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Mutations are bad, right?
Not always.  Some DNA changes are completely neutral. That&#8217;s how the human genome came to have so many variations. And some mutations are actually advantageous.
A case in point is the PCSK9 gene. So-called &#8220;loss-of-function&#8221; mutations that prevent the protein encoded by this gene from functioning properly actually lead to lower cholesterol levels.
Researchers at several pharmaceutical companies have taken inspiration from these PCSK9 mutations. They are now developing drugs that would block its function in people with non-mutated forms of the gene.   These drugs, though still in the early stages of testing, may offer a new way for the tens of millions of Americans with <a href="https://www.23andme.com/topics/health-predispositions/fh/">high cholesterol</a> to get their levels under control.
The PCSK9 protein binds to LDL cholesterol receptors on the surface of cells.   Once cholesterol binds to the receptor too, the whole complex is internalized into the cell, and the receptor is degraded.   When PCSK9 function is missing, the LDL receptor is able to recycle back to the cell&#8217;s surface after dropping off its cholesterol cargo in the cells, allowing it to sop up more &#8220;bad&#8221; cholesterol from the bloodstream.   There doesn&#8217;t seem to be any downside to the cholesterol-lowering PCSK9 mutations, suggesting that targeting the protein with drugs could be safe and effective way of reducing cholesterol.
One company, <a href="https://dx.doi.org/10.1073/pnas.0903849106" target="_blank" rel="noopener noreferrer">Amgen</a>, is tackling the problem with antibodies that attach to the PCSK9 protein outside of cells, targeting it for destruction by the immune system.   Two others, Isis and <a href="https://dx.doi.org/10.1073/pnas.0805434105" target="_blank" rel="noopener noreferrer">Alnylam</a>, are using small pieces of RNA designed to go inside cells and keep the PCSK9 protein from being made in the first place.   All three companies have shown reductions of LDL cholesterol in early animal experiments.   A review of their findings appeared recently in Nature Publishing Group&#8217;s <a href="https://dx.doi.org/10.1038/scibx.2009.895" target="_blank" rel="noopener noreferrer">Science-Business eXchange</a>.
People who need to lower their cholesterol but can&#8217;t tolerate statins stand to benefit most from any PCSK9 inhibitors that are developed.   But these drugs might be good for those taking statins too.   High doses of statins can actually increase the amount of PCSK9 in the body.   Taking a PCSK9 inhibitor along with a statin could help cut off this potentially backtracking side effect.   Unfortunately, unlike statins, none of the PCSK9 inhibitors under development can be taken orally.   They all need to be delivered through an injection.
Many years of clinical trials are ahead for each of these drugs.   Researchers will need to assess both their safety and efficacy.   But it&#8217;s exciting to see a genetics discovery be so quickly translated into an idea that could help millions of people.

23andMe Blog

23andMe Blog Team

Genetic Research Could Lead to New Cholesterol Drugs

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In 1974, scientists digging in the dry lake bed of Lake Mungo in southeastern Australia uncovered the skeleton of a man preserved in the deep layers of sand and clay. Dating techniques eventually revealed that this individual died about 40,000 years ago.
Scientists and the popular press dubbed the individual &#8220;Mungo Man.&#8221; Why did he make such a splash?   Not only because he was &#8211; and remains &#8211; one of the oldest and most complete skeletons of the earliest Australians, but because his appearance shattered the previously held notion that humans had first set foot in Australia less than 10,000 years ago. It was so far from where humans arose in Africa, and so remote.   So of course humans arrived there so much later than everywhere else, many experts reasoned. With the discovery of Mungo Man, this idea lost support, and scientists now concede that Australia was settled much earlier than many other parts of the world, including the Americas and parts of Europe.

While this discovery initially answered many questions regarding the peopling of Australia, it left many more unanswered – especially how people could have reached an island continent so soon after humans first expanded beyond Africa about 60,000 years ago.
The thinking is that after leaving Africa, one or more groups of humans journeyed from their homeland in East Africa into Arabia via the Red Sea. Over the next several thousand years, their descendants continued along the coasts of Arabia and India, eventually heading south into present-day Indonesia and finally to Australia, which was joined with the island of New Guinea at the time.
There has been some archaeological and genetic evidence of such a migration, but most of it has been indirect or circumstantial. Some scientists remain unconvinced because researchers have not been able to show a direct link between modern Australian Aboriginals and modern people living along the coastal route from Africa. But now, in a new study led by the Anthropological Survey of India, geneticists believe they&#8217;ve found the first concrete evidence of such a link. Their results are reported in the July 21 issue of <a id="t6n." title="BMC Evolutionary Biology" href="http://www.biomedcentral.com/1471-2148/9/173/abstract" target="_blank" rel="noopener">BMC Evolutionary Biology</a>.
The team, led by Satish Kumar, reasoned that if the hypothesis of an ancient migration along the Indian Ocean coast toward Australia was accurate, there would be evidence in the DNA of modern people living along that path. So they compared the DNA of modern Australian Aboriginals to that of tribes from India, such as the Baiga of central India and the Birhor of eastern India. These groups are often called &#8220;relic populations&#8221; because they are believed to share many cultural, linguistic, physical and genetic features with the region&#8217;s ancient inhabitants.
Experts have long noticed that the Baiga, Birhor and other relic populations share physical similarities with native Australians. Kumar and his team reasoned that there could be DNA similarities too.
Kumar led the extraction and analysis of mitochondrial DNA (mtDNA) from nearly 1,000 individuals from Indian relic populations. For comparison, they used Australian Aboriginal DNA data that had already been analyzed and published by colleagues. After comparing the two groups, they came to a startling conclusion: two specific genetic mutations on the mtDNA of the Indian and aboriginal samples matched perfectly. Not only that, but these particular mutations do not exist elsewhere in the world; they are shared exclusively between a few isolated tribes in India and native Australians.
Kumar and his colleagues concluded the two groups must share a common ancestry. To lend further credence to their theory, they calculated the date when the ancestors of the Indian tribes and Australian Aboriginals must have split.
Their calculations produced a date of 55,000 years ago, a time when early humans in India were probably hunting wildlife and gathering plant foods. Some of their descendants eventually formed tribes like the Baiga and Birhor; others moved eastward, traversing southeastern Asian and then using maritime technology to cross nearly 60 miles of open ocean between Indonesia and New Guinea.
After arriving in Australia, they moved into the heart of the Australian Outback. A few thousand years later, a direct descendant of these ancient explorers was laid to rest along the shores of Lake Mungo.

Direct Genetic Link between Australia and India Provides New Insight into the Origins of Australian Aboriginals

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Researchers  have identified a <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">genetic variant</a> that increases risk of follicular lymphoma (FL), a type of blood cancer.
FL is a type of Non-Hodgkin lymphoma (NHL), the fifth most common cancer in the U.S. Nearly 20,000 patients die and 66,000 more are diagnosed with NHL each year. The incidence of FL has doubled within the past 30 years.
In a study by Skibola et al., scientists analyzed the genomes of 4,805 people of European descent from the United States, Germany and Canada to search for genetic associations with four different subtypes of lymphoma.  The results, published online this week in the journal <a href="https://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.419.html" target="_blank" rel="noopener">Nature Genetics</a>, newly linked one SNP to an elevated risk for developing FL in European populations.
FL is a slow-progressing cancer of the white blood cells that affects middle-aged and elderly people. It is usually diagnosed in advanced stages, but patients live approximately 10 to 12 years after diagnosis.
Skibola et al. revealed that having one copy of the C version of a SNP located on chromosome 6, is associated with 1.69 times increased odds of FL compared to people with two copies of an A at this SNP. Carrying two copies of C at this SNP is associated with 2.22 times increased odds of FL. Because a majority of the population carries the C version, another way to look at these results is to say that those who have the A version of this SNP appear to be somewhat protected from FL.*
This SNP is located near a region that is associated with susceptibility to psoriasis. The researchers said that further studies are required to evaluate whether is also associated with psoriasis due to this genetic overlap. Future research may also determine whether FL is associated with exposure to viruses such as HIV.

Genetic Variant May Increase Risk of Follicular Lymphoma

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The Neanderthals have always held a special place in the field of anthropology. &nbsp; The skeletal remains of our short, stocky evolutionary relatives have been found everywhere from Spain to Iraq.
Their physical likeness to our own species, and the possibility that humans and Neanderthals may have interacted, has long fascinated experts and enthusiastic novices alike. &nbsp; But simply studying their skeletal remains and artifacts seemed to leave more questions than answers.
More than 10 years ago an international team of scientists became the first to extract and analyze ancient DNA (aDNA) from a Neanderthal skeleton. By examining the mitochondrial DNA (mtDNA) – which is more abundant in our cells than our nuclear DNA and therefore more likely to preserve – they found that there were enough genetic differences between this Neanderthal and modern humans to classify the two as separate species.
Since this initial foray into Neanderthal genetics there have been attempts to improve aDNA analysis, with the goal of filling in the gaps that traditional anthropological techniques had been unable to. &nbsp; Earlier this year, scientists at the Max Planck Institute for Evolutionary Anthropology became the first to sequence the entire Neanderthal mitochondrial genome &#8211; no easy feat. &nbsp;Now scientists have taken aDNA analysis to the next level by developing a novel technique to extract it more easily, yielding the most comprehensive and accurate results to date. &nbsp; Along the way, they have uncovered some intriguing clues to the possible fate of the Neanderthals. &nbsp;Their results are reported in the July 17 issue of <a id="rvka" title="Science" href="http://www.sciencemag.org/cgi/content/abstract/325/5938/318" target="_blank" rel="noopener noreferrer">Science</a>.

This new study, also led by Max Planck Institute scientists, centers around a novel method for finding and extracting that elusive aDNA from Neanderthal remains. The study took advantage of a new kind of aDNA extraction process, called Primer Extension Capture (PEC). This technique has many advantages over the others, primarily because it allows the aDNA to be completely isolated from all the other molecular junk &nbsp; that can accumulate over time. This yields highly accurate results with much less effort. So instead of simply using this technique on one Neanderthal individual, they analyzed five.
The remains they chose had been excavated from a variety of locations, from Croatia to Germany to Spain and Russia. &nbsp; Most of the remains were between 35,000 and 40,000 years old, which is very close to when Neanderthals were believed to have disappeared from most of their range. &nbsp; They also examined Neanderthal remains from Russia that dated to between 60,000 and 70,000 years old.
After successfully extracting and analyzing the DNA of these remains, the researchers came to a few startling conclusions. &nbsp; First, the level of genetic diversity among the samples was exceedingly low. &nbsp; In fact, the amount of genetic diversity of the Neanderthal samples was less than one-third the diversity we see in modern humans today. For example, two of the samples &#8212; one from Croatia and the other from Germany &#8212; had identical mtDNA genomes. For two individuals living nearly 1,000 miles apart, this is quite unusual; unless there wasn&#8217;t much variation in mtDNA in the first place.
The authors of this report think this genetic homogeneity means that there were far fewer Neanderthals living in Europe and western Asia than they&#8217;d previously thought. Based on their analysis of the five individuals, the they estimated that the total population size of Neanderthals in Europe 35,000 years ago may have had as few as 3,500 females (because mtDNA is passed down maternally, it cannot be used to estimate male population size).
The authors believe there are two possible explanations for this small population size. &nbsp; The first is that, over the 400,000 year history of Neanderthals, their population may have always been small. &nbsp; After all, for much of their existence they survived harsh ice age conditions, so low population size may have been necessary for survival.
But the authors offer an alternate explanation as well. They think this small population size is the result of long-term population decline, perhaps beginning about 40,000 years ago and continuing until Neanderthals were wiped out. To test their hypothesis, the researchers re-analyzed the Neanderthal mtDNA genomes and found that their protein-encoding genes had evolved much more quickly than those of humans or chimpanzees since the three species split, millions of years ago.
This high rate of evolution, the authors argue, was not present in the older Russian Neanderthal sample. &nbsp; This fact implies a pattern of decline in population size, not a population that had been small from the start. These results support their idea that the Neanderthal numbers were on the decline. &nbsp; Without direct evidence, they can only speculate as to the cause of of their decline, but the scientists believe it may be tied to the arrival of humans in Europe and western Asia about 40,000 years ago.
Today most experts believe the Neanderthals were being out-competed by the incoming humans, who had superior technology and language skills. &nbsp; Over time, the Neanderthals were forced to move to more isolated regions in the mountains of France and Spain. &nbsp; By 30,000 years ago, only a few traces remained. &nbsp; Soon after, they were gone. &nbsp; This study reveals some compelling evidence that humans were in fact responsible &#8211; whether directly or indirectly &#8211; for the demise of the Neanderthals.

Novel Techniques Suggest Neanderthal Populations Dwindled in the Face of Expanding Humans

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Researchers have identified a genetic variant that increases risk of atrial fibrillation (AF), an electrical disorder of the heart, which in turn increases risk of stroke.
AF affects one in four people over 40 years old, and stroke is the third leading cause of death in the United States.
In one of two studies, scientists scanned the genomes of 5,806 people from the United States, Iceland and Norway to look for genetic variations associated with AF. The other study combined data from several large studies comprising almost 47,000 people of European ancestry.

Their results, published online this month in Nature Genetics, newly linked one SNP to slightly elevated risk for developing AF in European populations.
Most strokes are caused by a blood clot that blocks circulation to the brain. Because AF causes ineffective beating of the heart, blood can pool and clot in the upper chambers, resulting in stroke if a clot leaves the heart and lodges in the brain. AF increases the risk of stroke four to five times across all age groups and is the cause behind 10 to 15 percent of all blood clot-related strokes.
In the first study, Gudbjartsson et al. studied people of European descent from the United States, Iceland and Norway to reveal that the T version of   a SNP on chromosome 16, is associated with 1.21 times increased odds of AF. This SNP was also associated with 1.11 times increased odds of ischemic stroke and 1.22 increased odds for cardioembolic stroke.
In the second study, Benjamin et al. associated AF with another SNP. Both SNPs are likely to be marking a third genetic variation that actually has a functional effect on AF. Further research will be necessary to identify both the variation and its effect.
Gudbjartsson et al. also assessed the association of AF with the T version of in more than 3,000 Han Chinese, but the association was not significant. They noted that the T allele of this SNP is much more frequent in Han Chinese than in European populations.

Genetic Variation May Increase Risk of Atrial Fibrillation And Stroke

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It may be you&#8217;ve heard a rumor that males are on the brink of extinction.
Whatever you may think of that prospect, the rumor is false. But over the past decade, numerous <a href="https://www.ncbi.nlm.nih.gov/pubmed/17400006?ordinalpos=1&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&amp;linkpos=1&amp;log$=relatedreviews&amp;logdbfrom=pubmed" target="_blank" rel="noopener">studies</a> have hinted that the Y chromosome, a male necessity, is going the way of the dodo.
Though other studies have suggested this idea may be a bit of an exaggeration, a new report this week suggests that the Y chromosome may indeed be endangered.
In most mammals, such as us humans, two chromosomes determine the sex of each individual organism: &nbsp; the X and the Y. &nbsp; If an individual&#8217;s cells contain two copies of the X chromosome, then they will be genetically female. &nbsp; If they contain one copy of the X and another of the Y, they will be male.

Yet even though these aptly named sex chromosomes have a similar duty – to confer sex – the X and the Y could not be more different. &nbsp; The most striking difference between the two is their size; the Y is less than half as big as the X, and contains only 78 genes, compared to the more than 2,000 found along the X chromosome. &nbsp; The evolutionary history of the two sex chromosomes and the question as to why they are so different from each other has been the subject of heated debate for many years. &nbsp; Now scientists at Pennsylvania State University believe they&#8217;ve found a way to uncover not only the difference between the X and Y, but how and why it arose and what this means for the future of the small, but essential, Y chromosome. &nbsp; Their results are reported in the July 17 issue of <a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000568" target="_blank" rel="noopener">PLOS Genetics</a>.
The research team, led by biologists Kateryna Makova and Melissa Wilson, believes the key to understanding the origins and future of the Y chromosome lie in some of our most distant mammalian relatives. &nbsp; There are three classes of mammals: egg-layers like the platypus, marsupials like the kangaroo, and the eutherians, which includes humans and thousands of other similar species. &nbsp; While there are many differences between the three groups, one of the most striking is the difference in the organization of the sex chromosomes. &nbsp; As Makova explained, &#8220;In eutherian mammals, the sex chromosomes contain an additional region of DNA whereas, in the marsupials and egg layers, this additional region of DNA [is not on a distinct chromosome, but] is [a region of] the non-sex chromosomes.&#8221;
The authors argue that the key to the origins of the X and the Y chromosomes may lie in this fundamental difference. &nbsp; By analyzing the X and Y of humans compared to the sex-determining regions of marsupials and egg-laying mammals, Makova and Wilson found that the X and Y split from the other chromosomes about 80 to 130 million years ago.
But that is not all they found. &nbsp; The authors also examined how fast the X and Y mutated over time, and noticed a startling change that occurred at about the same time as the split. &nbsp; &#8220;Our research revealed that the Y-specific DNA began to evolve rapidly at the same time that the DNA region split into two entities, while the X-specific DNA maintained the same evolutionary rate as it had previously,&#8221; Makova explained.
In other words, as soon as the X and the Y split their own distinct chromosomes, the Y began to evolve much more quickly than its counterpart, mutating at a much higher rate with each new generation. &nbsp; The faster the Y evolved, the faster its genes disappeared. &nbsp; Whereas at one point the Y may have contained thousands of genes, that number has dwindled to the mere 78.
The disappearance of these genes over time and the small number of those remaining on the Y begs the question: &nbsp; will the Y chromosome ever disappear entirely? &nbsp; The authors believed this was an important question to answer as well, and began additional analysis to determine the fate of the Y.
Makova and Wilson reasoned that there must be some utility to the Y, or else it surely would have disappeared by now. &nbsp; As Wilson states, &#8220;we know that a few of the genes on the Y chromosome are important, such as the ones involved in the formation of sperm &#8230; . &nbsp; Although there is evidence that the Y chromosome is still degrading, some of the surviving genes on the Y chromosome may be essential.&#8221; &nbsp; By performing additional tests, they found that there were indeed some genes on the Y that will probably never disappear entirely. &nbsp; But they also found several genes that were already disappearing, and were likely to be gone many generations from now.
Some recent studies have produced evidence that the genes on the Y may not be disappearing as fast as was initially thought. But, according to Makova, the Y chromosome may not be out of the woods just yet. &#8220;We still think there is a chance that the Y chromosome eventually could disappear,&#8221; she says. &nbsp; &#8220;[But] if this happens, it won&#8217;t be the end of males.&#8221; &nbsp; Instead, she believes that a new pair of sex chromosomes will arise from the genome, latching on to those few remaining genes, keeping alive the genes necessary for male survival.

The Disappearing Y: New Study Uncovers the History and Future of the Y Chromosome

On occasion, the Blog departs from its usual mission of bringing you the latest and greatest in human genetics news in order to report on particularly interesting discoveries in other species.
Many times these stories are about dogs and the reason is simple: dogs are awesome.
Well, there is more to it.
In addition to being faithful companions, dogs make great subjects for genetics research–the time between generations is much shorter in dogs than humans, they have multiple offspring per pregnancy and unlike in humans, it&#8217;s not unethical for scientists to decide which males and females breed together.
A luminary in the field of dog genetics is <a href="https://www.genome.gov/12513335" target="_blank" rel="noopener noreferrer">Elaine Ostrander</a>, chief of the Cancer Genetics Branch of the National Human Genome Research Institute.   Her lab uses dogs to study cancer susceptibility genes, but along the way they’ve made some fascinating discoveries about the incredible variation seen between the many breeds that make up the single species Canis lupus familiaris.
In 2007 Ostrander&#8217;s group showed that <a href="http://www.sciencedaily.com/releases/2007/04/070405144059.htm" target="_blank" rel="noopener noreferrer">small size in dogs</a>–think Chihuahuas and Pomeranians–can be traced to a single variant of the canine <a href="https://www.ncbi.nlm.nih.gov/pubmed/17412960?ordinalpos=16&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">IGF-1</a> gene.
Now, in a paper published online this week in <a href="http://www.sciencemag.org/cgi/content/abstract/1173275" target="_blank" rel="noopener noreferrer">Science</a> Express, they have shown that a single evolutionary event is behind the short, curved legs characteristic of all those adorable dachshunds, corgis and basset hounds.
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Ostrander&#8217;s group found that dogs having stubby little legs, technically termed chondrodysplasia, harbor an extra copy of a growth factor gene called FGF4.   But this is no ordinary gene duplication that happened as the result of a DNA replication error.
Instead, the researchers found that the extra copy of FGF4 is a retrogene, a piece of DNA copied from and then inserted back into the dog genome by a virus. Retrogenes are nothing new.   They&#8217;re known to be a major source of genetic change that takes place as different species split apart from each other.
But this new study is the first to show that a retrogene can cause long-lasting variation within a species. The various stumpy-legged dog breeds were developed in different places around the world, at different times and for various reasons.
So there&#8217;s no evidence that they share a recent common ancestor.   But the FGF4 retrogene appears to be identical in all of them, suggesting to the researchers that it arose only once, probably before early dogs split into modern breeds. These new findings don&#8217;t just represent an advance in the understanding of dog genetics, or even the fundamentals of DNA and evolution.   They also have implications for human health.   The type of growth disorder seen in the dogs with the retrogene is reminiscent of <a href="http://ghr.nlm.nih.gov/condition=hypochondroplasia" target="_blank" rel="noopener noreferrer">hypochondroplasia</a>, a type of dwarfism.   Scientists know that a mutation in one gene is responsible for most cases of this condition, but the cause of the rest remains a mystery.
According to Ostrander, her group&#8217;s results suggest that researchers interested in hypochondroplasia and other disorders of human growth and development should set their sights on FGF4. More Blog posts about dogs and genetics:
<ul>
<li><a href="https://blog.23andme.com/2008/11/07/gene-links-gout-in-humans-with-bladder-stones-in-dalmatian-dogs/" target="_blank" rel="noopener noreferrer">Gene Links Gout in Humans with Bladder Stones in Dalmatian Dogs</a></li>
<li><a href="https://blog.23andme.com/2008/08/07/learning-from-dog-eye-disorders/" target="_blank" rel="noopener noreferrer">Learning from Dog Eye Disorders</a></li>
</ul>
Picture Sources:
<ul>
<li><a href="https://en.wikipedia.org/wiki/File:MaddytheBHOUND.JPG" target="_blank" rel="noopener noreferrer">Basset hound</a></li>
<li><a href="https://en.wikipedia.org/wiki/File:Wire-haired_Dachshund_R_01.JPG" target="_blank" rel="noopener noreferrer">Dachshund</a></li>
</ul>

Single Gene Responsible For Stubby Legs In Dogs

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The exact causes of Crohn&#8217;s disease remain a mystery, but scientists do know that genetic factors play an important part. More than <a href="https://blog.23andme.com/articles/snpwatch-number-of-snps-associated-with-crohn%E2%80%99s-disease-triples/" target="_blank" rel="noopener">30 variations</a> have been associated with increased risk for the disease, but changes in one gene, NOD2, have been found to be especially critical. &nbsp; Three different variants in this gene have been associated with significantly increased risk for developing the disease. &nbsp; It&#8217;s estimated that 10-15% of people with Crohn&#8217;s disease have two copies of one of these variants.
Because changes in NOD2 are associated with so many cases of Crohn&#8217;s disease, medications made to interact with the protein the gene encodes would seem to be obvious candidates for drug development. &nbsp; But the NOD2 protein doesn&#8217;t have the type of function that can be modified by a drug.
A new avenue of drug research may have been opened, however, thanks to a study from Derek Abbott and colleagues at Case Western Reserve University. &nbsp; In a paper appearing in the August issue of <a href="https://dx.doi.org/10.1016/j.cub.2009.06.038" target="_blank" rel="noopener">Current Biology</a>, they show for the first time that a protein called ITCH can influence NOD2 biological pathways. &nbsp; This is important because, in the parlance of pharmaceutical development, ITCH is a &nbsp; &#8220;druggable&#8221; target.
NOD2 binds to bacteria that make their way into cells, setting off signals that activate the immune system. Research has shown that the Crohn&#8217;s disease-associated NOD2 variants decrease the signals that go through a particular protein called NFkB. &nbsp; Abbott&#8217;s lab found that ITCH also decreases NOD2-dependent NFkB signals. &nbsp; This is significant because studies have shown that increased NFkB signaling can help slow down the progression of Crohn&#8217;s disease.
&#8220;The thought is that if you could identify patients with NOD2 polymorphisms who also displayed early gastrointestinal trouble, you could block ITCH to increase NFkB signaling and not let the Crohn&#8217;s disease get to the acute stage,&#8221; Abbott said in an email.
Abbott and his fellow researchers are in the very early stages of looking for drugs that could be used to inhibit ITCH and possibly be useful in treating Crohn&#8217;s disease. &nbsp; But the road to drug discovery is a long one. &nbsp; ITCH interacts with many other proteins in cells and it&#8217;s not yet clear if blocking it would have unwanted effects on other important biological pathways. However, in the future this research could lead to a valuable drug against Crohn&#8217;s disease – at least for the 10 to 15% of patients who have variants that cause decreased NOD2 signaling.

Researchers Take A Step Toward Developing New Drugs For Crohn’s Disease

<img loading="lazy" decoding="async" class="alignright size-full wp-image-4040" title="istock_000004280142xsmall" src="https://blog-api.23andme.com/wp-content/uploads/2009/07/istock_000004280142xsmall.jpg" alt="istock_000004280142xsmall" width="352" height="233" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/07/istock_000004280142xsmall.jpg 425w, https://blogcms.23andme.com/wp-content/uploads/2009/07/istock_000004280142xsmall-300x199.jpg 300w" sizes="auto, (max-width: 352px) 100vw, 352px" />
There&#8217;s no shortage of books out there to help a woman know what to expect when she&#8217;s expecting, but when it comes to knowing how medications she might need during her pregnancy will affect her, there is very little guidance.
A woman&#8217;s body goes through profound physiological changes during pregnancy that have potential ramifications for the efficacy of a variety of drugs.   But despite a 1994 recommendation by the Institute of Medicine, most clinical trials still do not include pregnant women.   This means that for most drugs, doctors faced with a pregnant patient who needs a prescription have no choice but to guess the right thing to do.
&#8220;Any medicine taken to treat a woman&#8217;s illness during pregnancy — from hypertension to cancer, thromboembolism to asthma — is used without data adequate to guide dosing, make decisions about safety, or inform differential decisions about which medicine to prescribe.   The cost of this ignorance is profound,&#8221; Dr. Anne Lyerly and colleagues write in a recent article in the American Journal of Public Health.

The best strategy would be a large systematic study of women already taking medications during their pregnancies, so that there would be no extra risk for the unborn children.   According to Lyerly et al., just such an opportunity has presented itself in the form of the National Children&#8217;s Study (NCS).
The NCS aims to study the effects of the environment on 100,000 children from before birth to age 21.
Researchers hope to enroll 25% of the children before they are conceived, with 90% of the total being enrolled by the end of the first trimester. Lyerly et al. argue that this important study of children&#8217;s health also offers an unprecedented opportunity to collect information about the mothers too. But action must be taken soon to make sure that researchers don&#8217;t miss out on the chance to collect a wealth of information. Recruitment for the pilot phase of the study has already begun, and the final study protocol will be finalized in May 2010.


&#8220;Although the NCS will provide important and much-needed information about the effects of maternal medication use on the health of the fetus, absent is the other side of the coin: whether the medication is safe for the woman herself, whether it is effective in treating her underlying or emergent illness, and whether decisions to forgo medication or substitute older medications compromise her health,&#8221; the authors write.
Every additional piece of information collected will add to the already $3.2 billion projected cost of the NCS, but Lyerly et al. advocate for the inclusion of at least two additional research components:

<ul>
<li>Add questions to the surveys and medical chart evaluations already planned during the pregnancies of the women involved.</li>
<li>Take advantage of the maternal blood tests already planned to identify medications that are metabolized differently in pregnant women.   These drugs could then be investigated in more depth in follow-up studies.</li>
</ul>

&#8220;These two efforts together–at very little additional cost–would result in a rich data set that could lead to critical improvement in the care of pregnant women. Failure to include them would be hard to justify.&#8221;

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