Cisplatin, a cancer chemotherapy drug first approved by the FDA in 1978, revolutionized the treatment of many types of cancer.  Despite its effectiveness, in many cases doctors are forced to reduce the drug’s dose, or abandon it altogether, due to serious side effects on patients’ hearing.

Between 10-25% of adults and up to 60% of children being treated with cisplatin suffer from severe, permanent hearing loss in both ears. This is particularly damaging in kids, because even mild hearing loss can negatively impact learning and social development.

Researchers have suggested that genetic variants that affect the metabolism of cisplatin might explain why some people are susceptible to drug-induced hearing loss, while other patients receiving similar doses are not.  A new report, published online this week in the journal Nature Genetics, has identified variants in two genes that appear to greatly increase the risk of cisplatin-induced hearing loss.  Although the study is a small one, if replicated these findings could one day help doctors make better decisions about how to prescribe cipslatin.

A team led by Colin Ross from the University of British Columbia analyzed the DNA of 162 children (mostly of European ancestry) treated with cisplatin, focusing their search for genetic variants associated with drug-induced hearing loss on 220 genes known to be involved in the absorption, distribution, metabolism and elimination of medications and their breakdown products.

The variants with the largest effects were found in the TPMT gene.  For example, having one or two Cs at rs1142345 increased the odds of cisplatin-induced hearing loss by 10.51 times, although this result was not statistically significant once the researchers adjusted their data to account for the number of SNPs investigated.

(A larger and statistically significant effect was seen with closely related TPMT SNP, rs12201199, that 23andMe does not currently provide data for.  23andMe customers can use the links in this post to check their data using the Browse Raw Data feature.)

Rs1142345, as well as other variants that reduce the function of the TPMT enzyme, have been associated with adverse reactions to a class of drugs called thiopurines that are used as chemotherapy agents and immune system suppressants.

A second SNP associated with cisplatin-induced hearing was rs9332377 in the COMT gene.  Having one or two Ts at this SNP increased the odds of hearing loss by 5.52 times.  This result was also not statistically significant after adjusting the data.

Other variations in the COMT gene have been associated with a variety of traits, including pain sensitivity, willingness to explore new options, recovery from heart surgery, anxiety, and decreased breast cancer risk in tea drinkers.

None of the SNPs identified in this study were associated with hearing loss in children not treated with cisplatin, suggesting that their effect is specific for drug-induced hearing loss.

“These findings suggest that it may be possible identify individuals at higher risk of cisplatin otoxicity [hearing loss] based on genotype, which would improve counseling and treatment options,” the authors write.

They suggest, for example, that children with the riskier versions of the variants identified in this study could be given lower doses of cisplatin or treated instead with carboplatin, a drug that shows nearly similar cancer cure rates as cisplatin, but has less tendency to cause hearing damage.

The authors acknowledge, however, that their results will need to be replicated in independent populations before any decisions about how to use information about these variants in clinical settings can be made.  Research is also needed to understand what, if any, role these variants play in cisplatin-induced hearing loss in adult cancer patients.

Note: Recent studies by other researchers showed that variations in the megalin gene, the GSTP1 gene and the GSTM1 gene were also associated with the risk of cisplatin-induced hearing loss.  The current report from Ross et al. failed to replicate these associations.

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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It seems simple enough: if you eat only as many calories as you burn, you won’t pack on the pounds. Yet for many, balancing this equation is anything but easy. Obesity has become one of the most significant public health threats facing the United States and other developed countries. One-third of adults in the United States today can be considered clinically obese.

While lifestyle choices are certainly important, research has shown that genetics plays a significant role in determining a person’s propensity for being overweight or obese. One especially potent variant in the FTO gene has been consistently linked with weight in Europeans.

In a study of Scottish children published online yesterday by the New England Journal of Medicine, researchers suggest that this FTO variant may contribute to obesity by leading kids to chose foods that, pound for pound, pack a more powerful calorie punch.

[23andMe customers can see their data for an FTO SNP equivalent to the one used in this study by referring to the Health and Traits research report on obesity or using the Browse Raw Data feature. The T version of rs3751812 (equivalent to the A version of rs9939609 reported in this study) is associated with obesity]

Seventy-six kids between the ages of four and 10, selected from a larger study of 2,726 children who were having their height, weight, and FTO genotypes evaluated, also had their energy expenditure and food intake measured.

There was no difference in the number of calories burned while at rest between children who carried the higher weight-associated version of FTO and those who did not. Energy burned due to physical activity was actually higher for carriers than non-carriers. This suggests that the FTO variant isn’t affecting the basal metabolism rate or conferring a proclivity for a sedentary lifestyle.

There was also no difference in the total weight of the food ingested by the kids with the version of FTO linked to obesity. But these children did consume more calories than their non-carrier friends. The foods they chose during the test meals had “higher energy density” — they contained more calories per unit weight.

The authors note that most obesity disorders caused by defects in single genes (such as MCR4) affect eating behavior. These new results, and those of other studies (a few examples here, here, here and here), show that the common FTO variant is no different. It is unclear, however, whether FTO affects appetite regulation or the ability to sense how much food has been ingested.

In an accompanying editorial in NEJM, Dr. Rudolph Leibel says that although the proportion of obesity in the general population that can be attributed to variation in the FTO gene region is high, it’s probably still not enough to start using this SNP as a clinical screening tool.

But he goes on to say that in the not-so distant future more variants such as this one will be found and physicians will be able to assess a “score” based on maybe 15 to 20 genes to predict an individual’s risk for obesity.

“The important role that environment plays in enabling or resisting such susceptibility is clear evidence that such risk can be modified,” Leibel concludes.

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“Data, data, data! I want to see my data!” sang my 7-year-old, jumping around the kitchen, strumming his air guitar. What on earth was going through his mind? What did he think he’d get when he looked at his 23andMe data? We’ll probably never know, but, possibly influenced by his 12-year-old brother, he was definitely excited about seeing his data. His brother had been asking to see his own genetic information for days, ever since we told him it was available.

Both boys had joined my husband and me a few months earlier as we looked through our own data. They quickly learned how to predict their own genotypes given ours, especially for the easy cases such as when Daddy has an AA and Mama has a GG. So they did have some clue as to what it’s all about.

It took us a while to decide that we really did want to see our sons’ genetic data. The question of signing up children was in the air more than a year ago when Amy Harmon, science writer for the New York Times, interviewed employees at 23andMe as she prepared an article published last November. Amy was grappling with the question of whether or not to sign up her child.

The question of whether and under what circumstances children should be genotyped has been debated for decades, and this ethical discussion is a fascinating and important one. As a scientist however, I chose to take a pragmatic approach. I recall telling Amy that my plan was to look at my own data and my husband’s first, to get a sense of the possibilities for our kids. Dad and Mom both have a low genetic risk for type 1 diabetes? Kids are likely to have a low risk too. Mom has a higher than average risk for age-related macular degeneration and Dad has a typical risk? That’s a little tougher.

Furthermore, given that they’ve reached the ages of seven and 12 without serious illness, we know the boys have been spared some of the rare recessive genetic diseases (where two broken copies lead to disease) that show up early in life. And there is no history in my family or my husband’s of diseases that have a clear genetic basis.

After we had concluded from looking at our own data that we were comfortable with all the possible outcomes for the kids — at least for the current set of traits and conditions — there was one other big thing to consider: non-paternity. Fortunately that wasn’t an issue in our case — I was glad to be confident about that! Nonetheless, one of the first things I looked at when I initially explored my children’s data was the Paternal Line feature, which can reveal non-paternity. To my surprise I found myself a little nervous as I clicked on the link. If the boys’ paternal lines didn’t match my husband’s I was going to have to do a very quick investigation to see what had gone wrong! Sample mix-ups are unlikely, but that would have been my first guess. In any case, when I clicked on Paternal Line, I saw the boys reassuringly listed with their Dad, within Y haplogroup R1b1c. They also shared my maternal haplogroup, H10. Even though I knew they would, it was satisfying to see them there, just like the textbooks predict!

Before showing the boys their data, both my husband and I looked it over; this seemed like an important step. It is challenging because the site is so rich, but we concentrated on things we knew could have the biggest impact, such as age-related macular degeneration and venous thromboembolism. There is no way to check everything however, partly because 23andMe adds new information each month, so there is no way to know whether or not there will be dramatic findings in the boys’ genomes in the future.

I clicked on the Eye Color report, which we knew would be interesting. My husband and I have brown and hazel eyes; both our sons are blue-eyed. The odds of that are pretty low: depending on the parents’ genotype they can be either zero or about one in 16. But there the boys were, both of them, with GG genotypes, having received one G each from my husband and me.

Just because I was enjoying seeing the genetics work out, I clicked on the Bitter Taste report next. My boys had tasted the PTC paper (little strips of paper often used in genetics classes to explore this simple trait) at a 23andMe event last fall. The older one hadn’t tasted much, like me. The younger one, who’s generally pickier than his brother about food, had twisted up his face in disgust. Sure enough, the younger one showed up in the “taster” box with my husband, while the older one turned out to be a “non-taster” like me.

One of my favorite features, maybe because I’m a geneticist, is the Family Inheritance feature, where relatives can compare chromosomes. Each set of relatives has a characteristic pattern. My boys showed up with the characteristic sibling pattern when I compared them to each other — fully identical in 25% of their genomes, half-identical in 50% and unmatched in the remaining 25%. They share only one copy of the immune system genes on chromosome 6 (half-identity), so it is unlikely they would make ideal candidates for bone marrow donation to each other, were that to become necessary.

The boys do share the Alzheimer’s disease-associated APOE gene region at 100%, however. So even though we don’t know their genotypes because 23andMe doesn’t report on that gene (yet), we know the boys have the same genetic risk.

When we found some time one evening to show the boys their data, we first showed them their maternal and paternal lines, and how they matched ours. We then showed them the simple, non-disease traits such as Eye Color and Bitter Taste. My favorite moment was when we figured out that the boys had received their maternal blue eye color from my Dad, who died 20 years ago – my mother doesn’t carry the blue variant. My boys haven’t had many reasons to connect very directly with either of their deceased grandfathers, so when we made this discovery, I quickly looked around for a photo of my Dad, finding a tiny one on the office wall. I pointed it out to my younger son, who exclaimed, “My Grandpa!” Knowing he had received something in particular from his grandpa seemed to strengthen that otherwise wispy connection.

As we meandered around the site, my older son started getting antsy – he wanted to choose what to look at. “Obesity!” was his first choice. I think he may have been expecting a yes/no answer, so he might have been a little disappointed to see that he has close to average genetic risk – neither yes nor no. Type 2 Diabetes was another of his choices. That report revealed that one of the boys has twice the genetic risk of the other. We teased him that he will have to watch the candy intake. I didn’t see the need to make a big deal out of it, in part because I know that although the risk estimates appear quite different there are so many other factors (diet, exercise, other unknown genes) in play that the information is more a reminder to keep an eye out for any symptoms than anything else.

So, should parents get genetic testing for their children? More specifically, should parents who don’t work here sign their children up for 23andMe’s service?

The benefits and risks associated with knowing such information have not been studied systematically. The possible benefits include information that leads to better health decisions. Our family has also benefited from being reminded of our connections with each other and the things we share.

The fears typically revolve around the possibility that strong emotional reactions or misinterpretation of the information could lead to poor decisions. Discovery of non-paternity is a valid fear, as is the possibility that people will feel they are to blame for having passed down a disease-influencing genetic variant. But research studies have shown that most people who get genetic testing, even for serious diseases, may have a strong reaction initially but generally show no change in stress level or quality of life a few months later. That research has been an important factor in my decisions regarding 23andMe’s service.

And what if we are surprised one day, with news that one or both of the boys is at high genetic risk for a serious disease? I predict that we’ll use that information somehow. We’ll learn more about the disease, we’ll study all the prevention and treatment options. We’ll find out about the latest research, and take steps to prevent anyone from feeling that they “caused” this by handing down a mutation. We’ll be proactive. It’ll be a family project.

My older son has asked about getting direct access to his account. Children are not allowed to sign up for 23andMe’s service on their own, for good reason. I “own” my sons’ accounts, and they do not have the passwords. Currently I feel strongly that he should look at his data only with a parent. Maybe we will reconsider as he gets older.

We look forward to returning to the site with the kids as new reports come out and additional relatives sign up. My husband and I might start answering “23andWe” research surveys on our sons’ behalf soon – they can’t answer for themselves given the 23andWe rules, but together we can answer and thereby contribute to research. Another great topic for family discussion raised by 23andMe’s service.

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