Lifestyle Influences Metabolism Via DNA Methylation

An unhealthy lifestyle leaves traces in the DNA. These may have specific effects on metabolism, causing organ damage or disease. Scientists of Helmholtz Zentrum München have now identified 28 DNA alterations associated with metabolic traits. This world-first epigenome-wide association study (EWAS) of modified genes and metabolites has been now published in the journal Human Molecular Genetics.

In the course of life, aging processes, environmental influences and lifestyle factors such as smoking or diet induce biochemical alterations to the DNA. Frequently, these lead to DNA methylation, a process in which methyl groups are added to particular DNA segments, without changing the DNA sequence. Such processes can influence gene function and are known as epigenetics. Scientists of the Institute of Genetic Epidemiology (IGE) and the Research Unit Molecular Epidemiology (AME) at Helmholtz Zentrum München are seeking to determine what association exists between these epigenetic processes and the health consequences, in particular for the metabolism.

To this end, the team led by Christian Gieger (IGE) and Melanie Waldenberger (AME), in in collaboration with Karsten Suhre of Weill Cornell Medical College in Qatar analyzed blood samples from more than 1800 participants of the KORA study *. In doing so, they analyzed more than 457,000 loci in the DNA as to biochemical alterations and compared them with the concentrations of 649 different metabolites. The analysis showed that the methylation of 28 DNA segments changed a number of important metabolic processes.

In the relevant DNA regions there were also already known disease-related genes: for example, the TXNIP gene that regulates glucose metabolism and is associated with the development of diabetes mellitus. Appropriately, with the methylated TXNIP there were altered concentrations of metabolites from the lipid and glucose metabolism. Also genes that are known to be biochemically altered due to smoking affect different metabolic activities, and specifically those with corresponding biological functions.

"This study gives us new insights into how lifestyle factors can influence metabolism via the resulting alterations in the DNA," said Gieger, research group leader at the IGE. "We can now use these results to develop new diagnostic and therapeutic approaches for lifestyle-related diseases such as diabetes."

Tomado de: Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. "Lifestyle Influences Metabolism via DNA Methylation." ScienceDaily, 20 Sep. 2013. Web. 23 Sep. 2013.

Long-term Efficacy Data on CRC Screening Methods

Screening can reduce colorectal cancer mortality, as well as the incidence of the disease, but it is has been unclear which screening method is the best.

Two long-term studies confirm the effectiveness of major screening technologies, but leave the question of superiority up in the air. Both appear in the September 19 issue of the New England of Medicine.

In one study with a 22-year follow-up period, colonoscopy was shown to have advantages over sigmoidoscopy for the prevention of colorectal cancer. In addition, screening colonoscopy reduced the risk for any colorectal-cancer-associated death, whereas sigmoidoscopy lowered the risk of dying only from left-side tumors.

"Our data support the use of colonoscopy as a the preferred screening option for patients if the primary consideration is maximal reduction in risk of colorectal cancer," said study coauthor Andrew Chan, MD, MPH, associate professor of medicine, gastroenterology, at the Massachusetts General Hospital in Boston.

In the second study, which has a 30-year follow-up period, annual and biennial screening with fecal occult blood testing reduced the risk for death from colorectal cancer. The risk for death from colorectal cancer was 32% lower with annual screening, compared with no screening, and 22% lower with biennial screening.

The Best Method?

But how does colonoscopy compare to fecal occult blood screening?

Both of these tests are effective for colorectal cancer screening, and both these studies support current screening guidelines, according to an accompanying editorial by Theodore R. Levin, MD, and Douglas A. Corley, MD, PhD, from Kaiser Permanente Medical Centers in California.

In addition, the screening tests have improved since the trial participants first used them.

The editorialists emphasize that these studies are quite different from one another, which makes it difficult to make direct comparisons of effectiveness.

"It would be tempting to use these 2 studies to draw conclusions about which test is more effective," they write.

The reduction in mortality was better with colonoscopy than with annual fecal occult blood testing (68% vs 32%). However, it is a mistake to directly compare these results, the editorialists point out. "The 2 study populations are not comparable: one was a randomized trial, the other an observational study of volunteers, and both tests have undergone improvements since the studies were performed."

To date, no completed studies directly compare fecal occult blood testing with colonoscopy, although randomized trials are ongoing.

Although the performance of colonoscopy has probably improved because of the greater recognition of nonpolypoid colorectal neoplasia, and it "appears to have a performance edge over the old guaiac fecal occult blood test, fecal occult blood testing has largely been replaced by the more effective fecal immunochemical test (FIT)," they note. This newer test has better sensitivity than the guaiac fecal occult blood testing used in that study.

Of importance, recent data show that individuals were more likely to "complete screening if they were offered guaiac fecal occult blood tests, a choice between colonoscopy and guaiac fecal occult blood tests, or FIT alone, as compared with being offered colonoscopy alone," they write.

In the Kaiser Permanente Northern California health system, where both editorialists practice, a combined approach is used, and substantial improvement in rates of colorectal cancer screening has been achieved.

Colonoscopy vs Sigmoidoscopy

In the first study, Dr. Chan and colleagues evaluated the association between the use of lower endoscopy (updated biennially from 1988 to 2008) and colorectal cancer incidence (to June 2010) and mortality (to June 2012). The cohort involved 88,902 individuals who participated in the Nurses' Health Study and the Health Professionals Follow-up Study.

Over a follow-up period of 22 years, there were 1815 documented cases of colorectal cancers and 474 colorectal-cancer-specific deaths.

When endoscopy screening was compared with no screening, multivariate hazard ratios (HRs) for colorectal cancer were 0.57 after polypectomy, 0.60 after negative sigmoidoscopy, and 0.44 after negative colonoscopy.

A negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate HR, 0.73), and the rate of mortality from proximal colon cancer was lower after screening colonoscopy (multivariate HR, 0.47), but not after sigmoidoscopy.

The multivariate HRs for colorectal cancer mortality were 0.59 after screening sigmoidoscopy and 0.32 after screening colonoscopy.

Even though colonoscopy appears to have some advantages over sigmoidoscopy, there are reasons patients might opt for the latter. "A screening sigmoidoscopy generally does not require a full bowel preparation or the administration of sedation, so patients undergoing the procedure can generally expect to miss less work," Dr. Chan told Medscape Medical News.

"In addition, although serious complications from both colonoscopy and sigmoidoscopy are quite rare — generally about 1 to 3 per 1000 patients — they do occur at a higher rate with colonoscopy than with sigmoidoscopy," he noted.

Dr. Chan and colleagues point out that although randomized controlled trials have shown that screening with flexible sigmoidoscopy reduces the incidence of colorectal cancer and associated mortality, comparable data for screening colonoscopy are not yet available.

"I think that, based on the data assembled so far and the widespread availability of colonoscopy, we should continue our current practice of recommending colonoscopy as one of a few screening options, with a full discussion of the risks, benefits, and areas of uncertainty associated with each test," said Dr. Chan.

Reduces Long-term Risk

In the second study, Aasma Shaukat, MD, MPH, from the University of Minnesota in Minneapolis, and colleagues provide an update to the Minnesota Colon Cancer Control Study, which assessed the long-term effect of fecal occult blood test screening on all-cause and colorectal cancer mortality.

The initial cohort involved 46,551 participants 50 to 80 years of age who were randomized to usual care or to annual or biennial screening with fecal occult blood testing. Screening tests were performed from 1976 to 1982 and from 1986 to 1992.

The researchers used the National Death Index to obtain updated information about the participants and to determine cause of death.

A total of 33,020 participants (70.9%) died from any cause during the 30-year follow-up period; 732 of the deaths were attributable to colorectal cancer.

Table. Deaths From Colorectal Cancer in the Study Groups

Deaths	Annual Screening (n = 11,072)	Biennial Screening (n = 11,004)	Usual Care (n = 10,944)
n (%)	200 (1.8%)	237 (2.2%)	295 (2.7%)

Annual screening lowered colorectal cancer mortality (relative risk [RR], 0.68), as did biennial screening (RR, 0.78). There was no reduction in all-cause mortality with annual screening (RR, 1.00) or with biennial screening (RR, 0.99).

Men 60 to 69 years of age got the most benefit from screening. RR for death from colorectal cancer was 0.46 with annual screening, 0.42 with biennial screening, and 0.44 for either screening.

The overall reduction in colorectal cancer death associated with biennial screening was greater for men than women (P = .04 for interaction). This difference was not observed with annual screening (P = .30 for interaction) or with the 2 screening methods combined (P = .06 for interaction).

"The reductions in colorectal cancer mortality in the Minnesota Colon Cancer Control Study are comparable to those reported in randomized clinical trials of screening with flexible sigmoidoscopy, suggesting that fecal occult blood testing remains an effective and acceptable method of screening," the authors write. "Stool-based tests for colorectal cancer screening are an active area of current research, with development and testing of new stool-based tests."

Tomado de: medscape.com
Referencia: N Engl J Med. 2013; 369:1095-1105, 1106-1114, 1164-1166

Heart Attacks in Young Women -- Not All Have Chest Pain

hest pain is recognized as a symptom of heart troubles, but one out of five women aged 55 years or less having a heart attack do not experience this symptom, according to a study led by the Research Institute of the McGill University Health Centre (RI-MUHC). The research findings, gathered from partner institutions across Canada including the University of British Columbia (UBC), are the first to describe this phenomenon in young women. The study, published in JAMA Internal Medicine, has implications for emergency room healthcare professionals and for at-risk individuals, as seconds matter when it comes to the accurate diagnosis and treatment of heart attack.

We need to move away from the image of an older man clutching his chest, when we think about acute coronary syndrome (ACS -- the umbrella term referring to heart attacks and angina), says senior author of the study, Dr. Louise Pilote, director of the Division of General Internal Medicine at the MUHC and McGill University and professor of medicine at McGill University. "The reality is that chest pain, age and gender are no longer the definers of a heart attack. Our study demonstrates that young people and women who come into the emergency without chest pain, but other telltale ACS symptoms such as weakness, shortness of breath and/or rapid heartbeats are in crisis. We need to be able to recognize this and adapt to new standard assessments in previously unrecognized groups such as young women."

"Women less than 55 years old are more likely to have their ACS misdiagnosed in the ER than men, and they have higher risk of death," adds first author Dr. Nadia Khan, associate professor of Medicine, UBC. "The public and physicians need to be aware of this problem."

Pain not an indicator of disease severity

Drs. Pilote, Khan and colleagues evaluated more than 1000 young patients who were hospitalized for ACS. Their findings showed that women were less likely to experience chest pain compared with men and that the absence of this pain did not correlate with less severe heart attacks. Patients without chest pain had fewer symptoms overall but their ACS was not less severe. The diagnosis of ACS therefore depended on detailed cardiological assessments.

"It is important to remember that chest pain is a main indicator of ACS, but not the only one," says Dr. Pilote.

"We need to remind ourselves that even without chest pain, something serious could still be happening," adds Dr. Khan

McGill University Health Centre. "Heart attacks in young women -- not all have chest pain."ScienceDaily, 16 Sep. 2013. Web. 18 Sep. 2013

Researchers Extend Human Epigenomic Map

Ten years ago, scientists announced the end of the Human Genome Project, the international attempt to learn which combination of four nucleotides -- adenine, thymine, cytosine, and guanine -- is unique to Homo sapiens DNA. This biological alphabet helped researchers identify the approximately 25,000 genes coded in the human genome, but as time went on, questions arose about how all of these genes are controlled.

Now, Harvard Stem Cell Institute Principal Faculty member Alexander Meissner, PhD, reports another milestone, this time contributing to the multilayered NIH-funded human Roadmap Epigenomics Project. Epigenetics is the study of how the over 200 human cell types (e.g., muscle cells, nerve cells, liver cells, etc.) can have an identical complement of genes but express them differently. Part of the answer lies in the way that DNA is packaged, with tight areas silencing genes and open areas allowing for genes to be translated into proteins. Stem cells differentiate into various cell types by marking specific genes that will be open and closed after division.

New research by Meissner, published online as a letter in the journal Nature, describes the dynamics of DNA methylation across a wide range of human cell types. Chemically, these marks are the addition of a methyl group -- one carbon atom surrounded by three hydrogen atoms (CH3) -- anywhere a cytosine nucleotide sits next to a guanine nucleotide in the DNA sequence.

Meissner's team, led by graduate student Michael Ziller, at Harvard's Department of Stem Cell and Regenerative Biology mapped nearly all of the 28-million cytosine-guanine pairings among the 3-billion nucleotides that make up human DNA, and then wanted to know which of these 28 million are dynamic or static across all the cell types.

"When we asked, how many of them are changing, the answer was a very small fraction," said Meissner. The researchers found that eighty percent of the 28-million cytosine-guanine pairs are largely unchanged and might not participate in the regulation of the cell types, while the dynamic ones sit at sites that are relevant for gene expression -- in particular distal regulatory sites such as enhancers. "Importantly this allows us to improve our current approaches of mapping this important mark through more targeted strategies that still capture most of the dynamics," Meissner said.

The methylation map generated by the Meissner lab is part of a larger National Institutes of Health (NIH) consortium to look at all of the different epigenetic modification that are found across a large number of human cell and tissue types. Earlier this year, the Meissner's lab recorded all of the gene expression and multi-layered epigenetic dynamics that take place in early stem cell differentiation when they prepare to divide into their next fated cell type.

In addition to his roles at Harvard, Meissner is affiliated with the Broad Institute and the New York Stem Cell Foundation. Only a graduate student in 2007, he has quickly established himself as a leader in the epigenetics field. "It just happens to be that we're at the right time and at the right place, both physically and sort of in time, " he said. "Just five years ago, we would have had the same question, but we wouldn't have had the same tools to answer the question."

Harvard University. "Researchers extend human epigenomic map." ScienceDaily, 8 Aug. 2013. Web. 14 Sep. 2013.

Blood Test IDs Acute Kidney Injury in ED

A test that measures blood levels of neutrophil gelatinase-associated lipocalin (NGAL) accurately distinguished between acute kidney injury and reversible transient kidney dysfunction in the ED, researchers reported.

Among 616 patients with varying urgent health issues presenting to a hospital emergency department, the highest median levels of plasma NGAL were seen in those with acute kidney injury (146-174 ng/ml at various time points); levels also increased with acute kidney injury (AKI) severity (207-244 ng/ml for AKI Network stage 2 or greater disease).

Plasma NGAL also discriminated between patients with AKI, those with normal kidney function, and those with transient azotemia (area under the curve, 0.85 and 0.73, respectively); a plasma NGAL level of 133 ng/ml or greater was associated with a 10-fold increase in AKI risk, Prasad Devarajan, MD, and colleagues from Cincinnati Children's Hospital Medical Center and the Hospital Fernando Fonseca in Lisbon, Portugal wrote in the Sept. 5 issue of the Clinical Journal of the American Society of Nephrology.

AKI has been increasing in both the hospital and community settings, but diagnosis of the condition remains problematic, the researchers wrote.

Serum creatinine (SCr) is routinely used in emergency departments to diagnose AKI, but it's a delayed marker that rises only after kidney injury has been established, and there are other downsides to the test, Devarajan told MedPage Today.

"Especially in the community-acquired setting, it is very common to see an increase in SCr," he said. "In this setting it is very important to be able to distinguish between true, intrinsic AKI and transient, reversible kidney injury ... [I]n both cases SCr is going to be elevated."

Along with colleagues at Cincinnati Children's Hospital, Devarajan developed the NGAL test as a biomarker of early AKI. In earlier studies, the researchers showed it to be useful in a variety of hospital settings, including adult ICU and heart failure patients.

      Devarajan holds patents on the test, which is being commercially developed by the point-of-care diagnostic and services company Alere, Inc. of Waltham, Massachusetts. The test has been approved in parts of Europe and Asia, and the FDA is currently considering Alere's application in the U.S.

In the newly published study, the researchers examined the accuracy of plasma NGAL as a marker of AKI in patients with urgent health issues presenting to the ED.

     The study included 616 patients who presented to the ED of Fernando Fonseca Hospital and were admitted for treatment from March to November of 2008. Baseline renal function by SCr, medical history and demographic characteristics were obtained from hospital electronic records.

     Prospective renal function assessment was carried out by measuring SCr, serum cystatin C (SCysC), and plasma NGAL at 0, 6, 12, 24, and 48 hours from hospital admission.

     Plasma NGAL levels among patients with AKI remained significantly higher than in patients with normal kidney function for all time points  P menor a 0.001. When the combined group of AKI plus transient kidney injury patients was examined, the values of plasma NGAL remained significantly different from patients with normal kidney function P menor a 0.001 for all time points and the test was able to differentiate AKI from transient injury P menor a 0.001 for all time points.

Among the other findings:

·         Higher levels of plasma NGAL were associated with more severe AKI using AKI Network classification (median values ranging between 69 and 75, 125.5 and 148, 168 and 195, and 301.5 and 328.5 ng/ml for AKI Network stages 0,1,2, and 3, respectively.

·         ROC curves were generated to assess the discriminative ability of the NGAL test for diagnosing AKI. The area under the curves (AUCs) for AKI prediction were 0.77, 0.81, 0.82, 0.79 and 0.78 at 0, 6, 12, 24, and 48 hours, respectively. The AUC for discriminating between patients with AKI and those with normal kidney function was 0.85 (95% CI, 0.81-0.90) at the 12-hour time point.

·         The addition of plasma NGAL to the clinical model yielded a net reclassification improvement of 94.3% and an integrated discrimination improvement of 0.122.

·         When patients were classified into three grades of risk according to plasma NGAL levels  menor de 97 ng/ml was considered low risk and mayor que 133 ng/ml was considered high risk), those in the high risk category were found to have a 10-fold greater risk of AKI  odds ratio, 9.8; 95% CI, 5.6-16.9.

"When pNGAL concentrations are in the gray zone  mayor que 97 ng/ml to menos de 133 ng/ml we propose the recognition of risk factors that are independent predictors of AKI, including age, chronic kidney disease and comorbidities like cardiovascular disease," the researchers wrote. "Thus, patients with these risk factors may be considered at high risk of AKI, even when plasma NGAL levels are in the gray zone."

Devarajan said the findings prove the test could improve the clinical management of patients suspected of having AKI in the emergency treatment setting.

"The incidence of AKI varies from 20% to 40% in critical care patients and it is a significant cause of death," he said. "This test could markedly increase our ability to discriminate between true, intrinsic AKI and other conditions."

Tomado de Medpagetoday.com