Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease A Mendelian Randomization Analysis

ObjectivesThe purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD).BackgroundLDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified.MethodsWe conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin.ResultsAll 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I2 = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10−19).ConclusionsProlonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life

Adult Circadian Behavior in Drosophila Requires Developmental Expression of cycle, But Not period

Circadian clocks have evolved as internal time keeping mechanisms that allow anticipation of daily environmental changes and organization of a daily program of physiological and behavioral rhythms. To better examine the mechanisms underlying circadian clocks in animals and to ask whether clock gene expression and function during development affected subsequent daily time keeping in the adult, we used the genetic tools available in Drosophila to conditionally manipulate the function of the CYCLE component of the positive regulator CLOCK/CYCLE (CLK/CYC) or its negative feedback inhibitor PERIOD (PER). Differential manipulation of clock function during development and in adulthood indicated that there is no developmental requirement for either a running clock mechanism or expression of per. However, conditional suppression of CLK/CYC activity either via per over-expression or cyc depletion during metamorphosis resulted in persistent arrhythmic behavior in the adult. Two distinct mechanisms were identified that may contribute to this developmental function of CLK/CYC and both involve the ventral lateral clock neurons (LNvs) that are crucial to circadian control of locomotor behavior: (1) selective depletion of cyc expression in the LNvs resulted in abnormal peptidergic small-LNv dorsal projections, and (2) PER expression rhythms in the adult LNvs appeared to be affected by developmental inhibition of CLK/CYC activity. Given the conservation of clock genes and circuits among animals, this study provides a rationale for investigating a possible similar developmental role of the homologous mammalian CLOCK/BMAL1 complex

Developmental requirement for adult behavioural rhythmicity in Drosophila melanogaster

Endogenous circadian clocks are a consequence of the periodic nature of the environment we live in. They allow organisms to anticipate daily environmental changes and organize a wide array of biological functions, such as daily activity, sleep and feeding. The molecular clock circuits driving rhythmic locomotor behaviour in Drosophila melanogaster consist of two interlocked negative-feedback transcription loops, with a conserved central role for the heterodimeric transcription factor CLOCK/CYCLE (CLK/CYC) and its inhibitor PERIOD (PER). Research presented in this thesis aims to describe underlying developmental requirements for clock function in adult D. melanogaster. It has been demonstrated previously that major oscillator components CLK, CYC and PER are present in larvae and some circadian modulation to behavioural is demonstrated in larvae themselves. Moreover, a light pulse administered early in development is enough to establish a phase of the locomotor rhythm of adult flies, pointing out to the connection between a function of the circadian clock during development and adulthood.This research reveals that adult circadian behaviour does not require either a functioning clock or the expression of per during prior development (Chapter 3). However, inhibition of CLK/CYC activity during metamorphosis (post-pupal formation), either by depletion of CYC or over-expression of its inhibitor PER, irreversibly affects clock-controlled locomotor activity in adult flies (Chapter 4 and 5). Even when PER over-expression is restricted to 18 ventral lateral clock neurons (LNvs) expressing the neuropeptide PIGMENT DISPERSING FACTOR (PDF), subsequent adult circadian behaviour is disrupted. A subset of small ventral lateral neurons (s-LNvs) was implicated as particularly sensitive to CLK/CYC inhibition through constitutive PER over-expression, suggesting that these cells require CLK/CYC function during development (Chapter 5).Circadian oscillations in the peripheral tissue of adult flies were less dependent on developmental CLK/CYC activity than locomotor behaviour (Chapter 5). Thus, the newly discovered developmental function for CLK/CYC appears to be specific to the neural clock circuits. Analysis of the daily rhythms of TIMELESS protein localisation within clock neurons revealed that molecular oscillator is severely disrupted in small ventral lateral neurons (s-LNvs). Therefore my research suggests CLK/CYC is necessary during metamorphosis to establish a proper function of the molecular oscillator in s-LNvs (Chapter 5). I hypothesized that genes downstream from CLK/CYC are involved in this process, with Pdp1? and Mef2 as the strongest candidates, however this has not been confirmed (Chapter 6). Moreover, it appears that chromatin modifications are not involved in mediating the phenotype observed as result of developmental CLK/CYC inhibition (Chapter 6).In summary, my work presents data confirming that CLK/CYC, but not PER activity, is required in PDF-expressing ventrolateral neurons during metamorphosis for establishing adult locomotor rhythmicity

Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: A mendelian randomization analysis

Objectives: The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). Background: LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. Methods: We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. Results: All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I2 = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10-19). Conclusions: Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life. © 2012 American College of Cardiology Foundation