Influence of exonic polymorphisms in the gene for LDL receptor-related protein (LRP) on risk of coronary artery disease

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor involved in numerous biological processes relevant to vascular biology including lipoprotein metabolism. Several polymorphisms in the LRP gene have been described and in this study we examined their influence on coronary artery disease (CAD). We compared the frequencies of the exon 3 (C766T), exon 6 (C663T), exon 22 (C200T), and four rarer and more recently described polymorphisms in approximately 600 Caucasian subjects aged <50 years with angiographic CAD and approximately 700 similarly aged subjects without symptomatic CAD randomly selected from the community. We found the distribution of exon 22 C200T genotypes to differ significantly between the CAD (CC: 52%, CT: 39%, TT: 9%) and control subjects (CC: 43%, CT: 46%, TT: 11%, P=0.005), with the CC genotype conferring an odds ratio (OR) for CAD of 1.5 (95% CI: 1.2-1.8, P=0.001) despite a lack of significant influence on plasma cholesterol or triglyceride. The other LRP polymorphisms were less common. Two showed an association with CAD; for the exon 3 C766T polymorphism the TT genotype was significantly lower (1.0 vs. 2.7%; OR: 0.36; P=0.04) and, for the exon 6 C663T polymorphism, the heterozygote frequency was higher (6.2 vs. 3.4%; OR: 1.9; P=0.03) in CAD subjects. In conclusion, LRP gene polymorphisms, particularly the relatively common exon 22 C200T polymorphism, are a significant risk factor for premature CAD in Caucasians.     

Estimation of plasma small dense LDL cholesterol from classic lipid measures

Calculated low-density lipoprotein cholesterol (cLDL-C) may differ from direct measurement (dLDL-C), and this difference may depend on presence of small, dense LDL (sdLDL) particles in addition to variation in triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations. The presence of such dependence would offer a simple means to estimate sdLDL. We studied dependence of sdLDL on cLDL-C, dLDL-C, and other variables. We measured the levels of glucose, creatinine, total cholesterol, TG, HDL-C, and dLDL-C using standardized methods in 297 samples. For sdLDL cholesterol (sdLDL-C), a novel homogeneous assay was used. The cLDL-C was calculated using the Friedewald formula for 220 subjects after excluding for liver or renal disease. Using stepwise regression analysis identified non-HDL-C, cLDL-C, and dLDL-C as significant variables (P < .001; R(2) = 0.88). The regression equation was as follows: sdLDL-C (mg/dL) = 0.580 (non-HDL-C) + 0.407 (dLDL-C) - 0.719 (cLDL-C) - 12.05. The sdLDL-C concentration can be estimated from non-HDL-C, dLDL-C, and cLDL-C values. Identification of a simple, inexpensive marker for sdLDL particles provides a cost-effective method for screening cardiovascular disease risk.     

Atorvastatin increases expression of low‐density lipoprotein receptor mRNA in human circulating mononuclear cells

1. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR) inhibitors, or statins, are commonly used to lower plasma cholesterol levels. HMGCR and the low‐density lipoprotein (LDL) receptor (LDLR) are of central importance to cholesterol homeostasis and yet there is a paucity of data on the effect of statins on the regulation of the LDLR and HMGCR in humans. 2. In the present study, we examined the effect of atorvastatin on the expression of HMGCR, LDLR and LDLR‐related protein (LRP) mRNA in circulating mononuclear cells. Twelve human volunteers were treated with atorvastatin, 20 mg/day for 4 weeks. 3. Atorvastatin decreased plasma total and LDL–cholesterol by 29% (P < 0.0001) and 41% (P < 0.001), respectively, and increased LDLR mRNA abundance, in absolute terms, by 35% (P < 0.001) and 31% (P < 0.0001) and 37% (P = 0.01) relative to reference GAPDH and β‐actin mRNA, respectively. In contrast, atorvastatin had no significant effect on LRP or HMGCR mRNA levels. 4. The increase in LDLR mRNA in circulating mononuclear cells agrees with the few human studies conducted, as well as with in vitro and animal studies, whereas the unchanged HMGCR mRNA is consistent with the hepatic specificity of atorvastatin. The present study firmly documents an increase in LDLR mRNA levels in response to statin administration in normal humans.     

Risk factors for acute pulmonary edema after adenotonsillectomy in children

Objective

Adenotonsillectomy is a common surgical procedure in children. Acute pulmonary edema after this procedure is a rare complication but may be fatal. The factors associated with pulmonary edema after adenotonsillectomy were studied.

Methods

All consecutive patients with an age of less than 15 years who underwent adenotonsillectomy at Chiang Mai University Hospital were enrolled. The study period was from January 2004 to December 2008. Clinical factors were retrospectively retrieved from medical records. Factors associated with acute pulmonary edema after adenotonsillectomy were computed using multiple logistic regression analysis.

Results

There were 216 patients who underwent adenotonsillectomy due to airway obstruction during the study period. Five patients were excluded due to incomplete data. Of those included, 129 patients (61.1%) were male with mean age of 6.6 (SD 3.2) years. Four significant factors associated with the development of post-operative pulmonary edema after the adenotonsillectomy were procedure, age, obesity, and pulmonary hypertension.

Conclusion

Factors associated with acute pulmonary edema after adenotonsillectomy in children were adenotonsillectomy procedure, young age, obesity, or having pulmonary hypertension. Clinicians should be aware of these risk factors while performing adenotonsillectomy in children.     

LDL-receptor mRNA expression in men is downregulated within an hour of an acute fat load and is influenced by genetic polymorphism

Little is known about the immediate effects of dietary fat on the expression of genes involved in cholesterol metabolism in humans. We investigated the effects of a high-fat meal on circulating mononuclear cell messenger RNA (mRNA) for the LDL receptor (LDLR), LDLR-related protein (LRP), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) over 10 h. Selection of 12 C and 7 T homozygotes for the LRP exon 22 C200T polymorphism for the study also enabled us to examine the influence of this polymorphism on postprandial mRNA expression and lipoproteins, of relevance because of LRP's role in postprandial lipoprotein metabolism and association of the polymorphism with coronary artery disease. We found a postprandial decrease in LDLR mRNA abundance relative to the reference beta-actin (BA) mRNA. The decreased LDLR/BA mRNA value was apparent at 1 h (P < 0.005) and decreased to 25% of baseline at 6 h (P < 0.005). The LRP/BA mRNA value was also lower at 6 h (16% decrease, P < 0.05). HMGCR mRNA expression was unchanged. C homozygotes for the C200T polymorphism had higher LDLR/BA values than T homozygotes (P = 0.01) and although plasma LDL cholesterol (LDL-C) concentrations decreased in the postprandial period (P < 0.002), the decrease was less in C than in T homozygotes (P < 0.05). This study constitutes the first observation, to our knowledge, of postprandial changes in LDLR and LRP mRNA expression. It documents immediate effects of a fatty meal on these mRNA as well as an LRP genotype effect on LDLR mRNA and LDL-C.