Genome-wide study provides insights into platelet aggregation pathways and may also help identify new therapeutic targets for antiplatelet therapy
Researchers from the Johns Hopkins University (MD, USA) have just published their major research effort to identify the genetic factors behind platelet aggregation in the July 2010 issue of the journal, Nature Genetics.
“Our results give us a clear set of new molecular targets, the proteins produced from these genes, to develop tests that could help us identify people more at risk for blood clots and for whom certain blood-thinning drugs may work best or not”, commented Dr Lewis Becker, cardiologist and the co-senior study investigator.
The genome-wide study (GWAS) investigated approximately 2.5 million SNPs thought to be associated with platelet aggregation responses to three agonists (adenosine diphosphate [ADP], epinephrine and collagen). The study samples came from two cohorts of European ancestry: one consisting of 2753 individuals from the Framingham Heart Study and the other consisting of 1238 individuals from the Genetic Study of Atherosclerosis Risk, representing what researchers called a ‘a solid cross-section of American society‘. From the GWAS, seven loci associated with platelet aggregation near or within the following genes were identified: GP6, PEAR1, ADRA2A, PIK3CG, JMJD1C, MRVI1 and SHH.
Since three of the seven genes had been previously reported as having some role in platelet aggregation, Dr Becker explains that, “it was not until now that we put together all the major pieces of the genetic puzzle that will help us understand why some people‘s blood is more or less prone to clot than others and how this translates into promoting healing and stalling disease progression”.
Apparently, the teams‘ next research efforts are to study the various platelet antagonists, like aspirin, warfarin and clopidogrel (Plavix®), some the most common drugs currently available for the treatment of heart and vascular diseases. They hope to elucidate exactly which hereditary factors may distinguish people who are drug-resistant or not, and why some medications work for most but not all patients.
“Our combined study results really do set the path for personalizing a lot of treatments for cardiovascular disease to people based on their genetic make-up and who is likely to benefit most or not at all from these treatments”, concluded Dr Becker.
Sources: Johnson AD, Yanek LR, Chen MH et al.: Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat. Genet. 42(7), 608–613 (2010); John Hopkins Medicine Press Release: http://www.hopkinsmedicine.org/Press_releases/2010/06_22_10.html
A recent study published in the journal, Addiction, hopes to shed light on the ongoing debate of ‘nature versus nurture‘, that is, how much of what we are like is owing to our genetic make-up or how much of an influence our environment has on us.
Investigators from the Washington University in St Louis (MO, USA) examined a sample of approximately 2000 female twins, specifically searching for links between two types of data: first, women in the sample who regularly used tobacco, alcohol or drugs; and second, women whose friends were involved in regular substance use. Interestingly, they found that if an individual had a genetic predisposition towards regular use of alcohol, cigarettes and drugs, this would be exacerbated in the individual if exposed to friends who use alcohol, cigarettes and drugs.
Although it is well known that adolescents often choose friends who engage in similar behaviors to their own, this study demonstrated that peer selection also has a genetic basis. That is, an individual‘s genetic predisposition to regular substance use (or abuse) can be correlated with the likelihood of choosing friends who also use psychoactive or addictive substances. Therefore, the results of this study leads to the conclusion that the genetic factors that influence an individual‘s likelihood of using drugs may also modify an individual‘s likelihood of associating with friends who do the same. Most importantly, the study also found that heritable influences on an individual‘s own regular substance use increased as they affiliated themselves with more drug-using peers.
“Nature and nurture don‘t just combine to produce a woman who smokes, drinks, or uses drugs – nurture can also increase the effect of nature”, according to Dr Arpana Agrawal the lead author of the study.
Source: Agrawal A, Balasubramanian S, Smith E et al.: Peer substance involvement modifies genetic influences on regular substance involvement in young women. Addiction (2010) (Epub ahead of print).
At the American Society of Clinical Oncology Annual Meeting held at the beginning of June 2010 in Chicago (IL, USA), promising results from the Phase II clinical trial of investigational drug crizotinib (PF-02341066 [PF-1066], under development by Pfizer, NY, USA) were presented. The novel drug showed an objective response rate of 57% and a disease-control rate of 87% in non-small-cell lung cancer (NSCLC) in patients taking part in the Phase II trial whose tumors had a rearrangement of the anaplastic lymphoma kinase (ALK) gene.
In some patients with NSCLC, the ALK gene fuses with another gene, EML4. The resultant fusion produces an oncogene that promotes lung cancer cell growth. This fusion occurs in approximately 4% of NSCLC patients. The chances of a patient having the gene fusion increases to approximately 20% if they have the adenocarcinoma subtype of lung cancer, or are nonsmokers or former light smokers, among other clinical characteristics. Crizotinib inhibits the resultant protein that is produced from the ALK–EML4 gene fusion, allowing the cancer cells to die off.
Crizotinib is now in expanded clinical trials, including a randomized Phase III trial (PROFILE 1007) funded by Pfizer. The trials have already started recruiting patients and a central laboratory is currently carrying out the lung cancer tissue genotyping.
According to the American Cancer Society, more than 220,000 new lung cancer cases will be diagnosed in the USA in 2010 alone. However, even though only 4% of lung cancer suffer cases will qualify for inclusion in the Phase III clinical trial, approximately 9000 patients, for whom this new drug may help stop the growth of cancer, could benefit from this treatment.
“The results of the first two trials have been very encouraging”, enthused Dr Lyudmila Bazhenova, assistant clinical professor at University of California, San Diego (UCSD) School of Medicine (CA, USA) and a member of the Moores UCSD Cancer Center (CA, USA). “The Phase III clinical trials will be critical in determining if this drug goes to market”.
Sources: Bang Y, Kwak EL, Shaw AT et al.: Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC). J. Clin. Oncol. 28 (Suppl.), 18s (2010) (Abstract no. 3); University of California, San Diego Press Release: http://ucsdnews.ucsd.edu/newsrel/health/06–22ShrinkingTumors.asp
Scientists from the Pennsylvania (Penn) State University (PA, USA) recently carried out research that incorporated a novel laboratory mouse strain to study the behavioral, hormonal and neurochemical characteristics – similar to those seen in human patients – of drug-resistant forms of depression.
“A mouse can‘t tell us if it is feeling depressed, so we used a number of different kinds of tests – including some new ones that we developed – to gauge behavioral and hormonal changes, or phenotypes, of a type of depression that, in humans, does not respond well to some antidepressant drugs”, commented Professor Bernhard Luscher, a professor of biology at Penn State. “These indicators include reduced exploration of novel or otherwise aversive environments, failure to escape from a highly stressful situation and reduced pleasure-seeking behavior such as a reduced preference for sweet over plain water”.
The novel mouse strain used in this study harbors a genetic defect in the gene coding for the γ-aminobutyric acid (GABA) type A receptor, producing mice that are γ2-deficient. This defective gene found in the depressed mice seems to interfere with the function the GABA-A receptor in the brain, which controls the response to the neurotransmitter GABA. It has previously been found that the reduced function of these receptors has been known to be linked to anxiety (and not in depression) disorders because the drugs that are supposed to activate the GABA-A receptor are ineffective as antidepressants. “We have shown in this paper that this long-held conviction is flawed”, enthused Professor Luscher. “Our research shows that the GABA-A receptor is, in fact, an important part of the brain circuitry that is not working properly in depression”.
The team of scientists tested two kinds of antidepressant drugs in the mice fluoxetine (Prozac®) and desipramine (Norpramin®). They discovered that fluoxetine reduced symptoms of anxiety, but not depression, whereas the desipramine reduced both anxiety and depression symptoms in mice, which works on a different neurotransmitter, noradrenaline, which is an interesting finding since there is a large group of depressed patients that do not respond well to Prozac. “The [drug] that did not normalize depression-related behaviors is fluoxetine – the generic name for Prozac – which works on the neurotransmitter serotonin”, explained Professor Luscher.
One of the most important findings from this study is that it was demonstrated that some antidepressant drugs completely reverse the behavioral and hormonal symptoms of depression in the GABA-A-receptor-deficient mice, bringing their behavior even back to normal ‘wild-type‘ level found in mice, where on the other hand, the normal mice demonstrated almost no reaction to the drugs. “This result is expected of a mouse model that mimics depression because normal people do not seem to gain anything from taking antidepressants”, explained Professor Luscher.
The experiments performed in this study demonstrate that this new strain of genetically defective mice is a useful animal model for laboratory studies that could be helpful in understanding the complexity of human depression.
Source: Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B: γ-aminobutyric acid-type A receptor deficits cause hypothalamic–pituitary–adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol. Psychiatry (2010) (Epub ahead of print).