Case Western Reserve researchers have identified a genetic factor that blocks the blood vessel inflammation that can lead to heart attacks, strokes and other potentially life-threatening events.
The breakthrough involving Kruppel-like factor (KLF) 15 is the latest in a string of discoveries from the laboratory of professor of medicine Mukesh K. Jain, MD, FAHA, that involves a remarkable genetic family. Kruppel-like factors appear to play prominent roles in everything from cardiac health and obesity to metabolism and childhood muscular dystrophy.
School of Medicine instructor Yuan Lu, MD, a member of Jain’s team, led the study involving KLF-15 and its role in inflammation. Lu and colleagues observed that KLF-15 blocks the function of a molecule called NF-kB, a dominant factor responsible for triggering inflammation.
This finding reveals a new understanding of the origins of inflammation in vascular diseases, and may eventually lead to new, targeted treatment options.
‘It had been suspected that smooth muscle cells were related to inflammation, but it hadn’t been pinpointed and specifically linked to disease,’ said Jain, Ellery Sedgwick Jr. Chair and director, Case Cardiovascular Research Institute at Case Western Reserve School of Medicine. Jain also is chief research officer for the Harrington Heart & Vascular Institute at University Hospitals Case Medical Center. ‘This work provides cogent evidence that smooth muscle cells can initiate inflammation and thereby promote the development of vascular disease.’
Smooth muscle cells are only one of two major cell types within blood vessels walls. The other cell type, endothelium, has traditionally taken the blame for inflammation, but Jain’s study suggests that both cells are critically important in the development of vascular disease.
The researchers learned that expression of this factor appeared mainly in smooth muscle cells and that levels were markedly reduced in atherosclerotic human blood vessels. To establish causality, the team generated genetically-modified mice where they deleted KLF-15 gene in smooth muscle cells.
‘We expected to see more proliferation of the smooth muscle cells as this is a common response of this cell type in disease,’ Lu said, first author on the paper. ‘Instead, we were surprised to see rampant vascular inflammation and hyper activated NF-kB, the master regulator of inflammation.’
The results offer hope for the development of specific anti-inflammatory therapies for vascular disease. Cholesterol-lowering drugs such as statins have some anti-inflammatory effects, but despite their widespread use, the burden of vascular disease remains high. As statins’ primary role is to lower cholesterol levels, developing additional or more potent anti-inflammatory therapies are needed to compliment statins’ important function.
Jain’s previous research of the KLF family of genetic factors revealed regulator functions in blood vessels. KLF4 was shown to potently inhibit inflammation in the endothelium, the other major cell type in vessels. The current work is first to establish a role for these factors in smooth muscle inflammation. Case Western Reserve University School of Medicine

Obesity gene testing does not put people off weight loss and may help to reduce self-blame, according to a new study by researchers from the Health Behaviour Research Centre at UCL.

Previous studies have shown that genes play a role in a person’s risk of becoming overweight. One gene, called FTO, has been found to have the biggest influence so far.

FTO has two variants, one associated with greater risk of weight gain (A) and one associated with lower risk (T). One in two people carries at least one copy of the A variant. People who inherit two A variants (one from their mother and one from their father) are 70% more likely to become obese than those with two T variants. Even those who inherit one have a higher weight than those with two T variants.

Researchers can now use a gene test for FTO (although this is not yet commercially available). However, it was not known how people would react to finding out the results of the genetic test.
Regardless of gene status or weight, all the volunteers recognised that both genes and behaviour are important for weight control. The results indicate that people are unlikely to believe that genes are destiny and stop engaging with weight control once they know their FTO status.
Some clinicians thought it would help people to become motivated to manage their weight. Others thought that the ‘genes as destiny’ perspective might mean people felt there was nothing they could do about their weight. If people responded fatalistically it could be harmful because diet and exercise are still very important for health and weight control, perhaps even more so if a person is ‘battling against their biology’.

UCL’s Professor Jane Wardle and Susanne Meisel decided to test a small number of volunteers (18) for their FTO status and interview them about their experience. The sample of volunteers included men and women, who spanned the weight range from underweight to obese.

They found that the volunteers were very enthusiastic about receiving their genetic test result. Those who struggled with their weight said that the genetic test result was helpful because it removed some of the emotional stress attached to weight control and relieved some of the stigma and self-blame.

No one reported a negative reaction to the genetic test result, or said it made them feel there was nothing they could do to about their weight.

Susanne Meisel, who led the study said: ‘These results are encouraging. Regardless of gene status or weight, all the volunteers recognised that both genes and behaviour are important for weight control. The results indicate that people are unlikely to believe that genes are destiny and stop engaging with weight control once they know their FTO status. Although they knew that FTO’s effect is only small, they found it motivating and informative. We are now doing a larger study to confirm whether more people react in the same way.’ University of College London

Case Western Reserve University is part of a landmark study that has discovered four novel gene variations which are associated with blood pressure. The 19-site meta-analysis, involving nearly 30,000 African-Americans, also found that the set of genetic mutations are also associated with blood pressure across other populations.
Epidemiology and biostatistics professor Xiaofeng Zhu, PhD, is co-senior author of the paper. The Continental Origins and Genetic Epidemiology Network (COGENT) consortium conducted the research, which is the largest genome-wide association study of blood pressure in individuals of African ancestry. Most gene discovery studies to date have been performed using individuals of European ancestry. Previous genome-wide association studies using samples from individuals of African descent failed to detect any replicable genes associated with blood pressure.
‘In addition to their disproportionate suffering, hypertension occurs earlier in life for African-Americans compared to individuals of other ancestries,’ Zhu explained. ‘Therefore, it is important to study this population to better understand genetic susceptibility to hypertension.’
Zhu and his colleagues also confirmed that previous findings regarding other genes whose presence correlates with increased hypertension risk.
‘Although it is unknown how the genes regulate blood pressure,’ Zhu added, ‘our findings contribute to better understanding of blood pressure pathways that can lead to future development of drug target for hypertension and may guide therapy for clinical care.’
Experts estimate genetic make-up accounts for roughly 40-50 percent of individuals’ susceptibility to hypertension. Other factors associated with the disease include lifestyle, diet, and obesity. Compared to Americans of European-ancestry, African-Americans’ increased hypertension prevalence contributes to a greater risk of stroke, coronary heart disease, and end-stage renal disease.
‘We anticipated that individuals of African ancestry share similar biology to other populations. However, differences in genomic make-up between African ancestry and other populations have uncovered additional genes affecting blood pressure, in addition to genetic variants that are specific to individuals of African ancestry,’ said Nora Franceschini, MD, MPH, nephrologist and research assistant professor of epidemiology at the University of North Carolina at Chapel Hill and first author on the paper.
The next phase of study involving the newly discovered gene mutations will investigate their function using human blood samples at the molecular level. Zhu and his colleagues have begun conducting additional research to determine whether the newly identified genes respond to existing hypertension medications. Individuals typically respond differently to a given medication depending on which gene mutation they carry. The more information researchers gather, the greater opportunity clinicians will have prescribed the drug that is most efficacious based on the patient’s specific mutation.
‘The research findings do not have immediate implications for treatment, but the hope is that discovering genes associated with disease risks will bring scientists closer to biological pathways and may suggest useful targets for new treatments,’ said geneticist Brendan J. Keating, DPhil, one of co-senior authors of the paper, of The Center for Applied Genomics at The Children’s Hospital of Philadelphia and faculty at the Department of Pediatrics at the University of Pennsylvania. Case Western Reserve University School of Medicine

Researchers have discovered the first inherited gene mutation linked exclusively to acute lymphoblastic leukemia (ALL) occurring in multiple relatives in individual families. The discovery of the PAX5 gene mutation was led by St. Jude Children’s Research Hospital and others.
The mutation was identified in two unrelated families in which pediatric ALL has been diagnosed in multiple generations. The mutation involved a single change in the DNA sequence of PAX5, a gene that is known to be deleted, mutated or rearranged in some B cell tumours, including ALL. This is the first time changes in PAX5 have been linked to an inherited cancer risk.
‘Pioneering work from St. Jude and others has identified inherited variations in other genes that modestly increase the risk of developing ALL, but few had been identified in familial leukaemia,’ said co-corresponding author Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Department of Pathology. ‘Prior studies had identified inherited mutations in families with multiple types of cancer including leukaemia, but not in families with ALL alone.’
While inherited mutations have been linked to an increased risk of breast, colon and other cancers, particularly adult cancers, very few have been tied to childhood tumours. ALL affects about 3,000 children nationwide annually, making it the most common childhood tumour.
‘For families with several generations of cancer patients, it means a lot to know that scientists and clinicians are working together to better understand the genetic factors that explain their family’s increased risk,’ said co-author John T. Sandlund, a member of the St. Jude Department of Oncology. ‘They are hopeful that other families, as well as their own, might benefit from this research.’
The mutation was found in the normal cells and leukaemia cells of eight ALL patients from several generations of two unrelated families. The work was led by researchers at St. Jude, Memorial Sloan-Kettering Cancer Center in New York and the University of Washington, Seattle.
The newly identified mutation is a single letter change in the DNA sequence of PAX5. The change results in the amino acid glycine being substituted for serine at amino acid 183 in the PAX5 protein. While PAX5 sequence mutations are common in sporadic cases of ALL, this mutation is the first identified at this location in the protein.
The mutation was discovered by sequencing the exome of normal cells from seven ALL patients in the two families and the exomes of the leukemic cells of four of these patients. The exomes from three relatives unaffected by leukaemia were also sequenced.
Researchers reported that the leukaemia cells all carried a single copy of PAX5 that included the mutation. The patients had all lost the normal version of the gene due to the partial deletion of chromosome 9, where PAX5 is located. The loss resulted in a marked reduction of normal PAX5 activity in the leukaemia cells. In contrast, family members who carried the mutant gene, but who had not developed leukaemia, retained the normal copy of the gene.
Researchers studied 39 other families with a history of multiple tumors, including leukemia, without finding additional inherited PAX5 mutations. The researchers also examined more than 500 additional cases of non-inherited B cell ALL and found mutations at the same position of the PAX5 gene in two more patients. These two individuals had also lost the other copy of PAX5 through partial deletion of chromosome 9 in their leukemic cells. The findings suggested that the PAX5 mutation and deletion of the second, non-mutated copy of PAX5 contribute to the development of leukaemia.
The PAX5 gene encodes a transcription factor, which is a protein that regulates the activity of other genes. Working in cells growing in the laboratory, investigators found evidence that the newly identified PAX5 mutant resulted in reduced expression of genes normally regulated by PAX5 in developing and mature B cells. St. Jude Children’s Research Hospital

Kashin-Beck disease (KBD) and Keshan disease (KD) are major endemic diseases in China. Postgraduate Xi Wang et al., under the guidance of Professor Xiong Guo from the Institute of Endemic Diseases of the Faculty of Public Health, Medicine College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases in Ministry of Education, Key Laboratory of Trace Elements and Endemic Diseases of Health Ministry, set out to tackle these two endemic diseases. After several years of innovative research, they have made significant progress in determining the etiology and pathogenesis of these diseases at a molecular level; in particular, the identification of some common differentially expressed genes.

KBD and KD are distributed from the northeast to the southwest of China, where the selenium content is low in the soil. In China, there are 660000 KBD and 40000 KD patients, and approximately 30 million people are at risk. KBD is an endemic osteoarthropathy, the pathologic changes of KBD included significant alterations in chondrocyte phenotype, necrosis, and apoptosis, and abnormal terminal chondrocyte differentiation. The mainly pathologic changes of KD are multifocal myocardial necrosis and fibrosis that can result in cardiogenic shock and congestive heart failure. KD is an endemic myocardosis that happened in women and pre-schoolers. Since osteoarthritis and myocardium deformities, the most of KBD and KD patients will partially or completely lose their abilities to work even self-care, which seriously reduces their quality of life, and also bring heavy medical burden to society; the etiology and pathogenesis of KBD and KD remain unclear. However, both diseases happened in the same area of China. Moreover, the living conditions of KBD and KD patients are similar, for example, most patients live in remote rural areas and the areas of awful transportation, have a meager income, and a simply diet. There is little research conducted to compare KBD and KD gene expression profiles. Therefore, the two diseases may have a further relationship at the molecular biology level.

In this study, the Agilent Human 1A Oligo microarray was used to compare gene expression profiles of peripheral blood mononuclear cells (PBMCs) between KBD or KD patients and healthy controls, and identified the common genes differentially expressed in both diseases groups. One hundred and thirty-six differentially expressed genes (53 up-regulated and 83 down-regulated) were identified between KBD and normal controls. Moreover, comparing KD and normal controls, 3310 differentially expressed genes (3154 up-regulated and 156 down-regulated) were identified. Comparing all identified differentially expressed genes, 16 genes showed differential expression in both diseases, including nine with synchronous and seven with asynchronous expression. These 16 genes were subdivided into 11 categories, namely metabolism, cytochrome enzymes, transcription-related, G-protein-related, receptor, cytokine factor, ion channel transport protein, signal transduction, hematopoietic related, interleukin, and immune-related.

The distribution of KBD and KD is in the similar geographical regions, although the clinical presentations and target pathological focus are not same. The common differentially expressed genes identified in both KBD and KD could be helpful to identify the potential mechanisms of the different organ lesions, caused by similar environmental risk factors, selenium deficiency. These findings make a great contribution towards clarifying the etiology and pathogenesis of KBD and KD. EurekAlert