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Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.

ABSTRACT: Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history.

SUBMITTER: Romeo S

PROVIDER: S-EPMC2762948 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.

Romeo Stefano S Pennacchio Len A LA Fu Yunxin Y Boerwinkle Eric E Tybjaerg-Hansen Anne A Hobbs Helen H HH Cohen Jonathan C JC

Nature genetics 20070225 4

Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in approximately 3 ...[more]

PMID: 17322881

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Project description:BackgroundFood insecurity and metabolic diseases both disproportionately affect Hispanic children. Cross-sectional studies have linked food insecurity with adverse cardiometabolic markers, including elevated plasma triglycerides and glucose concentrations. However, the association between changes in food insecurity and changes in cardiometabolic markers in children remains to be explored. Furthermore, few studies have assessed the impact of school-based nutrition interventions on household food insecurity.ObjectiveThe objectives of this study are to assess the effect of the TX Sprouts intervention on household food insecurity and to examine the association between changes in household food insecurity and changes in cardiometabolic markers over 1 academic year.MethodsThis secondary analysis used data from TX Sprouts, a cluster-randomized school-based gardening, cooking, and nutrition trial. The study enrolled 3rd-5th-grade students from 16 schools that served primarily (>50%) Hispanic families with low income in Austin, TX. Participants (n = 619) provided household food insecurity data and fasting lipid panels at both baseline and postintervention, ∼9 mo following.ResultsThere was no intervention effect on household food insecurity. Independent of the intervention, a 1-point increase in food insecurity, indicative of becoming more food insecure, was associated with a 2.61 mg/dL increase in triglycerides (P = 0.001; 95% CI: 1.04, 4.19) at follow-up. Children who were food insecure at baseline and became food secure at follow-up had a mean 5.05 mg/dL decrease in triglycerides compared with a 7.50 mg/dL increase in triglycerides in children who remained food insecure throughout (95% CI: -23.40, -1.71, P = 0.023). There were no other associations between changes in food insecurity and cardiometabolic markers.ConclusionAlthough the intervention did not improve food insecurity, reductions in food insecurity over 9 mo were associated with improved cardiometabolic markers in high-risk children, emphasizing the need for interventions targeting food insecurity. The study is registered at clinicaltrials.gov under NCT02668744 (https://classic.Clinicaltrialsgov/ct2/show/NCT02668744).

Project description:Previous experimental studies showed that increasing high-density lipoprotein cholesterol (HDL) cholesterol shortens cardiac ventricular repolarization and the QT interval corrected for heart rate (QTc). However, little is known about the epidemiological relationship between HDL and QTc. The potential antiarrhythmic effect of HDL cholesterol remains a speculative hypothesis. In this cross-sectional population based study in adults living in the Italian-speaking part of Switzerland, we aimed to explore the association between HDL cholesterol and the QTc interval in the general population. A total of 1202 subjects were screened. electrocardiogram (ECG) recordings, measurements of lipid parameters and other laboratory tests were performed. QTc was corrected using Bazett's (QTcBaz) and Framingham (QTcFram) formulas. HDL was categorized according to percentile distributions: <25th (HDL-1; ?1.39 mmol/L); 25th-<50th (HDL-2; 1.40-1.69 mmol/L); 50th-<75th (HDL-3; 1.69-1.99 mmol/L); and ?75th (HDL-4; ?2.0 mmol/L). After exclusion procedures, data of 1085 subjects were analyzed. Compared with the HDL reference group (HDL-1), HDL-2 and HDL-3 were associated with a reduction of QTcBaz and QTcFram duration in crude (HDL-2, QTcBaz/QTcFram: ?-11.306/-10.186, SE 4.625/4.016; p = 0.016/0.012; HDL-3, ?-12.347/-12.048, SE 4.875/4.233, p = 0.012/<0.001) and adjusted (HDL-2: ?-11.697/-10.908, SE 4.333/4.151, p < 0.001/0.010; HDL-3 ?-11.786/-11.002, SE 4.719/4.521, p = 0.014/0.016) linear regression models in women. In adjusted logistic regression models higher HDL, were also associated with lower risk of prolonged QTcBaz/QTcFram (HDL-2: OR 0.16/0.17, CI 0.03-0.83/0.47-0.65; HDL-3: OR 0.10/0.14, CI 0.10-0.64/0.03-0.63) in women. Restricted cubic spline analysis confirmed a non linear association (p < 0.001). The present findings indicate an epidemiological association between HDL cholesterol and QTc duration. To draw firm conclusions, further investigations in other populations and with a prospective cohort design are needed.

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Project description:Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.

Dataset Information

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.

Publications

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.

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