Genetics Archives - GT health

A future of high triglycerides

Familial chylomicronemia syndrome is rare. Its prevalence is about 1 in 1 million. It is characterized by defective or deficient lipoprotein lipase (LPL) enzyme, severely high triglycerides, and recurrent pancreatitis. Apoprotein C3 antagonizes LPL activity leading to hypertriglyceridemia. Much effort has been done to target Apo C3 pharmacologically. Now we have an anti-sense inhibitor to the hepatic Apo C3 mRNA, called volanesorsen.

This phase 3, double-blind randomized clinical trial shows that volanesorsen lowers both Apo C3 and triglycerides remarkably. Apo C3 is decreased by 25.7 mg/dL and triglycerides by about 1700 mg/dL (Δ80% reduction). Low platelet count and injection site reactions were seen more commonly with volanesorsen than placebo. Although the study was designed to evaluate changes in triglyceride levels, clinical outcomes (pancreatitis) are also expected to improve.

Study findings are of major importance as it provides us with another tool and pathway of lowering elevated triglycerides. Hypertriglyceridemia, commonly found in patients with metabolic syndrome, is a well-established independent risk factor for cardiovascular events. I anticipate that the antisense inhibitor technology will also be tested in patients with metabolic syndrome, insulin resistance, prediabetes, and diabetes; as these conditions are far more prevalent than familial chylomicronemia syndrome.

Cathepsin Z, the blood test we have been waiting for osteoporosis

Osteoporosis is a highly prevalent illness, especially among postmenopausal women. Left untreated, it can lead to fragility and compression fractures; in turn, associated with increased mortality and morbidity. Diagnosis of osteoporosis is currently made by bone density scan (DEXA) or when the patient experiences symptoms (fragility or compression fractures).

This scientific report published in Nature is of great significance as for the first-time its authors identify a potential blood test to diagnose osteoporosis – without having patients undergo bone scanning or present with symptoms. The test is Cathepsin Z mRNA and is measured in human peripheral blood mononuclear cells. Cathepsin Z is a protease synthesized by both bone remodeling cells – osteoclast and osteoblasts.

The test is not influenced by acute or chronic inflammation. Its diagnostic positive predictive value (PPV) is 95% with a negative predictive value (NPV) of 80%. Authors found a strong correlation of elevated levels of Cathepsin Z mRNA in patients with osteopenia in addition to those with osteoporosis.

Although study findings need to be fully validated, the results are exciting. Early diagnosis and treatment of osteoporosis are crucial to preventing fractures and its complications.

Lipoprotein(a) is an independent ASCVD risk

Blood Lipoprotein(a) measurements are genetically determined. Lifestyle, physical activity or dietary habits do not change its levels. Epidemiologically, Lp(a) has been found to be an independent risk factor for poor ASCVD outcomes. Lp(a) is a promoter of atherosclerosis, thrombosis and aortic valve stenosis.

In this meta-analysis of 7 statin-outcome randomized clinical trials, authors showed that baseline and on-statin treatment Lp(a) levels correlated positively and linearly with ASCVD events: the higher the Lp(a) measurements, the higher the cardiovascular outcomes.

Development of specific drug therapies in reducing Lp(a) are needed. These therapies would then be tested in outcome driven ASCVD clinical trials.

ACLY variants vs. cardiovascular outcomes

ATP citrate lyase is a key enzyme in cholesterol and fatty acid biosynthesis. It helps convert citrate to Acetyl CoA, the precursor to endogenous lipid genesis. Recent studies have shown that pharmacological inhibition of ATP citrate lyase causes a 30% reduction in LDLc, 50% reduction when combined with ezetimibe, and an extra 20% LDLc lowering when added to statin therapy.

This major Mendelian randomization study revealed that genetic variants in the ACLY gene led to similar clinical and biochemical outcomes as HMGCR variants. This provides a theoretical basis that medical inhibition of ATP citrate lyase could have similar cardiovascular benefits as statin therapies.

Mendelian randomization is considered nature’s randomized “clinical trial”. About 800,000 participants were included and analyzed.

Lipoprotein(a), Familial Hypercholesterolemia and CVD

Familial hypercholesterolemia (FH) has a high prevalence of cardiovascular morbidity and mortality, due to the lifelong cumulative exposure of high serum cholesterol levels.

The study finds that only a minority of patients are capable of achieving LDLc targets set by the European guidelines. About 25% of FH patients reach LDLc ≤100 mg/dL and only 8% of very high-risk CVD patients reach LDLc ≤70 mg/dL.

Importantly, those with high Lp(a) experienced twice as much CHD events than those with low Lp(a) levels. Specific drug development toward Lp(a) would be a breakthrough in helping patients with familial hypercholesterolemia.

A group of 714 FH adults were followed for about 11 years.

Familial Hypercholesterolemia and CVD risk factors

Genetic inability to clear LDL-particles leads to familial hypercholesterolemia. Persistent high serum LDLc and total-cholesterol are major cumulative risk factors for premature cardiovascular disease.

The article identifies other independent risk factors contributing to CVD in these patients. Such factors are male sex, smoking, hypertension, diabetes, elevated Lp(a), and family history of CVD.

Obviously, the modifiable contributors; hypertension, smoking and diabetes need to be managed aggressively.

Prolactinoma, pheochromocytoma and MAX gene

Pheochromocytomas are rare neuroendocrine tumors. They could be adrenal vs. extra-adrenal, sporadic vs. familial, isolated vs. multifocal, or benign vs. malignant. MAX gene mutation has recently been recognized as an unusual cause of familial pheochromocytoma.

This article documents the first patient with simultaneous germline MAX mutation, pituitary prolactinoma, bilateral pheochromocytoma and mild primary hyperparathyroidism.

Could the germline MAX mutation be a direct cause of prolactinoma as well?

Lipoprotein (a): sneaky and dangerous

Lipoprotein (a) is an independent risk factor for poor cardiovascular outcomes. Authors find that PCSK9-i lowers Lp(a) and LDL by 20% and 50% respectively. Lp(a) and LDL reduction are 60% concordant, suggesting that some Lipoprotein (a) improvement could be via non-LDL-receptor pathway. More research is needed as pharmacological options targeting Lp (a) are limited.

Children, Lipodystrophy and Leptin

Lipodystrophy (LD) could be familial or acquired, partial or generalized. This original NIH study shows that metreleptin, a leptin analog, can nicely improve LD metabolic anomalies; such as high glucose, triglycerides and liver enzymes. These benefits are expected to decrease long-term lipodystrophy complications in young individuals.

Heterozygous familial hypercholesterolemia & PCSK9 inhibition

PCSK9 inhibitors are a new cholesterol-reducing class of medications. In this study, PCSK9 inhibition by alirocumab reduced LDL nicely by about 50% even in individuals with heterozygous familial hypercholesterolemia. Adverse event profile was overall similar between the alirocumab and placebo arm. A group of 1300 patients were followed for about 2 years.

Homozygous Familial Hypercholesterolemia: PCSK9 inhibitor

This original research shows that PCSK9 inhibitor can lower LDL and Lipoprotein(a) approximately by 25% and 10% in young individuals with severe form of familial hypercholesterolemia, regardless if treated with aphaeresis.

Although clinical outcomes were not assessed, drop in LDL and L(a) are expected to be beneficial. Study duration was about 2 years. Main adverse events were nasopharyngitis, influenza, headaches and upper respiratory tract infections.

Homozygous familial hypercholesterolemia: LDL Apheresis

Homozygous familial hypercholesterolemia results from full deficiency of malfunction of LDL receptors in the liver. Risk of coronary artery disease is skyrocketed. It is often hard to treat with statin-based combination therapy. Lipoprotein apheresis could be the only hope for affected individuals.

Please find below a nice case study of LDL-apheresis effectiveness in 3 siblings. Twice weekly session with 1.5 exchange volume brought LDL-C to target without any noticeable adverse events.