Researchers Analyze a Man's Full Genome for Disease Risks

From Staff Reports

Scientists at Stanford and Harvard Universities collaborated to assess the clinical usefulness of analyzing a patient's full genome for disease risks and unusual drug responses. The work brings closer to reality the concept that whole-genome sequencing might one day play a clinical role.

The authors evaluated the entire genome of a 40-year old man and compared it to several databases of disease-related gene variants. They also factored in the patient's medical and family history and statistical disease risks. As part of the work, the researchers provided the patient with genetic counseling and clinical tests relevant to his family history.

The genome analysis revealed variants associated with diseases in the man's family (osteoarthritis, vascular disease and early sudden death). It also uncovered variants linked to conditions not in his family (iron overload and thyroid and parathyroid diseases). Some variants suggested that he might have unusual responses to certain heart medications, which is meaningful in light of his risk for cardiovascular disorders.

The authors viewed their work as a proof of concept that whole-genome sequencing can yield clinically useful information for individual patients. They acknowledged that many challenges remain, including the effect of the environment, which is difficult to quantify and often changes throughout a person's life.

The paper concluded that the transition to genome-informed medical care will require an integrated team including medical and genetics professionals, ethicists and health-care delivery organizations. The analysis appeared in the May 1, 2010, issue of Lancet.

Hormone Mimic Effective Against PLD

A hormone mimic called Octreotide may be effective for treating polycystic liver disease (PLD) caused by ADPKD, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology.

In addition to causing kidney failure, ADPKD also often leads to PLD, a condition characterized by multiple variably sized cysts in the liver. Octreotide mimics the somatostatin hormone that regulates the secretion of several other hormones in the body. Somatostatin exerts its effects by blocking both the formation of the chemical cyclic AMP and the secretion of fluids by cells, two factors thought to play a role in the development of kidney and liver cystic diseases.

A team of researchers led by the Mayo Clinic College of Medicine designed a clinical trial to examine whether Octreotide could shrink the cyst-filled livers of patients with PLD. The randomized, double-blind, placebo-controlled trial enrolled 42 patients with severe PLD caused by ADPKD (34 patients) or autosomal dominant PLD (eight patients). (Autosomal dominant PLD is a genetic form of PLD not caused by ADPKD.) Patients received Octreotide or placebo, and treatments were administered as monthly injections.

After one year, liver volume decreased by an average of approximately 5 percent in patients taking Octreotide but slightly increased (by approximately 1 percent) in patients taking placebo. Octreotide also had an effect on the diseased kidneys of patients with ADPKD. Among those patients, total kidney volume remained practically unchanged in the Octreotide group but increased by more than 8 percent on average in the placebo group. Kidney function was similar in both groups of patients. Octreotide was well tolerated, and treated individuals reported an improved perception of bodily pain and physical activity.

Progesterone and Altered Stem Cells

Cancer researchers at Princess Margaret Hospital have discovered that the ovarian hormone progesterone plays a pivotal role in altering breast stem cells, a finding that has implications for breast cancer risk.

The findings, published online in Nature, are significant because reproductive history is among the strongest risk factors for breast cancer, researchers said.. Other major known risk factors are age, genetics and breast density.

The research showed that progesterone peaks during the second half of the menstrual cycle, and starts a cross-talk between stem cells and neighboring cells that propels normal breast stem cells to expand in number, and may trigger an environment where cancer can begin.

Until now, breast stem cells were thought to be generally inactive in the adult female breast, the researchers said. In this study, the team replicated the human natural reproductive cycle in mice to determine the impact of hormones on breast stem cells. How hormones change those stem cells opens a new pathway to understanding the cell growth that begins breast cancer, and with further research, will open new ways of targeting stem cells, investigators said.

Milk, Renal Cancer Link Questioned

While previous research had suggested that drinking milk was related to factors that may increase the risk of renal cell cancer, results of a recent study exploiting the genetic contribution to variation in milk consumption suggested that may not be the case.

Previously reported studies suggested a connection between milk intake and renal cell carcinoma risk, and whether that represents a causal association or is the result of bias is currently unclear. Researchers at the MRC CAiTE Center in the department of social medicine at the University of Bristol, UK, used a genetic marker to try to untangle that observation.

From 1999 through 2003, the researchers conducted a large, hospital-based, case-control study from four central and eastern European countries. Using observational, genetic and phenotypic data, they determined whether the genetic variant at the gene MCM6 - known to be associated with lactose tolerance - may be used as a nonconfounded and unbiased marker for milk consumption's link to cancer risk.

For adult milk drinkers vs. nonmilk drinkers in the study, the difference in the odds of renal cell carcinoma was about 35 percent. However, when assessing the relationship in a more direct way by using genetic data, there was no association between the two.

The study results were published in the May 2010 issue of Cancer Epidemiology, Biomarkers & Prevention.

Methane Breath and Obesity

New Cedars-Sinai research showed obese patients who test positive for methane on their breath have a significantly higher body mass index (BMI) than their peers.

The study, presented recently at Digestive Disease Week in New Orleans, is the first in humans to show a link between the presence of methane-producing bacteria in the gut and elevated BMI, indicating that bacteria may play a role in obesity.

In the study, 58 patients ages 18 to 65 with BMIs between 30 and 60 were given a breath test to determine if methane was present. About 20 percent of those patients tested methane-positive. The methane-positive patients had a BMI of up to 7 points higher than those patients who did not show methane on their breath tests. BMI is used as a measurement that correlates with obesity. A methane-positive test indicates the patient has certain bacteria in the gut that produce the gas.

Previous research by the Cedars-Sinai GI Motility Program has shown that methane from methane-producing bacteria can slow the gut down. That could play a role in explaining why obese patients with the methane type of bacteria have a higher BMI since methane, by slowing the gut, could increase calorie harvest, researchers said.

Another Dark Chocolate Benefit

Researchers at Johns Hopkins have discovered that a compound in dark chocolate may protect the brain after a stroke by increasing cellular signals already known to shield nerve cells from damage.

Ninety minutes after feeding mice a single modest dose of epicatechin, a compound found naturally in dark chocolate, the scientists induced an ischemic stroke by essentially cutting off blood supply to the animals' brains. They found that the animals that had preventively ingested the epicatechin suffered significantly less brain damage than the ones that had not been given the compound.

While most treatments against stroke in humans have to be given within a two- to three-hour time window to be effective, epicatechin appeared to limit further neuronal damage when given to mice 3.5 hours after a stroke. Given six hours after a stroke, however, the compound offered no protection to brain cells.

Clumping Breast-Milk Cells

New research led by McGill University researchers helped explain why breast-milk cells lose their structure, causing them to clump up in strange ways and sometimes become cancer tumors. The researchers discovered how one particular gene regulates epithelial cells - cells that normally form in sheets and are polarized to enable the transport of molecules in a single direction. It's that loss of polarity that is thought to play an important role in breast tumor development.

By using mouse models, investigators discovered that the cells do not form neat structures when the gene malfunctions.

The research, published in Genes and Development, showed that if the gene is reintroduced into a tumour, polarity can be restored. The investigators pointed out that the gene functions by working with more than 40 various proteins, of which only one, a scaffold protein, has been identified.

Serotonin's Role in IBS

Serotonin is commonly associated with brain neurology, but a Mayo Clinic research team has identified a number of genetic variants in serotonin genes that impact irritable bowel syndrome (IBS).

The Mayo team used high-throughput technology to study nearly 400 tagged single-nucleotide polymorphisms (SNPs) in more than 20 serotonin-related genes, and found a number of previously unknown IBS associations. The conclusion: Many more serotonin-related SNPs were implicated in IBS than first thought. The implicated genes relate to serotonin synthesis, metabolism and receptors. The researchers also found IBS may be caused by multiple genes - not just one or a few - and there may be distinct as well as overlapping molecular mechanisms that cause diarrhea and constipation, two major symptoms of IBS.

The findings were presented at Digestive Disease Week 2010 in New Orleans.