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Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

ABSTRACT: Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points.

SUBMITTER: Larach DB

PROVIDER: S-EPMC4217288 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

Larach Daniel B DB Cuchel Marina M Rader Daniel J DJ

Clinical lipidology 20131201 6

Identification of the <i>CETP, LIPG</i> (encoding endothelial lipase) and <i>APOC3</i> genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeuti ...[more]

PMID: 25374625

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Project description:Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.

Project description:BACKGROUND:Extended elevations of non-high-density lipoprotein cholesterol (non-HDL-C) across a lifespan are associated with increased risk of cardiovascular disease (CVD). However, optimal testing intervals to identify individuals with high lipid-related CVD risk are unknown. OBJECTIVES:This study determined the extent to which lipid levels in young adulthood predict future lipid trajectories and associated long-term CVD risk. METHODS:A sample of 2,516 Framingham Offspring study participants 25 to 40 years of age free of CVD and diabetes had their non-HDL-C progression modeled over 8 study examinations (mean follow-up 32.6 years) using group-based methods. CVD risk based on 25 to 30 years of follow-up was evaluated using Kaplan-Meier analyses for those with mean non-HDL-C ?160 mg/dl ("high") and <130 mg/dl ("low") at the first 2 examinations. Levels of non-HDL-C for participants on lipid treatment were adjusted by nonparametric algorithm. RESULTS:The trajectories of the lipid levels were generally stable over the 30-year life course; mean non-HDL-C measured in young adulthood were highly predictive of levels later in life. Individuals could be reliably assigned to high and low non-HDL-C groups based on 2 measurements collected between 25 to 40 years of age. Overall, 80% of those with non-HDL-C ?160 mg/dl at the first 2 exams remained in the high group on subsequent 25-year testing, whereas 88% of those with non-HDL-C <130 mg/dl remained below 160 mg/dl. Those with high non-HDL-C in young adulthood had a 22.6% risk of CVD in the next 25 years as compared with a 6.4% risk in those with low non-HDL-C. CONCLUSIONS:Most adults with elevated non-HDL-C early in life continue to have high non-HDL-C over their life course, leading to significantly increased risk of CVD. The results demonstrate that early lipid monitoring before 40 years of age would identify a majority of those with a high likelihood for lifetime elevated lipid levels who also have a high long-term risk for CVD. This information could facilitate informed patient-provider discussion about the potential benefits of preventive lipid-lowering efforts during the early midlife period.

Project description:Background: Almonds may increase circulating HDL cholesterol when substituted for a high-carbohydrate snack in an isocaloric diet, yet little is known about the effects on HDL biology and function.Objective: The objective was to determine whether incorporating 43 g almonds/d in a cholesterol-lowering diet would improve HDL subspecies and function, which were secondary study outcomes.Methods: In a randomized, 2-period, crossover, controlled-feeding study, a diet with 43 g almonds/d (percentage of total energy: 51% carbohydrate, 16% protein, and 32% total and 8% saturated fat) was compared with a similar diet with an isocaloric muffin substitution (58% carbohydrate, 15% protein, and 26% total and 8% saturated fat) in men and women with elevated LDL cholesterol. Plasma HDL subspecies and cholesterol efflux from J774 macrophages to human serum were measured at baseline and after each diet period. Diet effects were examined in all participants (n = 48) and in normal-weight (body mass index: <25; n = 14) and overweight or obese (?25; n = 34) participants by using linear mixed models.Results: The almond diet, compared with the control diet, increased ?-1 HDL [mean ± SEM: 26.7 ± 1.5 compared with 24.3 ± 1.3 mg apolipoprotein A-I (apoA-I)/dL; P = 0.001]. In normal-weight participants, the almond diet, relative to the control diet, increased ?-1 HDL (33.7 ± 3.2 compared with 28.4 ± 2.6 mg apoA-I/dL), the ?-1 to pre-?-1 ratio [geometric mean (95% CI): 4.3 (3.3, 5.7) compared with 3.1 (2.4, 4.0)], and non-ATP-binding cassette transporter A1 cholesterol efflux (8.3% ± 0.4% compared with 7.8% ± 0.3%) and decreased pre-?-2 (3.8 ± 0.4 compared with 4.6 ± 0.4 mg apoA-I/dL) and ?-3 (23.5 ± 0.9 compared with 26.9 ± 1.1 mg apoA-I/dL) HDL (P < 0.05). No diet effects were observed in the overweight or obese group.Conclusions: Substituting almonds for a carbohydrate-rich snack within a lower-saturated-fat diet may be a simple strategy to maintain a favorable circulating HDL subpopulation distribution and improve cholesterol efflux in normal-weight individuals with elevated LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01101230.

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Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

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Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

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