Association between inflammatory bowel disease and heart disease found

Researchers analyzed medical-record data from more than 17.5 million patients found that people with inflammatory bowel disease (IBD) are at increased risk for a heart attack, regardless of whether or not they have risk factors for heart disease. This research is presented at the American College of Cardiology’s 67th Annual Scientific Session.

“Younger patients had about nine times the risk of a heart attack compared to their peers in the same age group [who didn’t have IBD], and this risk continued to decline with age,” said Muhammad S. Panhwar, MD, a resident in internal medicine at Case Western Reserve University/University Hospitals Cleveland Medical Center in Cleveland and lead author of the study. “Our findings suggest that IBD should be considered an independent risk factor for heart disease.”

Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Per Centers for Disease Control and Prevention (CDC) data, as of 2015, an estimated three million Americans have IBD, and about 70,000 new cases are diagnosed every year.

Researchers utilized IBM Explorys, a database of de-identified data from electronic records for patients of 26 nationwide health care systems in the U.S. They then identified 211,870 patients aged 18 to 65 diagnosed with of inflammatory bowel disease (IBD) between 2014 and 2017. Researchers then looked at the rate of heart attacks in the normal population and those with inflammatory bowel disease. Compared with patients who did not have Inflammatory bowel disease, heart attacks occurred roughly twice as often in those with Inflammatory bowel disease.

Researchers also found that people with Inflammatory bowel disease (IBD) were also more likely to have diabetes, hypertension, high cholesterol, and smoking than people without inflammatory bowel disease.  After adjusting for age, race, sex and traditional heart disease risk factors, Panhwar and his colleagues found that the patients with inflammatory bowel disease had about a 23 percent higher risk of having a heart attack. Women under the age of 40 with IBD were at higher risk for a heart attack than men with IBD in the same age group. In patients over the age of 40, heart attack risk was similar for men and women with inflammatory bowel disease.

“Our study adds considerably to a growing set of literature highlighting the importance of chronic inflammation in IBD as having a role in the development of heart disease,” Panhwar said.

Adapted from press release by the American College of Cardiology.

Animal study finds MeXis gene protective against coronary artery disease

UCLA scientists have identified a gene called MeXis that may play a protective role in preventing heart disease. Their findings suggests that this gene acts within macrophages inside clogged arteries to help remove excess cholesterol from blood vessels by controlling cholesterol pump protein expression. Research is published in the journal Nature Medicine.

MeXis is an example of a “selfish” gene, one that is presumed to have no function because it does not make a protein product. However, recent studies have suggested that these so-called “unhelpful” genes can actually perform important biological functions without making proteins and instead producing a special class of molecules called long non-coding RNAs, or lncRNAs.

“What this study tells us is that lncRNAs are important for the inner workings of cells involved in the development of heart disease,” said Dr. Peter Tontonoz, senior author of the study. “Considering many genes like MeXis have completely unknown functions, our study suggests that further exploring how other long non-coding RNAs act will lead to exciting insights into both normal physiology and disease.”

In the study, researchers found that mice lacking MeXis had almost twice as many blockages in their blood vessels compared to mice with normal MeXis levels. In addition, boosting MeXis levels made cells more effective at removing excess cholesterol. In the next phase of the study, researchers will further explore how MeXis affects the function of cells in the artery wall and will test various approaches to altering MeXis activity. The researchers are interested in finding out if MeXis could be targeted for therapy of cardiovascular disease.

Citation: Sallam, Tamer, Marius Jones, Brandon J. Thomas, Xiaohui Wu, Thomas Gilliland, Kevin Qian, Ascia Eskin, David Casero, Zhengyi Zhang, Jaspreet Sandhu, David Salisbury, Prashant Rajbhandari, Mete Civelek, Cynthia Hong, Ayaka Ito, Xin Liu, Bence Daniel, Aldons J. Lusis, Julian Whitelegge, Laszlo Nagy, Antonio Castrillo, Stephen Smale, and Peter Tontonoz. “Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA.” Nature Medicine, 2018. doi:10.1038/nm.4479.

Funding: NIH/National Heart, Lung and Blood Institute, Burroughs Wellcome Fund Career Awards for Medical Scientists, UCLA Cardiovascular Discovery Fund, Lauren B. Leichtman and Arthur E. Levine Investigator Award.

Adapted from press release by the University of California Los Angles Health Sciences.

Obesity related Epigenetic changes in DNA

Obesity has been linked to “letter” changes at many different sites in the genome, yet these differences do not fully explain the variation in people’s body mass index (BMI) or why some overweight people develop health complications while others don’t. A large study from Boston Children’s Hospital, the University of Edinburgh, the Harvard School of Public Health, the Framingham Heart Study and the National Heart, Lung, and Blood Institute (NHLBI) provides more insight, linking obesity with epigenetic modifications to DNA that in turn are tied to an increased risk of weight-related health problems such as coronary artery disease.

The study is one of the largest to date to examine the link between BMI, obesity-related disease and DNA methylation  a type of epigenetic modification that influences whether genes are turned on or off. Findings were published in PLoS Medicine.

“Even though we’ve genetically sequenced more and more people at greater and greater breadth and depth, we haven’t completely explained who develops obesity and why,” says Michael Mendelson, MD, ScM, a pediatric cardiologist with the Preventive Cardiology Program at Boston Children’s Hospital, who shared first authorship on the paper with Riccardo Marioni of the University of Edinburgh. “We found that obesity is related to widespread changes in DNA methylation. Unlike your DNA sequence, these regulatory modifications change over time and can influence your risk of disease in later life.”

The researchers studied blood samples from 7,800 adults from the Framingham Heart Study, the Lothian Birth Cohort and three other population studies. They systematically looked for markers of DNA methylation at more than 400,000 sites in the genome. They then looked to see if these markers differed according to BMI in a predictable pattern.

Their analysis identified strong associations between BMI and DNA methylation at 83 locations in 62 different genes. Methylation at these sites was, in turn, associated with differences in the expression of genes involved in energy balance and lipid metabolism.

When Mendelson and colleagues scored people in the study for how many methylation changes they had, they found that the more changes, the greater their BMI. The methylation score captured 18 percent of the variation in BMI when tested in a separate population. For each standard deviation increase in the score, the odds ratio for obesity was 2.8 times higher.

The researchers then applied a statistical technique called Mendelian randomization, which provides supportive evidence that a detected association is causal. They concluded that 16 of the 83 identified sites in the genome were differently methylated as a result of obesity, a finding that held true across people of different ethnicities.

Difference in methylation at one gene, SREBF1, appeared to be causative of obesity and was clearly linked with unhealthy blood lipid profiles, glycemic traits (a risk factor for diabetes) and coronary artery disease. It encodes a known regulator of lipid metabolism and could be a target for a drug treatment, the researchers say.

“Taken together, these results suggest that epigenetic modifications may help identify therapeutic targets to prevent or treat obesity-related disease in the population,” says Mendelson, who is also a research fellow in the Population Sciences Branch of the NHLBI. “The next step is to understand how we can modify epigenetic modifications to prevent the development of cardiometabolic disease.”
Since the study was done in blood cells, it also suggests that with further study, methylation markers could be easily accessible biomarkers to guide therapy bringing a “precision medicine” approach to preventive cardiology, says Mendelson.

“We’ve known for a long time that people who are overweight or obese are more likely to develop metabolic risk factors like diabetes, lipid abnormalities and hypertension,” adds study coauthor Daniel Levy, MD. He is director of the Framingham Heart Study, which is supported by the NHLBI. “This study may help us understand the molecular mechanism linking obesity to metabolic risk, and that knowledge may pave the way for new approaches to prevent even more dire complications such as cardiovascular disease.”

Citation: Michael M. Mendelson, Riccardo E. Marioni, Roby Joehanes, Chunyu Liu, Åsa K. Hedman, Stella Aslibekyan, Ellen W. Demerath, Weihua Guan, Degui Zhi, Chen Yao, Tianxiao Huan, Christine Willinger, Brian Chen, Paul Courchesne, Michael Multhaup, Marguerite R. Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan Bressler, Kari North, Johan Sundström, Stefan Gustafsson, Sonia Shah, Allan F. McRae, Sarah E. Harris, Jude Gibson, Paul Redmond, Janie Corley, Lee Murphy, John M. Starr, Erica Kleinbrink, Leonard Lipovich, Peter M. Visscher, Naomi R. Wray, Ronald M. Krauss, Daniele Fallin, Andrew Feinberg, Devin M. Absher, Myriam Fornage, James S. Pankow, Lars Lind, Caroline Fox, Erik Ingelsson, Donna K. Arnett, Eric Boerwinkle, Liming Liang, Daniel Levy and Ian J. Deary. “Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardio metabolic Disease: A Mendelian Randomization Approach.”
DOI: 10.1371/journal.pmed.1002215

Research funding: National Heart, Lung, and Blood Institute of the NIH, Tommy Kaplan Fund (Department of Cardiology, Boston Children’s Hospital), UK Biotechnology and Biological Sciences Research Council, UK Royal Society, Chief Scientist Office of the Scottish Government, Age UK, Wellcome Trust Institutional Strategic Support Fund, UK Economic and Social Research Council, UK Medical Research Council, Australian National Health and Medical Research Council.

Adapted from press release by Boston Children’s Hospital.