Categorized | Heart Disease

Cholesterol Ups and Downs


cholesterol

cholesterol

My favorite part of freelance science writing is when seemingly unrelated stories connect. The phenomenon is a metaphor for what’s happening in human genome analysis, as researchers link seemingly unrelated diseases by shared gene expression, illuminating opportunities to repurpose drug treatments.

Consider cholesterol. We associate it with blocked arteries, statin drugs, and feared numbers on lab tests. But cholesterol, like other biomolecules, is vital – if the levels are within a certain range.

My two current cholesterol stories have to do with two pediatric conditions: Rett syndrome and infantile hypertrophic pyloric stenosis (IHPS). Rett syndrome is inherited; the mutation is in a transcription factor gene on the X chromosome. IHPS is a birth defect with a little-understood inherited component.

TOO MUCH CHOLESTEROL – RETT SYNDROME

The only thing better than an unexpected research finding about a disease is when a drug to treat it may already exist – but nobody knew of the connection. That’s what recently happened with Rett syndrome. I wrote the news release about it for the Rett Syndrome Research Trust. Finding that statins might treat Rett syndrome also validates the use of mouse models of human disease.

Annie (Rett Syndrome Research Trust)

Annie (Rett Syndrome Research Trust)

Rett syndrome affects only girls. The first sign is slowed head growth, which starts during the second to fourth months. Then development slows, and regresses, as young girls lose speech, mobility, and wring their hands in a characteristic way. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett syndrome affects about 1 in 10,000 girls born in the U.S. each year.

Rett syndrome is more complex than many other genetic diseases. The implicated gene, MeCP2, encodes methyl-CpG-binding protein 2, which turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.

Controlling the controllers is always a challenge, and because in genetics simpler is more likely to work, Monica Justice, PhD, professor in the departments of molecular and human genetics and molecular physiology and biophysics at the Baylor College of Medicine and her group looked beyond MeCP2 for genes with which it interacts, hoping to find new targets for drugs that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible. Here’s the news release updating that work.

Dr. Monica Justice (Baylor College of Medicine)

Dr. Monica Justice (Baylor College of Medicine)

Dr. Justice and her team injected healthy male mice with a chemical that mutates sperm stem cells randomly, then mated the males to Rett females. By genotyping the second-generation males from cells snipped from the tails, the researchers followed male offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health). The researchers followed males because female mammals express different X chromosomes in different cells, leading to variability too great to track.

Telling sick from healthy mice was easy. “About the time we got the genotyping results back, we could see the first symptoms, but we were looking for suppression of symptoms. When you see a rescued male versus his littermate, you see how different he is. He’s more active when the other, affected males are starting to get lethargic and begin to squint, which mice do when they’re not feeling well,” Dr. Justice explains.

Nor did the rescued mice develop the characteristic tremor, poor limb-clasping, obesity, and general scruffiness of their sick cage-mates. They hung on to a rotating rod longer and lived longer. And further crosses showed that resistance to the mouse version of Rett syndrome passed to the next generation, one gene suppressing another.

The most exciting gene to emerge from the screen was Sqle, which encodes a rate-limiting enzyme in the cholesterol pathway different from the one (HMG CoA reductase) that statins target. The findings appear in Nature Genetics.

Lovastatin

Lovastatin

The researchers could hardly wait to follow up with the obvious experiments: test statin drugs (fluvastatin and lovastatin) on Rett mice. And like the Sqle mutation, the drugs, even in very low doses, prevented symptoms. Treated mice mastered the rotating rod with flying colors, and seemed to be on the way to long lives.

How could an artery-clogger affect the brain? Cholesterol helps to form insulating myelin on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis. Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett syndrome.

“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what’s going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” says Christie Buchovecky, a graduate student in the Justice lab.

Sasha Djukic, MD, PhD, pediatric neurologist and director of the Tri-State Rett Syndrome Center in the Bronx, reviewed lipid data in girls with Rett syndrome and indeed found that some of them have early elevated cholesterol that decreases with age. Dr. Djukic is planning a clinical trial. But meanwhile, she and Dr. Justice caution parents to resist the urge to try their statins on their daughters – there’s still much to be learned before this particular bench finding can translate to the bedside.

252px-Stomach_colon_rectum_diagram.svgTOO LITTLE CHOLESTEROL: A DIGESTIVE BLOCK
The first signs of infantile hypertrophic pyloric stenosis are hard to miss: a 2-to-8 week old baby will suddenly projectile vomit, and soon dehydration develops and weight loss becomes obvious. IHPS blocks the passageway from the stomach to the small intestine.

The problem gave some hints of a cholesterol connection. The condition is 150 times more prevalent among children with Smith-Lemli-Opitz syndrome, who have low serum cholesterol at birth. Boys with isolated pyloric stenosis outnumber affected girls more than 4 to 1, which could be because of higher blood serum cholesterol in girls due to more fat – perhaps the one time in life we appreciate the extra padding. And breastfed babies are less likely to have the problem than bottlefed babies, presumably because human milk is fattier than formula.

Bjarke Feenstra, PhD of the Statens Serum Institute in Copenhagen and colleagues dug deeper for genetic risk factors of IHPS. And they found one that is a chromosomal neighbor of the APOA1 gene, whose protein product is a major component of HDL. Their report was published in the Journal of the American Medical Association this week. For my short version see Medscape Medical News.

The shared strength of the Rett and IHPS studies is that they interrogated genomes in an hypothesis-free manner, rather than focusing on candidate genes, the “round up the usual suspects” approach that can miss unexpected connections.

To track down markers of IHPS, the researchers did three things. First, they combined data on human genetic variation from the 1000 Genomes Project with single nucleotide polymorphisms (SNPs) peppering the genomes from 1001 blood spot samples. The samples came from the Danish National Biobank from infants with isolated IHPS, and from 2371 controls.

Next the researchers searched for SNPs associated with pyloric stenosis in 1663 cases and 2315 controls from Denmark, Sweden, and the US. Finally, they compared levels of total cholesterol, LDL, HDL, and triglycerides in plasma from 46 IHPS cases and 189 controls from umbilical cord blood stored as part of the Danish National Birth Cohort.

A 4-week-old after pyloric stenosis surgery

A 4-week-old after pyloric stenosis surgery

The SNP dubbed rs12721025 stood out, and may indeed provide a lovely marker for the low cholesterol that seems to signal increased risk of pyloric stenosis in newborns. The researchers filed a patent for a blood test, presumably for the SNP, but perhaps just a quick cholesterol check of the newborn will do the trick. Babies with low cholesterol could then be checked for looming intestinal blockage, and the defect surgically corrected sooner, or perhaps prevented. Even better, the newly discovered genetic connection may reveal how the condition develops in the first place, which might suggest ways to treat it other than surgery.

Keep those connections coming!

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The Cholesterol Ups and Downs by DNA Science Blog, unless otherwise expressly stated, is licensed under a Creative Commons Attribution 3.0 Unported License.

Article source: http://blogs.plos.org/dnascience/2013/08/22/cholesterol-ups-and-downs/