Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque

Background and Purpose - Coding single nucleotide polymorphisms (cSNPs) in the lipoprotein lipase (LPL) gene have been associated with lipoprotein phenotypes and vascular disease risk. We studied the association between LPL cSNPs and a novel noninvasive measure of disease, namely, cross-sectional carotid plaque area (CPA) on B-mode ultrasound. Methods - Four hundred fifty-two patients from an atherosclerosis prevention clinic had determinations of baseline and total CPA. Traditional atherosclerosis risk factors were recorded, and the LPL D9N, N291S, and S447X cSNPs were genotyped. Multiple regression analysis was used to identify determinants of CPA. Results - Minor allele frequencies for LPL D9N, N291S, and S447X were 2.8%, 0.9%, and 4.4%, respectively. There were no significant between-genotype differences in treated fasting lipids. The LPL D9N genotype was a significant predictor of both baseline CPA (P=0.008) and plaque progression from baseline to 1 year later (P=0.001). Heterozygotes for the N9 allele had higher mean baseline CPA and plaque progression than did LPL D9/D9 homozygotes. Conclusions - LPL D9N genotype may be a determinant of atherosclerosis as estimated by static baseline CPA and by progression of CPA

NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe

BACKGROUND: NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe. RESULTS: In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol. CONCLUSION: These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment

Genetic determinants of statin intolerance

BACKGROUND: Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint. RESULTS: COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively. CONCLUSION: These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway

Environmental changes and violent conflict

This letter reviews the scientific literature on whether and how environmental changes affect the risk of violent conflict. The available evidence from qualitative case studies indicates that environmental stress can contribute to violent conflict in some specific cases. Results from quantitative large-N studies, however, strongly suggest that we should be careful in drawing general conclusions. Those large-N studies that we regard as the most sophisticated ones obtain results that are not robust to alternative model specifications and, thus, have been debated. This suggests that environmental changes may, under specific circumstances, increase the risk of violent conflict, but not necessarily in a systematic way and unconditionally. Hence there is, to date, no scientific consensus on the impact of environmental changes on violent conflict. This letter also highlights the most important challenges for further research on the subject. One of the key issues is that the effects of environmental changes on violent conflict are likely to be contingent on a set of economic and political conditions that determine adaptation capacity. In the authors' view, the most important indirect effects are likely to lead from environmental changes via economic performance and migration to violent conflict. © 2012 IOP Publishing Ltd

A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism—‘hyperlipoproteinemia’ (HLP)—it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie—to an apparently even greater degree—susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample

<p>Abstract</p> <p>Background</p> <p>Common polymorphisms in the promoter of the <it>APOC3 </it>gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the <it>INSIG2 </it>gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the <it>APOC3 </it>-455T>C and the <it>INSIG2 </it>rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample.</p> <p>Methods</p> <p>Subjects were genotyped for both the <it>APOC3 </it>-455T>C and <it>INSIG2 </it>rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (≥18 years of age) from six different geographical ancestries.</p> <p>Results</p> <p>For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of ≥1 copy of <it>APOC3 </it>-455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with <it>APOC3 </it>-455T>C genotype. The <it>INSIG2 </it>rs7566605 polymorphism was not associated with MetS or measures of obesity.</p> <p>Conclusion</p> <p>Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in <it>APOC3 </it>was associated with an approximately 2-fold increased risk of MetS, whereas the <it>INSIG2 </it>rs7566605 polymorphism was not associated with MetS.</p

Albiglutide, a Long Lasting Glucagon-Like Peptide-1 Analog, Protects the Rat Heart against Ischemia/Reperfusion Injury: Evidence for Improving Cardiac Metabolic Efficiency

BACKGROUND: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency. METHODS/PRINCIPAL FINDINGS: Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide. CONCLUSION/SIGNIFICANCE: Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function