The 223A>G polymorphism of the leptin receptor gene and lipid-lowering efficacy of simvastatin in Chinese patients with coronary heart disease

Objective  To investigate whether leptin receptor (LEPR) 223A>G polymorphism influences serum lipid levels and whether this polymorphism affects the effectiveness of simvastatin in Chinese patients with coronary heart disease (CHD). Methods  A total of 312 patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids were determined before and after 12 weeks of treatment. Results  Patients with AA genotype had significantly higher total cholesterol (TC) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than those with GG genotype (P < 0.05) before simvastatin treatment. In addition, the ability of simvastatin to increase HDL-C levels was significantly lower in patients with AA genotype than those with GG genotype (P < 0.05). Conclusions  The 223A>G polymorphism of LEPR significantly modulates the HDL-C response to simvastatin in Chinese patients with CHD. Yan-Ming Sun and Jia Li contributed equally to this study.     

Role of active metabolites in the use of opioids

The opioid class of drugs, a large group, is mainly used for the treatment of acute and chronic persistent pain. All are eliminated from the body via metabolism involving principally CYP3A4 and the highly polymorphic CYP2D6, which markedly affects the drug’s function, and by conjugation reactions mainly by UGT2B7. In many cases, the resultant metabolites have the same pharmacological activity as the parent opioid; however in many cases, plasma metabolite concentrations are too low to make a meaningful contribution to the overall clinical effects of the parent drug. These metabolites are invariably more water soluble and require renal clearance as an important overall elimination pathway. Such metabolites have the potential to accumulate in the elderly and in those with declining renal function with resultant accumulation to a much greater extent than the parent opioid. The best known example is the accumulation of morphine-6-glucuronide from morphine. Some opioids have active metabolites but at different target sites. These are norpethidine, a neurotoxic agent, and nordextropropoxyphene, a cardiotoxic agent. Clinicians need to be aware that many opioids have active metabolites that will become therapeutically important, for example in cases of altered pathology, drug interactions and genetic polymorphisms of drug-metabolizing enzymes. Thus, dose individualisation and the avoidance of adverse effects of opioids due to the accumulation of active metabolites or lack of formation of active metabolites are important considerations when opioids are used.     

HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients

Rationale  Aripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole. Objectives  This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. Materials and methods  After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment. Results  We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment. Conclusions  The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.     

C-type lectin protein isoforms of Macrovipera lebetina: cDNA cloning and genetic diversity

Snake venom contains a complex protein mixture belonging to a few well-characterized protein families: disintegrins, phospholipase A2, serine protease, l-amino acid oxidase, Zn-dependent metalloproteinase, natriuretic peptides, myotoxins, cysteine-rich secretory protein (CRISP) toxins, Kunitz-type protease inhibitors and C-type lectin-like. Despite their pharmacological importance, little is known about the exact composition of each protein family. We report here the cloning of 25 complete ORFs from Macrovipera lebetina transmediterranea venom gland that encodes several isoforms and novel C-type lectins (CTLs). 16 alpha and nine beta CTL chains were identified. Based on their sequence alignment, we categorized the 16 CTL alpha subunits into five groups and the nine CTL beta subunits into four groups to deduce the phylogenetic tree of M. lebetina transmediterranea CTLs. Sequence analysis revealed that they share a high degree of similarity with each other and with other snake venom CTLs. The M. lebetina transmediterranea CTL sequences described here contain a C-lectin carbohydrate recognition domain-like fold (C-lectin CRD-like) characterized by several conserved amino acid residues in their structure, especially the cysteine. Finally, based on the comparison of some Macrovipera CTL, we propose that some new CTL gene versions should have occurred through “domains shuffling” from former genes.     

Lack of association of alcohol dependence and habitual smoking with catechol-O-methyltransferase

OBJECTIVE: To test whether variation in the gene encoding the enzyme catechol-O-methyltransferase (COMT), which catalyzes the breakdown of dopamine and other catecholamine neurotransmitters, is associated with the risk for alcohol dependence and habitual smoking. METHODS: Single nucleotide polymophisms (SNPs) were genotyped in a sample of 219 multiplex alcohol-dependent families of European American descent from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based tests of association were performed to evaluate the evidence of association between the 18 SNPs distributed throughout COMT, including the functional Val158Met polymorphism, and the phenotypes of alcohol dependence, early onset alcohol dependence, habitual smoking, and comorbid alcohol dependence and habitual smoking. RESULTS: No significant, consistent evidence of association was found with alcohol dependence, early onset alcohol dependence, habitual smoking or the comorbid phenotype. There was no evidence that the functional Val158Met polymorphism, previously reported to be associated with these phenotypes, was associated with any of them. CONCLUSION: Despite the substantial size of this study, we did not find evidence to support an association between alcohol dependence or habitual smoking and variation in COMT.     

Genetics in liver diseases

In recent years, few fields in medicine have witnessed discoveries as momentous as those pertaining to the liver. Dramatic advances have been made, particularly in the areas of molecular biology and genetics. A joint EASL/AASLD Monothematic Conference was held on June 23rd-24th, 2006, in Modena, Italy, to bring the latest breakthroughs in different fields of genetics to hepatologists. This article reports the highlights of the conference and summarizes the main conclusions and implications for clinical and experimental hepatology.     

Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects

Aims/hypothesis Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity. Subjects and methods The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n = 161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n = 1,163). Results Significant association was found for a 5′ variant (rs6857715) in the NPY2R gene with both severe adult obesity (p = 0.002) and childhood obesity (p = 0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n = 928) vs the control subjects (n = 938) (p = 0.0004, odds ratio = 1.3, 95% CI 1.1–1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p = 0.005, recessive model p = 0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p = 0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family. Conclusions/interpretation These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

Aims/hypothesis The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic and environmental factors influencing this cluster in a general population of twin pairs. Materials and methods A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. Results All endophenotypes showed moderate to high heritability (0.31–0.69) and small common environmental variance (0.05–0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs of endophenotypes. However, moderate correlations between insulin resistance indices and either obesity-related endophenotypes or triacylglycerol levels indicated that some common genetic backgrounds are shared between those components. Conclusions/interpretation We demonstrated that, in a general population, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Phospholipase C expression and activity in smooth muscle cells of renal arterioles and aorta of young, spontaneously hypertensive rats during culture

BACKGROUND: Phospholipase C (PLC)-beta(1) and -delta(1), but not -gamma(1), protein expressions in fresh renal arterioles and aorta are greater in 6-week-old, spontaneously hypertensive rats (SHRs) versus normotensive Wistar-Kyoto rats (WKYs). This PLC activity is also greater in both vessels of SHRs. In the present study, we tested whether cultured vascular smooth muscle cells (VSMCs) of preglomerular arterioles and aorta accurately reflect strain differences observed in fresh vessels, with VSMCs of SHRs predicted to have higher levels of PLC isozymes and enzyme activity. We assessed the stability of variables over passages 3 to 11. METHODS: The VSMCs were isolated and cultured using standard techniques. The PLC-isozyme protein levels and catalytic activity were determined by Western blot analysis and inositol 1,4,5-trisphosphate (IP(3)) production, respectively. RESULTS: Immunoblots showed expression of PLC-gamma(1) and -delta(1), but not PLC-beta(1), in VSMCs from both vessels. Arteriolar VSMCs of SHRs had three-to-fivefold higher levels of PLC-gamma(1) and -delta(1) during passages 3 to 8. Enzymatic activity in these VSMCs was higher in SHRs versus WKYs, especially during passages 6 to 11. In contrast, cultured aortic VSMCs of SHRs had two-to-threefold lower densities of PLC-gamma(1) and -delta(1) protein. CONCLUSIONS: Compared with fresh resistance arterioles and aorta, cultured VSMCs exhibit changes in PLC-isozyme protein levels and enzyme activity that vary with passage. The differences between cultured VSMCs of SHRs and WKYs do not accurately reflect those in fresh resistance and conduit vessels, either qualitatively or quantitatively. The results of VSMC culture studies should be interpreted with caution and should ideally be compared with more physiologically relevant fresh preparations.