Type 2 diabetes is a common disease characterized by high blood glucose levels and unresponsiveness to insulin. Individuals with type 2 diabetes may produce insulin at normal levels but do not respond to it sufficiently, either because the insulin receptors in their cells have become less sensitive or because the insulin produced in the pancreas isn’t being delivered to other cells. One reason that insulin might not make it where it’s supposed to go is that insulin secretion from pancreatic β cells is impaired.

In an article published in Science last week, Anders Rosengren, Erik Renstrom and their team from the Lund University Diabetes Centre in Sweden used newly created rat strains – called N1I5 and N1I11, both derived from a well-studied type 2 diabetes strain – to identify the Adra2a gene as one of the genetic culprits behind defective insulin secretion. They then tied a variation in this gene to type 2 diabetes in humans.

When Rosengren and his colleagues stimulated β cells from each strain with glucose, they found that N1I5 cells secreted less insulin than both N1I11 and normal cells. Other experiments verified that whatever was causing impaired insulin secretion was unique to N1I5.

Of the handful of possible gene candidates, only Adra2a showed different expression between the two strains, causing N1I5 cells to produce almost twice as much of the encoded α(2A)AR  protein as N1I11 cells. Additional experiments confirmed that α(2A)AR was indeed responsible for impaired insulin secretion. α(2A)AR is known to be involved in suppressing insulin secretion but variations in the gene had not previously been associated with the development of type 2 diabetes.

Based on the strong evidence from their rat experiments, Rosengren’s group hypothesized that variations in the human version of Adra2a, helpfully called ADRA2A, would contribute to type 2 diabetes risk in humans. Using two independent populations totaling about 5500 people, they first found that the less common A version of rs553668 was associated with impaired insulin secretion.

To see whether the results extended to actual diabetes risk, Rosengren and his team then compared a group of 2830 type 2 diabetics to 3740 non-diabetics. They found that rs553668 was also significantly associated with type 2 diabetes, with each copy of the A version increasing the odds of having the disease by about 1.4 times. The final piece of evidence came from laboratory experiments. Pancreatic cells from people carrying the riskier A version of rs553668 behaved just like the cells from the insulin-secretion impaired N1I5 rats.

(23andMe Complete Edition customers can check their data for rs553668 using the Browse Raw Data feature.)

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Scientists who are studying mice with a mutation that makes them resistant to obesity even in the face of a high-fat diet may have identified a new way to treat both obesity and diabetes.

Carrying extra weight is known to trigger a state of chronic, low-grade inflammation in the body, which can lead to insulin resistance and, in turn, diabetes.  When scientists at the University of Michigan discovered that an inflammatory protein called IKKε seemed to be a key step in this pathway, they theorized that they could protect mice fed a high-fat diet from developing signs of diabetes by genetically engineering them to lack the protein.

Much to the researchers’ surprise, IKKε knockout mice were spared from not only from chronic inflammation and insulin resistance⎯they also stayed relatively slim even when fed a lard-like chow with 45% of its calories from fat. After three months on this diet, normal mice gained 20 grams, while the IKKε-deficient mice gained only 12 grams.

“We’ve studied other genes associated with obesity … but this is the first one we’ve found that, when deleted, stops the animal from gaining weight.  The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising,” said the study’s senior author, Alan Saltiel, in a statement.

The results were published this week in the journal Cell.

Saltiel’s lab is already working to find drugs that inhibit IKKε and could someday be used to prevent obesity and diabetes in humans.  He estimates that new treatments could be available in about a decade, once successful candidate compounds are identified.

But finding a compound that inhibits IKKε isn’t the only obstacle on the road from the lab to the pharmacy.  Researchers will also need to confirm that IKKe works in humans the same way it does in mice.

Then there’s the issue of safety.  Mice lacking the IKKe gene were protected from obesity and related complications, but they were more susceptible to lethal viral infections than their normal littermates⎯a complication that would need to be carefully evaluated before any attempt to reduce IKKε activity is undertaken in humans.

Image: George Shuklin

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Type 1 diabetes is on the rise in European children, says a new report.

Researchers studied type 1 diabetes data collected between 1989 and 2003 at 20 centers in 17 European countries. Their results, published online yesterday in the Lancet, show that more children, especially younger children, are being diagnosed with the disease each year.  Based on the trends they saw, the scientists calculate that there were 94,000 kids under the age of 15 with type 1 diabetes in Europe in 2005, and that by 2020 that number will soar to 160,000.

While researchers aren’t exactly sure why this is, they do know that it’s not due to changes in the prevalence of susceptibility genes.  Genes just don’t change that quickly.

An almost 70% increase in disease prevalence in one generation must be due to changes in non-genetic factors. Most random genetic changes in a population come and go pretty quickly, especially mutations that reduce fitness.  And if a new mutation does manage to stick, it would take millions of years, not tens of years, to see its effects.  Even for mutations that provide a benefit, like the one that led to the lactose tolerance seen in many people with European ancestry today, it takes a few hundred years to build-up to high enough levels in the population to cause an observable change in a trait.

An increase in disease incidence due to changes in non-genetic factors, whether they are environmental or cultural, has been seen for many diseases.  It’s especially apparent when groups migrate from low- to high-risk countries for a particular condition.  Just this month a study showed that Asian Americans who are more “westernized” have adopted the sunbathing ways of their families’ new homes, which the authors suggest may be the cause of increasing rates of skin cancer in this group.

But the effects of lifestyle changes can also be seen in shifts in disease rates within a population. The prevalence of obesity in United States adults, for example, jumped from 15% in the late 1970’s to nearly 35% today thanks to the trend toward eating more and exercising less.  And because of the increase in obesity, rates of type 2 diabetes are also up.

Many scientists attribute the increase in incidence of several immune system-related disease to what on the surface seems like a good thing about modern lifestyles: fewer infections.  The so-called “hygiene hypothesis” suggests that without the types of infections our species evolved to deal with (many of which are still prevalent in developing nations), our immune systems don’t get the right training.  The lack of challenges to the immune system has been linked to increased rates of allergic diseases like asthma and eczema and autoimmune diseases like Crohn’s and multiple sclerosis.

For some diseases, the reason behind their apparent increases has more to do with increased detection than changes in environment. Up until a few years ago, for example, it was thought that only about one in every 3,000 people in the United States had celiac disease.  But now, thanks to better guidelines on how to diagnose the disease, physicians are finding that about one in every 133 is affected.

On the other hand, some conditions may appear to be increasing because disease awareness is a hammer that makes a lot of people feel like nails.  It has been put forward that restless legs syndrome, for example, is far less prevalent than some estimates suggest and that increases in diagnoses can be traced to “disease mongering” by pharmaceutical companies.

The authors of the Lancet study suggest that the changes in type 1 diabetes rates they are seeing are due to something about modernization.  They point to the fact that the biggest increases were seen in eastern European countries, which have seen the most rapid changes in lifestyle in the last few decades.  But whatever the culprit is, it is obviously not affecting all children.  And that’s where genetic susceptibility comes in.  DNA variations that increase risk may not be changing in prevalence, but type 1 diabetes, like almost every other common disease, is the result of a complex interplay of genes and environment.

(23andMe customers can see how their genes influence their risk of type 1 diabetes in Clinical Reports.)

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Chronic kidney disease (CKD), characterized by the gradual loss of the kidneys’ filtering ability, currently affects about 10-13% of adults in the United States.  Patients suffering from the most severe form of the condition, end-stage renal disease, require dialysis or a kidney transplant to survive.

High blood pressure and diabetes are known risk factors for CKD, but evidence from multiple studies indicates that there is a genetic component to the condition too.  Rare mutations that cause kidney disease have been identified, but finding common variations that impact susceptibility to CKD has been difficult.  Now a new study, published online this week in the journal Nature Genetics, shows that a variation in the gene that encodes the most common protein found in urine is associated with kidney disease risk.

The Tamm-Horsfall protein, encoded by the UMOD gene, was discovered almost 60 years ago, but its role in the body continues to baffle scientists.  Some studies have suggested it may be involved in protection against inflammation and infection, while others have suggested it functions in kidney development.

Researchers found that each G at rs4293393 in the UMOD gene decreased the odds of CKD by 24%.  Approximately 18% of people with European ancestry have at least one G at this SNP.

(23andMe customers can check their data for rs4293393 using the Browse Raw Data feature This SNP is a proxy for the SNP found in the study, rs12917707.)

“We have known for a long time that a higher level of proteins, such as albumin, which aren’t usually present in urine, is a risk factor for kidney disease and its progression. The UMOD finding suggests that Tamm-Horsfall protein, which is thought to be a normal part of the urine, deserves attention since its genetic variation relates to risk,” said Josef Coresh, professor in the Johns Hopkins Bloomberg School of Public Health’s Department of Epidemiology and Biostatistics and a co-author of the study, in a statement.

Another study from Johns Hopkins, appearing last year in Nature Genetics, found an association between variations in the MYH9 gene and end-stage renal disease in African Americans.

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New research in mice suggests that people who get lucky and inherit a genetic variant that has been shown to reduce the risk of type 2 diabetes are not totally in the clear. What they eat could turn the protective variant into a risky one.

PPARG is a protein involved in fat storage. The relatively rare Pro12Ala variant of this gene (which changes the 12th amino acid of the protein from a proline to an alanine) has been associated with reduced weight gain, improved insulin sensitivity and a lower risk for type 2 diabetes in several studies. But these associations are not as strong in obese subjects. Some researchers have actually found that among obese subjects, the Pro12Ala variant is associated with increased – not decreased — weight gain.

A team of scientists from France, Finland and the United States turned to genetically engineered mice to gain insight into this conundrum. Their results, published online today in Cell Metabolism, show that animals with two copies of the Pro12Ala variant are in fact leaner than animals without the variant. They also have improved insulin sensitivity and blood lipid profiles.

But when the mice consumed a diet that provided 58% of its calories as fat, compared to the normal 10% fat diet, the benefits of the Pro12Ala variant disappeared. In fact, the Pro12Ala mice were slightly heavier than the mice without the variant, although the difference was not statistically significant. For comparison, the U.S. Department of Agriculture recommends that humans keep their fat intake between 20 and 35% of total calories; recent CDC data suggest that Americans consume on average about 30 to 35% of their calories as fat.

The mice with the Pro12Ala variant also live longer than the non-variant mice, but only on the normal (not high-fat) diet. The authors note that previous research in humans had suggested that this variant might impact longevity. They suggest that further research be done to investigate the impact of drugs that inhibit PPARG on lifespan.

(23andMe customers can find out if they have the Pro12Ala variant using the Browse Raw Data feature. Each copy of the G version of rs1801282 is a copy of the Pro12Ala variant.)

The researchers suggest that diet affects the PPARG protein’s interactions with hormones and other molecules involved in metabolism. When an animal (mouse or human) eats a normal diet, the proline version of the PPARG protein is more efficient at storing fat than the alanine version. But in animals that take in more energy than they expend, the alanine version of the protein ends up being more pro-fat.

“These data … may provide avenues to better, possibly Pro12Ala genotype-dependent, treatment strategies for insulin resistance in T2DM and the metabolic syndrome,” the authors write.

The results may also help people prevent these disorders in the first place.

“Through dietary counseling, carriers could be informed that they really need to watch out for high fat in their diets,” said the study’s senior author Johan Auwerx in a statement.

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Our SNPwatch posts here at The Spittoon are one of our most exciting features. They give our customers the opportunity to connect their genetic data to the newest discoveries, often within just hours of a study’s publication.

Looking ahead to 2009, we can only begin to imagine the exciting discoveries that will be made in genetics. In the meantime, here are a few of our favorite SNPwatches from 2008:

SNPs That Affect Drug Response
We reported on several studies this year that showed the importance of genetic variations in determining how different people react to certain medications.

• A report in Nature Genetics showed that some women with a particular version of a SNP in the NQO1 are less likely to survive breast cancer after treatment with the commonly used chemotherapeutic epirubicin.
• A study by the SEARCH Collaborative Group found that a version of one SNP is associated with an increased risk for myopathy (muscle pain and/or weakness) in people taking cholesterol-lowering drugs called statins.
• Mayo clinic researchers found that the weight loss drug sibutramine (Meridia) is effective only in people with specific versions of three different genes.
• And just this month we brought you news of three studies that showed that a genetic variant known to affect the metabolism of the anti-clotting drug clopidogrel (Plavix) also affects heart attack patients’ risk of a second major cardiovascular event.

Shared SNPs
Sometimes multiple conditions strike the same person or run in families. Several studies published this year showed that shared genetic risk factors may be part of the reason why.

• Obesity is a known risk factor for many cancers. Researchers found that a variant of adiponectin, a hormone released by fat cells, can increase the risk of developing colorectal cancer.
• Other researchers found variants that affect the risk of developing both type 1 diabetes and celiac disease, two autoimmune diseases that tend to cluster together. One of these shared variants is also associated with HIV resistance.
• Finally, a report published this month in the Proceedings of the National Academy of Sciences showed that a single genetic variant can make a person prone to greater indulgence in both smoking and drinking.

SNPs Associated with Risk Factors for Disease
Several studies this year looked beyond disease itself and instead found associations between SNPs and traits known to be risk factors for disease.

• One study found an association between several SNPs and fasting plasma glucose, a measure of how well a person’s body can control blood sugar levels – a process that goes awry in diabetes.
• Another research group reported SNPs associated with glycated hemoglobin levels, a measure of long-term blood sugar control and another factor associated with the risk of developing diabetes.
• The findings of three papers published in Nature Genetics roughly doubled the number of SNPs associated with blood levels of cholesterol and triglycerides, important risk factors for cardiovascular disease.
• And finally, in a study that looked at behavior instead of metabolic markers, researchers found that a variant in the FTO gene known to increase the risk for obesity affects food choices in children, pushing them towards foods denser in calories.

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The complications of type 2 diabetes – damage to the kidneys, nerves, eyes, and cardiovascular system – result from chronically high blood sugar. While routine blood tests can provide a snapshot of blood sugar levels at one point in time, a more complete picture of long-term blood sugar control is obtained by measuring the extent to which sugar molecules are attached to hemoglobin, the oxygen carrying protein found in red blood cells. Measurement of this “glycated hemoglobin” reflects the total amount of sugar blood cells have been exposed to over the preceding eight to 12 weeks.

Clinical trials have shown that elevated, yet sub-diabetic, glycated hemoglobin levels increase risk for type 2 diabetes and cardiovascular disease. But although many studies have looked for genetic variants associated with type 2 diabetes itself, much less work has been done to uncover the genetic determinants of glycated hemoglobin levels.

Guillaume Paré and colleagues from Harvard Medical School and Amgen, Inc., scanned the genomes of more than 14,000 apparently healthy (i.e. non-diabetic women) to look for SNPs that correlate with glycated hemoglobin. Their results, published online today in PLoS Genetics, show that a variant in a gene never before linked to diabetes, HK1, is associated with glycated hemoglobin levels. Three other genes previously linked to diabetes and blood glucose concentration – GCK, SLC30A8 and G6PC2 – also harbored significantly associated variants.

According to the authors, the discovery of a link between the HK1 gene and glycated hemoglobin levels paves the way for further studies of the role of this gene in glucose metabolism and diabetes. The HK1 gene encodes the enzyme that carries out the first step of sugar breakdown in many cells throughout the body.

Together the four variants the researchers found account for only a very small proportion of the total variance in glycated hemoglobin levels in the population – just 1.4%. Age, body mass index (BMI) and menopause status, on the other hand, explain about 9.5% of the variance.

Glycation of proteins in tissues other than red blood cells is thought to underlie the long-term complications of diabetes. The authors say it remains an open question whether the differences in glycated hemoglobin associated with the genetic variants identified in this study are paralleled in other parts of the body.

The SNPs associated with glycated hemoglobin levels are listed below by rsid#, gene, and the version associated with higher levels.

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Diabetics have to be worried about more than just their cholesterol when it comes to the health of their arteries. They also have to watch their blood sugar to help prevent the build up of fatty plaques that can block blood flow.

But new research from the Joslin Diabetes Center and Harvard Medical School shows that high blood sugar may be more dangerous to some diabetics than others.

Dr. Alessandro Doria and colleagues found that a genetic variant on chromosome 9 previously associated with coronary artery disease (CAD) risk in the general population has an even greater effect in diabetics with poor blood sugar control. These results, published online today in the Journal of the American Medical Association, could someday help doctors identify people with diabetes who are at higher risk of CAD earlier, allowing them to aggressively target these patients for intervention.

People with diabetes are at least twice as likely as those without to have heart disease. Some studies suggest that middle-aged diabetics have the same high heart attack risk as people without diabetes who have already suffered a heart attack.

The first of two study groups was composed of 322 diabetics with coronary artery disease and 412 without. The researchers found that the risk for CAD was about the same in people with either the AA or AG genotype at rs2383206, even if they had poorly controlled blood sugar.

Having the GG genotype at rs2383206, however, increased the odds of CAD by about two-fold for diabetics with well-controlled blood sugar. And when high blood sugar was thrown into the mix, the odds of CAD for people with two Gs went up higher still – about four times compared to the lowest risk group.

In people with the GG genotype and a long history of high blood sugar, the odds of CAD were increased about seven times compared to diabetics with a history of well-controlled blood sugar.

(The study looked at rs2383206, which is available to 23andMe customers who were genotyped on the second version of our custom chip. But people who were genotyped on the first version can use rs2383207, the SNP we feature in the Health and Traits research report on Heart Attack, as a substitute. The G version is riskier for both SNPs.)

In a separate study group of 475 diabetics who were followed for 10 years, people with the AA or AG genotype at rs2383206 had the same risk of dying in general, or from cardiovascular disease in particular, regardless of their blood sugar. But for people with the GG genotype, the risk of death went up by a factor of two when blood sugar was not under control.

Both groups of diabetics Doria et al. studied were of European ancestry.

“While good glucose control is important for all people with diabetes, testing for this predisposing variant may help doctors identify patients for whom better control is an absolute necessity,” said Doria in a statement. The authors estimate that 30% of diabetics will have two Gs at rs2383206.

The probability of clinically significant CAD is about 30% for type 2 diabetics in general. The authors say this number could shoot up to 60% for diabetics with the GG genotype at rs2383206 and poorly controlled blood sugar.

The authors admit that this is a small study that will need verification. They also note that their findings are at odds with a previous report that found no difference between the risk conferred by SNPs in the 9p21 chromosomal region (where rs2383206 lies) in diabetic vs. non-diabetic subjects. Due to a number of methodological differences between the two studies, Doria et al say that no direct comparison of the results is possible.

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Recent genetic discoveries have taught researchers a lot about type 2 diabetes, and identified particular genetic variants that can influence a person’s risk of developing the condition.

But two studies published this week in the New England Journal of Medicine conclude that genetic information still pales in comparison to factors like body weight, smoking, cholesterol levels and other medical diagnostics when it comes to predicting who will develop the condition.

The papers are a reminder that although personal genomics promises to become a valuable supplement to preventive medicine, the information it provides shouldn’t be considered a replacement for regular check-ups and a healthy lifestyle. And though genetics certainly plays a role, diet, exercise and other environmental factors have a substantially greater impact on whether a person will develop type 2 diabetes.

Both studies looked at one-letter DNA variations known as single-nucleotide polymorphisms (SNPs) that have been linked to diabetes. The 23andMe Personal Genome Service™ provides information on nine diabetes-associated SNPs.

One study used data from the legendary Framingham Heart Study, which has followed three generations of participants over a period of 60 years, to show that inheriting a greater number of high-risk diabetes genes does increase a person’s chances of developing the condition. But when added to traditional measures of diabetes risk such as family history, body-mass index, fasting plasma glucose level and blood pressure, a person’s genotype at the 18 SNPs studied did not significantly improve the researchers’ ability to predict which of the 2,377 study participants became diabetic over a period of 28 years.

The other study, which looked at 16 SNPs in 16,061 Swedish and 2,770 Finnish subjects who had been followed for an average of 23.5 years, produced a similar result. The authors concluded that “common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes.”

However, because the physiological risk factors typically develop later in life (though they are becoming distressingly common in younger populations) the authors of the Framingham-based study suggest genetic information could be useful in motivating young people who have inherited a high diabetes risk to control their weight and take other preventive measures.

And research is bound to produce more knowledge about the genetic roots of diabetes. So in the not-too-distant future, a person’s genotype is likely to provide substantial predictive information beyond what is available from family history and physiology.

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The amount of sugar in the bloodstream must be tightly controlled. Too much can cause damage to nerves, blood vessels and organs. But too little sugar starves the body, especially the brain, of the energy it needs.

Fasting plasma glucose (FPG) levels are a measure of how well a person’s body can control blood sugar levels, a process that goes awry in diabetes. A report published online today in Science Express finds that FPG levels can be impacted by single-letter variations in genes known to be involved in blood sugar regulation.

Physicians routinely test their patients’ FPG levels to screen for diabetes and pre-diabetes. A high blood concentration of glucose after 8 to 10 hours of fasting indicates that a person’s ability to regulate blood sugar is impaired. High FPG levels are also associated with coronary heart disease mortality for both diabetic and non-diabetic individuals.

In order to identify genetic variants involved in blood sugar control, Nabila Bouatia-Naji and colleagues carried out a genome-wide association study to find single-nucleotide polymorphisms, or SNPs, correlated with FPG levels.

The most strongly associated SNP in an initial sample of about 650 non-obese French people was rs560887. The same SNP was correlated with FPG levels in a secondary sample that included about 3,400 French people, approximately 5,000 Finns and a group of about 860 obese French children.

Combining the results of all the study samples, the researchers found that each copy of the T version of rs560887 leads to a .06mmol/L reduction in FPG.

A FPG level below 5.5 mmol/L is considered normal. People with an FPG level between 5.6 mmol/L and 6.9 mmol/L have impaired fasting glucose or “pre-diabetes.” An FPG level above 7 mmol/L is consistent with diabetes.

Rs560887 did not correlate with subjects’ insulin levels or BMI. Over a 9-year follow-up period in the French samples rs560887 also did not correlate with type 2 diabetes risk.

Two other SNPs – rs1260326 and rs1799884—that were previously found to be associated with FPG were also found to be significantly associated with FPG levels in this study. The researchers believe that these genes affected by these SNPs affect the threshold level of glucose in the bloodstream, which triggers the secretion of insulin by the pancreas. The higher the threshold, the higher the blood glucose level will rise before insulin starts to regulate it.

“These sequences explain about 5 per cent of the normal variation in blood glucose levels between otherwise healthy people,” explained Robert Sladek, one of the study’s senior authors.

When all three SNPs were considered together to create a score (each person has two copies of each SNP and gets one point for each “low FPG” version, meaning the score can range from 0 to 6), the researchers found that on average people who scored a 5 or 6 had FGP levels 0.24 mmol/l lower than people who scored 0 or 1.

23andMe customers can use the table below to calculate their scores. Each “T” at rs560887 or rs1260326, and each “C” at rs1799884, is worth one point.

“It’s important to know that a high blood glucose level, even within the normal and non-diabetic range, is a risk factor for early mortality,” said Dr. Philippe Froguel of Imperial College and CNRS. “Epidemiological studies have shown that 80 per cent of the risk of cardiovascular disease is related to a blood glucose level just above the average.” The researchers propose that the three SNPs they identified “are likely to have a non-negligible impact on human health.”

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