Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile.

According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10-22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.

Diabetes incidence and glucose intolerance prevalence increase with higher outdoor temperature.

OBJECTIVE: Rising global temperatures might contribute to the current worldwide diabetes epidemic, as higher ambient temperature can negatively impact glucose metabolism via a reduction in brown adipose tissue activity. Therefore, we examined the association between outdoor temperature and diabetes incidence in the USA as well as the prevalence of glucose intolerance worldwide. RESEARCH DESIGN AND METHODS: Using meta-regression, we determined the association between mean annual temperature and diabetes incidence during 1996-2009 for each US state separately. Subsequently, results were pooled in a meta-analysis. On a global scale, we performed a meta-regression analysis to assess the association between mean annual temperature and the prevalence of glucose intolerance. RESULTS: We demonstrated that, on average, per 1°C increase in temperature, age-adjusted diabetes incidence increased with 0.314 (95% CI 0.194 to 0.434) per 1000. Similarly, the worldwide prevalence of glucose intolerance increased by 0.170% (95% CI 0.107% to 0.234%) per 1°C rise in temperature. These associations persisted after adjustment for obesity. CONCLUSIONS: Our findings indicate that the diabetes incidence rate in the USA and prevalence of glucose intolerance worldwide increase with higher outdoor temperature.