137[CC,CT] near CCNE resulted in an
unadjusted odds ratio of 2.59 (95% CI = 1.93-3.47; P =
1.87x10-10), while the individual variant odds ratios ranged
only between 1.11-1.30. The combination replicated in the New
England and Spanish bladder Cancer Studies (ORunadjusted=1.60,
95% CI = 1.10-2.33; P = 0.013). The four-variant combination is
relatively frequent, with 25% in never smoking cases and 11% in
never smoking controls (total study group: 19% cases, 14%
controls). In conclusion, we show that four high risk variants
can statistically interact to confer increased bladder cancer
risk particularly in never smokers
Spironolactone prevents the inducibility of ventricular tachyarrhythmia in rats with aldosteronism
Myocardial fibrosis is considered a substrate for fatal ventricular arrhythmias (VAs). In rats receiving aldosterone/salt treatment (ALDOST) for ≥4 weeks, foci of myocardial scarring that replace necrotic cardiomyocytes appear scattered throughout the right and left sides of the heart. We hypothesized that this adverse structural remodeling would promote the inducibility of VA, which could be prevented by cotreatment with spironolactone (A+Spiro), an aldosterone receptor antagonist and cardioprotective agent. In controls and each treatment group, we monitored: (1) electrocardiogram, ventricular electrogram, and arterial pressure before, during, and after bipolar electrical stimulation of the right ventricular outflow tract and apex at a strength 3× the pacing threshold, using both programmed stimulation with premature extra stimuli and 50-Hz burst pacing for 3 different durations; and (2) myocardial collagen volume fraction (CVF) as a marker of cardiac fibrosis. We found that VA (duration \u3e200 ms accompanied by declining arterial pressure) was more inducible (P \u3c 0.05) at 4 weeks (4 of 6) and with even greater frequency at 6 weeks (9 of 10) of ALDOST versus controls (0 of 6) and A+Spiro for 6 weeks (2 of 11). CVF (%) was proportionally increased (P \u3c 0.05) at 4 and 6 weeks (8.4 ± 0.74 and 13.9 ± 1.9, respectively) of ALDOST compared with control group (2.6 ± 0.4) and A+Spiro group (5.3 ± 0.7). However, the effective refractory period was indistinguishable between groups, whereas the probability of VA was nonlinearly related to CVF. Thus, in rats with aldosteronism, in which a reduction in effective refractory period was not evident, the mechanism for VA susceptibility is presumably linked to a decrease in conduction velocity and/or increased dispersion of refractoriness, probably caused by consequential myocardial fibrosis. Copyright © 2011 by Lippincott Williams & Wilkins