SNPs on Chromosome 15 Associated with Smoking and Lung Cancer

by Dr. Hsien-Hsien Lei
Posted April 3, 2008 in DNA and Disease

Despite recent downsizing, deCODE Genetics has published a new study in Nature on the genetics of smoking and lung cancer. Two other studies with the same focus were also published in Nature and Nature Genetics.

All three studies identified regions on chromosome 15 that are associated with nicotine dependence, lung cancer, and peripheral artery disease. The deCODE study focused on SNP rs1051730 located on chromosome 15q24 in the CHRNA3 nicotine acetylcholine receptor. People with one copy of the “T” version of this SNP had:

• 30% increase in risk of lung cancer
• 20% increase in risk of peripheral artery disease

Half of people of European descent have at least one copy of the higher risk SNP and 10% may have two copies which increases their cancer risk by 80%.

• A smoker has a 15% risk of lung cancer over his/her lifetime
• Smokers with two copies of the T SNP variant has a 23% risk of lung cancer.
• People who’ve smoked less than 100 cigarettes in their lifetime have a <1% risk of lung cancer.

Researchers also hypothesized that the higher risk T SNP variant may influence a person to smoke more cigarettes and become more easily dependent on nicotine. The deCODE study found that those with one copy of the T SNP variant smoked an additional cigarette per day than those without the variant. Two copies of the T SNP variant was associated an two more cigarettes per day.

Last month for No Smoking Day in the UK, Alicia Sparks at Mental Health Notes gave five reasons why smoking is dangerous to her mental health. Aside from the obvious negative health effects, she says smoking does not make her happy, makes her worry, gives her too much to deal with, stresses her out, and makes her feel guilty. What do you think about smoking?

NB: Bioethicist Arthur Caplan discussed the possibility of lung cancer genetic testing in the New York Times.

Such testing could carry risks all its own, bioethicist Arthur Caplan of the University of Pennsylvania warned. People who have been found to have a genetic predisposition to addiction and lung cancer could find it harder to get health or life insurance, or their employer might drop their coverage, he said.

”The good news is that getting these risk estimates will help focus anti-smoking campaigns, and some people will want to voluntarily get into anti-addiction programs early, where they will probably work better,” Caplan said in an e-mail. But if such testing is done, it should be voluntary, and the results should be kept private, he said.

Update: Dr. Ann Turner comments on these findings at GENEALOGY-DNA.

The SNP, rs1051730, has already been incorporated into reports for deCODEme customers (literally within a few minutes of the press release). It is also tested by 23andMe, but it is not on the Affymetrix 6.0 chip used by SeqWright and a new company http://geneessence.com. However, the Affy chip could have a near-by SNP that would be in linkage disequilibrium with rs1051730.

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Genes May Increase Chance of Baby Born Breech

by Dr. Hsien-Hsien Lei
Posted March 31, 2008 in DNA and Disease

At my 30-week prenatal visit last week, the doctor told me the baby was in a transverse position. Hopefully she’ll get her little rear in gear at my 34-week visit and be head down unless she wants to be really ornery as only about 3 percent of babies are breech at birth (buttocks or the feet down). Her older brother was in the “correct” position almost the entire time so I can tell she’s going to be a handful!

Risk factors for breech delivery include:

• First baby
• Older mother
• Low gestational age
• Low birth weight
• Uterine malformations
• Pelvic tumours
• Site of placental attachment
• Low volume of amniotic fluid
• Congenital anomalies

Breech delivery is associated with increased perinatal mortality and morbidity.

One reason I’m not worrying too much is because a large population-based study in Norway was published last week in BMJ that showed breech deliveries are more common if the baby’s parents were born breech themselves. I know I was not born breech and I’ll assume my husband wasn’t either or my mother-in-law would have mentioned it. If the mother or father was born breech, their baby has an approximately 2-fold increase in odds of being born breech as well. The authors conclude:

Intergenerational recurrence risk of breech delivery in offspring was equally high when transmitted through fathers and mothers. It seems reasonable to attribute the observed pattern of familial predisposition to term breech delivery to genetic inheritance, predominantly through the fetus.

They also recommend that parents who were born breech inform their healthcare providers so their babies can be more closely monitored if necessary.

Please cross your fingers for me!

Image: Newborn baby from Wellcome Images under Creative Commons

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Consumer Genomics and Personalized Medicine

by Dr. Hsien-Hsien Lei
Posted March 24, 2008 in DNA and Disease

Pharmaceutical companies are searching through their dusty shelves and archives to find drugs in abandoned pipelines that may be potentially effective in groups of people defined by their genetic make-up. The Wall Street Journal reports that personalized medicine is gathering speed:

While the markets for these therapies are smaller than for those that treat the general population, pharmaceutical companies are realizing there are hefty profits to be made because patients are more likely to use, and stick with, a tailored medicine that works better than a one-size-fits-all drug.

Of course, personalized medicine is dependent upon genetic information to succeed. Prior to consumer genomics, access to genetic testing was limited to those who could find a genetic counselor or medical geneticist within a reasonable physical distance. With the Internet and DNA technologies combined, however, it is now possible for patients to develop a personalized medicine strategy with the help of in-house genetics experts at companies that offer consumer genomics.

Even at this early stage of consumer genomics and personalized medicine, consumers can already use genetic information to prevent or treat disease either in themselves or their offspring. Pharmacogenomics is particularly useful for helping patients and their physicians determine treatments and dosages that are the most effective yet with the fewest side effects. Consumers can access many of the genetic tests with or without the help of their personal physician via companies that offer direct-to-consumer genetic testing*. Some of these companies offer genetic counseling services and other resources to help consumers understand their test results and take action. Others, such as nutrigenomic companies, also sell supplements that purportedly address perceived genetic deficiencies.

In one of this month’s JAMA commentaries, Drs. Feero, Guttmacher, and Collins list the following obstacles confronting personalized medicine:

1. Not enough information on prevalence and risk conferred by genetic markers across population groups
2. Unclear inheritance of multiple markers and effects on risk of disease
3. Incomplete picture of gene x environment interactions
4. Not enough studies on common diseases and effect of interventions based on genetic risk factors
5. Limited evidence of benefit for personalized medicine esp. when there are no clinical studies
6. Fear of genetic discrimination

The authors conclude that education of health care professionals and the general population is necessary. Despite all the news about developments in genomic technology, consumers still have much to learn. The key to helping consumers decide which genomic services they need and which are nice to have, but not necessary, is to empower them with information.

Within the decade, genetics experts predict that genome sequencing will no longer feel like a breakthrough and costs will drop to about $1,000 per genome. Point-of-care or point-of-use handheld devices will make it even easier to incorporate consumer genomics into medical care. These portable machines will be able to analyze whole blood in the clinic and deliver genetic testing results within minutes. Other portable machines would be targeted to consumers for personal use and would possibly contain data from an individual’s complete genome linked to a database of relevant disease information that can be easily updated via the Web. Jay Flatley, CEO of Illumina, already has his “genotype” on an Apple iPhone.

The intersection between consumer genomics and personalized medicine is about more than breakthroughs in technology. It is also about a change in the way consumers approach healthcare. Consumers may lead the way by first accessing genomic technology on their own then sharing their genetic information with healthcare providers later on a need-to-know basis. Or they may wait for qualified genetics professionals to take the lead. No one knows exactly how consumers will embrace genomics and personalized medicine when they become part of standard medical care. There is no doubt, however, that the trickle of consumer genomics will soon grow into a torrent. Are we prepared?

*Disclosure: I work with DNA Direct.

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deCODE Launches PrCa Prostate Cancer DNA Test

by Dr. Hsien-Hsien Lei
Posted February 12, 2008 in DNA Testing, DNA and Disease

The genetic testing market is highly competitive. No sooner does one company launch a first-of-its-kind test than another launches a similar one. In January, Proactive Genomics made available the $300 prostate cancer genetic test, Focus5 Prostate Cancer Risk Test, that examines five SNPs. (Although it’s not clear from their website how consumers can order the test.) Less than a month later, deCODE Diagnostics follows suit with the $500 deCODE PrCa test that analyzes eight SNPs for prostate cancer:

• Three on chromosome 8 (8q24)
• Two on chromosome 17 (17q12, 17q24.3)
• One on chromosome 2 (2p15)
• One on chromosome 11 (11q13.3)
• One on X-chromosome (Xp11.22)

deCODE states that the relative risk of prostate cancer for those of European ancestry who are homozygous at all eight is 17.6 times higher than the reference group.

• About 40% of the population has a genotype combination of the tested markers that have an increased relative risk (>1) over the general population
• About 10% of the population has a genotype combination that confer an average two-fold relative risk
• About 1% have relative risk above 3

The deCODE PrCa test is available from physicians and medical practitioners. Patients can kick start the process by downloading the test order forms and bringing them to their doctor’s visit.

There is a strong market for prostate cancer testing. Prostate cancer is the second leading cause of cancer-related death in American men. According to the National Cancer Institute, there were almost 220,000 new cases of prostate cancer in 2007 and over 27,000 deaths attributed to the disease. The American Cancer Society recommends screening for men starting at age 50 with men at higher risk receiving screening starting at age 45.

Screening, however, is controversial. Some studies have not observed a decrease in mortality rate from early screening for prostate cancer. Early detection at younger ages may not be particularly useful because prostate cancer develops slowly and would be better left alone until many years down the line. deCODE literature emphasizes that the five-year survival rate among prostate cancer patients is 100 percent due to early detection.

From the Prostate Cancer Foundation:

…there is no unanimous opinion in the medical community regarding the benefits of prostate cancer screening. Those who advocate regular screening believe that finding and treating prostate cancer early offers men more treatment options with potentially fewer side effects. Those who recommend against regular screening note that because most prostate cancers grow very slowly, the side effects of treatment would likely outweigh any benefit that might be derived from detecting the cancer at a stage when it is unlikely to cause problems.

The Independent asks “The Big Question: Are we on the brink of a breakthrough in the fight against prostate cancer?”

Can prostate cancer be beaten?

Yes

• A new genetic test will enable men at high risk to be identified for regular screening
• More accurate blood tests based on a new gene target could mean earlier identification of the disease
• Treatment could be offered to those men with fast-growing, aggressive cancers

No

• The existing PSA blood test cannot distinguish between a cancerous prostate and a benignly enlarged one
• Even when cancer is diagnosed there is often no way of knowing if it needs treating
• Prostate cancer is unique in that it can be so slow to develop that more men die with it than from it

More on prostate cancer genetic testing from Cancer Genetics.

NB: DNA Direct (for whom I work) partners with deCODE to offer free pre- and post-testing consultation and genetic counselling.

Photo credit: Wellcome Photo Library, Colour artwork of the urinary bladder with its two ureters and also the seminal vesicles and the ampulla of vas, leading to the vas deferens. The prostate gland and its passages are at the base of the bladder in this posterior drawing.

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Genetic Testing for Psychiatric Diseases

by Dr. Hsien-Hsien Lei
Posted February 6, 2008 in DNA Testing, DNA and Disease

Three companies–Neuromark, Psynomics, and SureGene–are joining the genetic testing fray. Each is offering genetic tests for variants associated with mental illness.

• Neuromark’s Mark-C test is undergoing confirmatory studies (according to the website). The test will examine two genetic markers, GRIK2 and GRIA3, that appear to increase the risk of suicidal thoughts in people taking antidepressant drug Celexa.
• Psynomics claims to be the “first and only” company in the world to offer DNA tests for mental illness. Psynome tests for two mutations in the GRK3 gene associated with bipolar disorder. Psynome2 tests for mutations in the Promoter L allele gene that are associated with response to serotonin-based drugs.
• SureGene has developed the AssureGene test that examines a panel of (unspecified) genes and markers that is being marketed to aid in the diagnosis of patients at risk of developing psychosis. The test may also be used to predict drug response to antipsychotic medications.

Not surprisingly, the genetic tests have met with skepticism. Dr Cathryn Lewis at the Institute of Psychiatry, London was quoted in Guardian:

The general risk of developing bipolar depression is around one per cent. If you possess the worst set of gene variants, then your risk rises to three per cent. That means you are three times more likely than average to get bipolar depression. That may seem worrying but it is still a very low risk. It is still 97 per cent likely that you won’t get depression. People are not likely to realise that, however.

Without seeing the reports issued by these companies and not knowing whether genetic counselors are available by phone or email, I can’t say for sure that these companies are not providing proper customer service and information. At this early stage of genetic testing, however, potential consumers who have done their homework and studied their family medical history may find that these tests provide a tip-off towards more careful follow-up.

Family practice physician Tim Janzen wrote the following in a GENEALOGY-DNA list discussion (reprinted with permission):

I think that those in the medical profession are going to have positions all over the map on this topic. Some will be afraid that the results of genetic tests will cause unnecessary anxiety among those who are tested and shown to be predisposed to certain diseases. I fully admit that it may do that for at least some people. Others will welcome the information in that it will hopefully allow the doctors to be better informed as to which of their patients are at higher risk for mental illness.

I wouldn’t be surprised if the results of genetic tests are eventually integrated into treatment algorithms for people with mental illness. For instance, if a patient presents with depression and the genetic tests indicate a strong predisposition to depression, the doctor may be more inclined to treat that patient for many years with an antidepressant rather than just the 6 month minimum that is generally recommended for patients who present with depression for the first time.

The medical profession will simply need to keep in mind that these genetic tests will show predispositions to certain diseases, but a predisposition is frequently not equivalent to being destined to have the disease. We already welcome information such as cholesterol levels and blood pressure readings that tell us which patients are predisposed to heart disease and stroke. We act on those results accordingly.

Patients who have a family history of mental illness or other conditions already know that they have a predisposition (unless they are adopted). Thus the genetic results will either reinforce the fact that specific patients are at increased personal risk or they will show that they are at lower risk than they might otherwise be. We shouldn’t forget that environment also plays a role in mental health. Drug abuse is one environmental factor that also predisposes to mental illness.

For more about mental health, visit Alicia Spark’s Mental Health Notes.

NB: Andro Hsu of 23andMe has made a similar point in the past about presenting risk information.

(HT: UCL Institute of Human Genetics and Health)

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Eye on DNA Headlines for 24 January 2008

by Dr. Hsien-Hsien Lei
Posted January 24, 2008 in DNA and Disease, Eye on DNA Headlines, Genetically Modified Foods and Organisms, Personalities with DNA

• Gene Genie Issue #24 is up at Biomarker-Driven Mental Health 2.0.
• Sue Trinidad at Women’s Bioethics Blog wants to know how far genetic researchers can take your DNA beyond your initial informed consent.
• Sam Karlin of Stanford University who created BLAST with Stephen Altshul died in December of a massive heart attack.

  “Because of the common descent of all living things, it is often possible to learn a lot about a new DNA sequence by finding out what is known about other sequences that are similar,” (Russ) Altman said. BLAST compares the new sequence to an enormous database of sequences. “It estimates the significance of the match between the input sequence and the ‘hits’ that are pulled out. This is where Sam’s contribution was—he worked out the statistical theory for how to judge which matches really meant something. So BLAST is basically the Google of biological research.”

• The newest (42nd) member of The DNA Network is Genetic Future by Australian researcher Daniel MacArthur. His latest post looks at the ethical challenges of whole-genome sequencing. Welcome, Daniel! We’re glad to have you.
• Four reasons why genetically modified food is inevitable. (HT: Mark Evans)
• Hypertensive patients with a copy or more of the T2238C variant of the atrial natruiretic precursor A (NPPA) gene may have a decreased risk of coronary heart disease (CHD), stroke, all-cause death, combined CHD, and combined CVD if treated with the diuretic chlorthalidone (also known as Clorpres, Tenoretic, and Thalitone). Those with the most common TT genotype appear to do better when treated with a calcium channel blocker (amlodipine aka Norvasc). (Medical News Today)

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Eye on DNA Headlines for 18 January 2008

by Dr. Hsien-Hsien Lei
Posted January 18, 2008 in DNA Testing, DNA and Disease, Eye on DNA Headlines

• Proactive Genomics has launched a $300 prostate cancer genetic test based on research published in the New England Journal of Medicine (January 2008). SNPs at five chromosomal regions were found to be associated with prostate cancer: 17q12 (rs4430796), 17q24.3 (rs1859962), and 8q24 regions 1 (rs16901979), 2 (rs6983267), and 3 (rs1447295). The company looks as if they have plans to expand into the genetics of common diseases as well as personal genomics. More from The New York Times.
• Genetic Testing is now the official journal of Genetic Alliance. (press release)

  The journal covers all aspects of genetic testing, including molecular, biochemical, and varied sets of clinical situations; ethical, legal, social, and economic aspects of genetic testing; and issues concerning effective genetic counseling.

• My first stop for information about autism is Autism Vox where today, Kristina Chew looks at geneticist Michael Wigler and his “unified genetic theory of autism.”
• Look who I found at Big Think! There is a video of George Church, Harvard prof. of genetics answering the question: What is the state of global medicine today? as well as one where he’s musing on The Genomic Revolution. If you feel like responding, you can do so via writing, video, or audio slide show. (via TechCrunch)
• Sperm produced by mice exposed to air pollution have been found to have more genetic mutations and DNA methylation. Not to worry – just use cloned sperm!
• Just Science 2008 is now accepting participants.

  By signing up you stipulate that you will post at minimum 1 scientific post per day between February 4th and 8th of 2008. Additionally, you may not post any non-science entries for this period so that we may offer only science on our aggregated feed.

(>> Start a discussion!)

Opaldia to Offer Diagenic Breast Cancer Genetic Test

by Dr. Hsien-Hsien Lei
Posted December 18, 2007 in DNA Testing, DNA and Disease

UK genetic testing company Opaldia will be offering the Diagenic breast cancer blood test starting in 2008. The test detects gene expression patterns in peripheral (circulating) blood and is touted as being able to diagnose asymptomatic breast cancer before it can be detected by manual breast exam or mammograms. In 2005, Diagenic company researchers published an article in Breast Cancer Research detailing 37 predictive genes for breast cancer (pdf).

Dr. James Mackay, Opaldia Medical Director:

I think it is really important to investigate better ways of detecting early breast cancer in young women.

All health professionals who work with breast cancer are concerned that mammograms may be sub optimal in young women under 47. Therefore a new test used alongside mammography would provide the optimal chance of detecting the cancer as early as possible.

Analyzing gene expression signatures from peripheral blood is based on the following principles (adapted from the Diagenic website):

• The body responds to disease in a way that can be detected by measuring the amount of mRNA transcribed from a specific set of genes associated with disease
• These gene expression patterns can be analyzed using whole genome microarrays
• Gene expression signatures can be used to diagnose disease

Diagenic also offers a similar test for Alzheimer’s Disease.

NB: Opaldia CEO Elaine Warburton blogs about their partnership with Diagenic at Genetics and Health.

via Medgadget

Tags: genetics, genes, dna, breast cancer, opaldia, diagenic

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Eye on DNA Headlines for 17 December 2007

by Dr. Hsien-Hsien Lei
Posted December 17, 2007 in DNA and Disease, DNA and the Law, Eye on DNA Headlines

• Illumina, provider of SNP genotyping BeadChips to companies like 23andMe and deCODEme, is in the spotlight at the San Diego Business Journal. Over the past five years, Illumina has grown 250 percent and now has operations in five countries.
• So far, it’s pretty obvious that 23andMe is winning the PR campaign with celebrities and other noted technorati signing up for their services. Andrew Meyers of Buzzyeah wants to join them and is asking for donations. Frankly, I’m astounded that he’s already raised $300. Andrew promises to blog all if he is able to get his genome scanned.
• The SciAm 50 Awards have been announced. I’m a little embarrassed to say that I don’t know most of the names on the list but I do recognize the X Prize Foundation at #3.
• Topping the genetics headlines today is the discovery of genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 that are associated with an increased risk of colorectal (colon) cancer. The CRAC1 aka HMPS gene was previously associated with colon cancer in the Ashkenazi population. This study has found that it also moderately increases cancer risk in the general population from an average 5% lifetime risk in the UK to 7% for people with both “bad” copies of the genetic variant. (via The Guardian)
• Dayton Daily News has created a Frequently Asked Questions (FAQ) about DNA in forensic investigations. I found this Q&A particularly interesting:

  Q How do forensic scientists determine if there is DNA evidence and how do they examine it in the lab?

  A Generally, we’re looking for a body fluid, mainly blood, semen and saliva. There are tests to identify these body fluids. We can also take samples on evidence that might contain skin cells. Usually, we are looking for evidence discarded at the scene which might contain DNA from the perpetrator. Next we take these samples through the DNA process to see if we obtain a DNA profile.

Tags: genetics, genes, dna, forensics, colon cancer

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Eye on DNA Headlines for 6 December 2007

by Dr. Hsien-Hsien Lei
Posted December 6, 2007 in DNA and Disease, Eye on DNA Headlines, Personalities with DNA

• Congratulations to Dr. Elizabeth Blackburn of UCSF who has won the L’ORÉAL-UNESCO For Women in Science Award. She is a pioneer in telomere and telomerase research and is also a strong contender for a Nobel Prize.

  Dr. Blackburn’s research examines the function of the enzyme as it relates to cell aging and mutations that can cause cancer. During DNA synthesis, telomerase restores the ends of eukaryotic chromosomes, called telomeres, and Dr. Blackburn’s research has found that mutant variations of telomerase impair cell division, which can contribute to aging and cancer.

• The Economist explores consumer genomics and genetic sequencing in this week’s issue.
• Nine genetic markers for schizophrenia have been uncovered using whole genome homozygosity association (WGHA) analysis. Published in PNAS, the study genotyped 500,000 markers in 178 schizophrenia cases and 144 healthy controls.

  Four of these 9 “risk ROHs” contained or neighbored genes associated with schizophrenia (NOS1AP, ATF2, NSF, and PIK3C3).

• Four times as many imprinted genes have been identified in a recent study at Duke University. Most of the imprinted genes found in this study are within genomic regions associated with cancer, diabetes, autism, and obesity.
• A small study of 102 men and 101 women found that those with one form of the AVPR1a gene were more likely to be generous when playing an online game involving money. Israeli researchers found that those with generous AVPR1a gene variant gave away 50% more money on average. I wonder if deCODEme or 23andMe will find that a disproportionate number of their customers have the “generous” AVPR1a genetic variation.

Tags: telomeres, telomerase, elizabeth blackburn, genetics, genes, dna, dna sequencing, schizophrenia

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