ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons.

[From phenotype to genotype: a glimpse behind the scenes of an unending story].

Mendelian conditions direct attention at basic mechanisms. In the 1990's DNA sequencing allowed elucidating such conditions. We embarked on an unexpected adventure to study a monogenic autosomal-dominant form of hypertension causing also a specific form of short fingers.

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB).

Avoidance of the Ames test liability for aryl-amines via computation.

Aryl-amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed.

Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen.

Improvement of postprandial lipid handling and glucose tolerance in a non-diabetic population by the dual PPARalpha/gamma agonist, tesaglitazar.

This study examined the effect of tesaglitazar (GALIDA), a dual peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist, on postprandial metabolism. This investigation was part of the Study in Insulin Resistance (SIR) (SH-SBT-0001), a randomised, double-blind, placebo-controlled study that reported improvements in fasting lipid and glucose values with tesaglitazar (0.1, 0.

Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance.

Aim: To determine the effects of the peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar on serum levels of apolipoprotein (apo) A-I, apoB, and apoCIII in non-diabetic insulin-resistant subjects.

Methods: This randomized, double-blind, multicentre, placebo-controlled trial examined the effect of tesaglitazar (0.1, 0.

Relating two deep-rooted pedigrees from Central Germany by high-resolution Y-STR haplotyping.

Y-STR haplotyping is a powerful forensic and anthropological tool for identifying male lineages. We used high-resolution Y-STR haplotyping to evaluate the possibility of a blood relationship between two deep-rooted paternal genealogies with the same surname and originating from the same geographical region in Central Germany. One pedigree comprised 13 generations covering >450 years, the other comprised nine generations covering >300 years.

The GALAXY Program: an update on studies investigating efficacy and tolerability of rosuvastatin for reducing cardiovascular risk.

The GALAXY Program is a series of clinical studies investigating the efficacy and tolerability of rosuvastatin in line with the hypothesis that the statin with the greatest efficacy for improving the atherogenic lipid profile and beneficially modifying inflammatory markers will also slow progression of atherosclerosis and improve cardiovascular outcomes. Completed studies report that rosuvastatin is more effective than comparator statins in reducing low-density lipoprotein cholesterol, improving the lipid profile and enabling patients to achieve lipid goals, including revised, more stringent goals, even in high-risk patients. Studies have also reported that rosuvastatin can arrest and even regress atherosclerosis.

Effects of switching statins on lipid and apolipoprotein ratios in the MERCURY I study.

Background: Lipid ratios are clinically useful markers of coronary artery disease (CAD) risk. The effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on lipid ratios were investigated in the Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY (MERCURY) I trial.

Methods: This trial was conducted in 3140 hypercholesterolemic patients with CAD, atherosclerosis, type 2 diabetes mellitus, or a 20% 10-year risk for CAD.

Investigating cardiovascular risk reduction--the Rosuvastatin GALAXY Programme.

The GALAXY Programme is a comprehensive global research initiative that will address several important unanswered questions in statin research and investigate the impact of rosuvastatin on cardiovascular risk reduction and patient outcomes. Studies already completed demonstrate that rosuvastatin provides greater reductions in low-density lipoprotein cholesterol (LDL-C) than other statins, enabling more patients to achieve LDL-C treatment goals. Additionally, rosuvastatin provides beneficial effects on other components of the atherogenic lipid profile.

Effects of switching statins on achievement of lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study.

Background: In a multinational trial (4522IL/0081), we assessed the effects of switching to low doses of rosuvastatin from commonly used doses of atorvastatin, simvastatin, and pravastatin on low-density lipoprotein cholesterol (LDL-C) goal achievement in high-risk patients.

Methods: Hypercholesterolemic patients (n = 3140) with coronary heart disease, atherosclerosis, or type 2 diabetes were randomized to open-label rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, or pravastatin 40 mg for 8 weeks. Patients either remained on these treatments for another 8 weeks or switched treatments from atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg to rosuvastatin 10 mg or from atorvastatin 20 mg to rosuvastatin 10 or 20 mg.

Risk assessment and strategies to achieve lipid goals: lessons from real-world clinical practice.

Coronary heart disease (CHD) risk assessment to establish risk category and appropriate plasma lipid goals as well as achievement of those lipid goals, are important elements of treatment for dyslipidemia in clinical practice. Cases from clinical practice are presented to illustrate risk assessment and treatment in the settings of peripheral arterial disease (PAD) and heterozygous familial hypercholesterolemia (hFH). Patients with PAD are at high risk of CHD and cardiovascular mortality and may require aggressive lipid-lowering therapy irrespective of the degree of hypercholesterolemia at presentation.

Haplotypes and SNPs in 13 lipid-relevant genes explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein cholesterol.

Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may explain genetic variance in complex traits; however, this hypothesis has not been rigorously tested. In an earlier study we analyzed six genes and have now expanded this investigation to include 13. We studied 250 families including 1054 individuals and measured lipid phenotypes.

Rosuvastatin--a highly effective new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor: review of clinical trial data at 10-40 mg doses in dyslipidemic patients.

Rosuvastatin (Crestor; licensed to AstraZeneca, Macclesfield, UK from Shionogi, Osaka, Japan) is a new statin with pharmacologic characteristics that translate into selectivity of effect in hepatic cells and enhanced potency in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition. It is approved for use at doses of 10-40 mg once daily to reduce low-density lipoprotein (LDL) cholesterol, increase high-density lipoprotein (HDL) cholesterol and improve other lipid measures in dyslipidemic patients. In a dose-ranging study in mild/moderate hypercholesterolemia, rosuvastatin reduced LDL cholesterol by 52-63% at 10-40 mg.

Single nucleotide polymorphism haplotypes in the cholesteryl-ester transfer protein (CETP) gene and lipid phenotypes.

We studied the association between high (HDL) and low-density (LDL) cholesterol concentrations and family-derived haplotypes based on six common SNPs in the cholesteryl-ester transfer protein (CETP) gene. We based our analysis on 201 founders from families recruited throughout Germany. The analysis revealed one subhaplotype block with complete, pairwise, linkage disequilibrium between 5 SNPs located in the promoter and intron 1.

Managing the high-risk patient: therapeutic approaches in 2002.

Populations of patients at high risk of coronary heart disease (CHD) include those with type 2 diabetes and those with heterozygous familial hypercholesterolemia (HeFH). Despite benefits of statin lipid-lowering therapy in reducing CHD risk in diabetic patients, screening for dyslipidemia in such patients is inadequate, and patients frequently fail to achieve recommended low-density lipoprotein goals. Diagnosis of HeFH is also suboptimal, despite the reliability of family lipid screening in confirming clinical diagnosis and utility of screening in identifying other family members who are at risk.

DNA testing for familial hypercholesterolemia: improving disease recognition and patient care.

Cardiovascular disease is the leading cause of death worldwide and, like most chronic diseases, it has major genetic and environmental components. Among patients with coronary heart disease onset before the age of 55, about 5% of cases are attributable to heterozygous familial hypercholesterolemia (FH), a disease following autosomal dominant inheritance. About 50% of individuals with FH die before the age of 60 due to myocardial infarction.

The impact of fatty acid oxidation on energy utilization: targets and therapy.

Utilization of fat as a long-term energy storage vehicle is crucial for the maintenance of cellular metabolism and is under intricate and many times redundant control mechanisms. Aberrations in the control of energy metabolism is apparent in diseases such as diabetes and obesity and is evident early on in patients with impaired glucose tolerance. Insulin resistance has been observed at the level of muscle, liver and adipose tissue.

Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population.

We studied the association between common haplotypes in six relevant lipid metabolism genes with plasma lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), low-density lipoprotein cholesterol receptor (LDLR), apolipoprotein E (ApoE) and lecithin-cholesterol acyltransferase (LCAT) genes, and studied 732 individuals from 184 German families. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) were similar to those reported in other European and American populations.