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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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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