GWAS establishing links in HYPERTENSION..

High blood pressure or hypertension affects more than one in three people worldwide and is a major cause of strokes, heart attacks and heart failure .In USA alone About 74.5 million people in the United States age 20 and older have high blood pressure.  The degree with which blood pressure traits can be inherited suggests a genetic component. However, limited consistent evidence of genes associated with blood pressure have been produced.  large-scale genome-wide association studies (GWAS) have been used successfully to identify genes associated with common diseases and traits,however  studies on blood pressure or hypertension have failed to identify loci at a genome-wide significant threshold (p-value < 5 x 10^-8). The significance of GWAS data relies on several variables, including the accuracy of phenotypic measures, density of markers and size of the study population. Thus, if blood pressure variation in the general population is due to multiple genetic factors with small effects, a very large sample size is needed to identify them.

Researchers at the Johns Hopkins University School of Medicine, along with an international team of collaborators, established the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium to address the need for a very large sample size. The CHARGE Consortium was formed to “facilitate genome-wide association study meta-analyses and replication opportunities among multiple large and well-phenotyped longitudinal cohort studies.” In other words, they’re combining data from a number of large GWAS studies that collect data in a standardized fashion to perform a “study of studies”. The Consortium consists of almost 30,000 people of European descent whose average systolic blood pressure (meaning the blood pressure when the heart is contracting) ranged from 118 mm Hg to 143 mm Hg and average diastolic blood pressure (meaning the blood pressure when the heart relaxes between beats) ranged from 72 mm Hg to 83 mm Hg.

Using data from the CHARGE Consortium, scientists report that they have identified a number of single nucleotide polymorphisms (SNPs) for blood pressure and hypertension that just missed the significance threshold for GWAS.

he top ten CHARGE SNPs for systolic blood pressure, diastolic blood pressure and hypertension were then included in a joint meta-analysis with the Global Blood Pressure Genetics (Global BPgen) Consortium consisting of another 34,000 people of European ancestry published in the same issue of the journal Nature Genetics . Eleven CHARGE genes showed significant associations across the genome, attaining genome-wide significance (p-value < 5 x 10^-8).

Four CHARGE loci attained genome-wide significance for systolic blood pressure:

• ATPase, Ca(2+)-transporting, Plasma membrane (ATP2B1)
• Cytochrome P450, Family 17, Subfamily A, Polypeptide 1 (CYP17A1)
• Pleckstrin homology domain-containing protein, Family A, Member 7 (PLEKHA7)
• SH2B adaptor protein 3 (SH2B3)

Six CHARGE loci attained genome-wide significance for diastolic blood pressure:

• ATPase, Ca(2+)-transporting, Plasma membrane (ATP2B1)
• Calcium channel, Voltage-dependent, Beta-2 subunit (CACNB2)
• Cytoplasmic tyrosine kinase (CSK) – Unc51-like kinase 3 (ULK3)
• SH2B adaptor protein 3 (SH2B3)
• T-Box 3 (TBX3) – T-Box 5 (TBX5)
• Unc51-like kinase 4 (ULK4)

One CHARGE loci attained genome-wide significance for hypertension:

• ATPase, Ca(2+)-transporting, Plasma membrane (ATP2B1)

One gene in particular, ATP2B1 was linked to all three traits: systolic blood pressure, diastolic blood pressure and hypertension. The gene ATP2B1 encodes a plasma membrane protein that pumps calcium out of cells that line the vascular endothelium – the thin layer of cells that line the inside of blood vessels. A high concentration of intracellular calcium causes endothelial cells to contract, constricting the blood vessel and reducing flow. This is why calcium channel blockers are frequently prescribed to lower blood pressure. Thus, it’s not surprising to find a calcium-specific protein pump in the list of genes associated with blood pressure and hypertension .SH2B adaptor protein 3 (SH2B3) was associated with both systolic and diastolic blood pressure. The SH2B3 gene encodes a protein that mediates the interaction between extracellular receptors and intracellular signaling pathways. In addition, there is evidence that SH2B3 is involved in controlling adaptive immune responses. SH2B also regulates proliferation of several hematopoietic cell lineages (meaning blood cells).

New links established between DNA damage and tumour suppression!

p53   encoded by the TP53 gene is very important in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome".
However recently NCI scientists have linked p53  with TRF2, a protein that forms a complex that protects the ends of chromosomes from undergoing erosion. The ends of chromosomes are known as telomeres, and these end-pieces have been shown to influence cell longevity as well as cancer.  While activated p53 can be an indicator of DNA damage due to telomere malfunction, this study is the first to show that p53 also functions by negatively regulating the telomere-binding protein TRF2, thus suggesting the presence of a novel feedback loop. The study, lead by Curtis C. Harris, M.D., with coworkers Kaori Fujita, Ph.D., and Izumi Horikawa, M.D., of the Laboratory of Human Carcinogenesis, Center for Cancer Research.
Telomeres are capped at each end to protect them from degrading and from being recognized as damaged DNA. At the end of their lifespan, telomeres lose this protection and DNA-damage signaling pathways are triggered that activate p53. Harris and his team found that p53 controls TRF2 levels, through an intermediary component known as Siah-1. In this experiment, TRF2 was found to be repressed and Siah-1 was induced in normal human tissue cells when p53 was activated. The scientists also found that p53 affects DNA damage signaling from uncapped telomeres, as well as regulating the telomere-capping complex. This suggests that the p53-Siah-1-TRF2 pathway plays an integral part in orchestrating the DNA damage response of telomeres. Both p53 and telomeres have therapeutic significance in cancer. This discovery, therefore, provides not only a new mechanistic insight into p53- and telomere-based cancer therapeutics currently used or tested, but also the experimental basis for the development of new therapies, according to the scientists.
This can later prove to be a landmark link in cancer therapies.

New Ray of Hope for diabetics!

Type 2 diabetes comprises 90% of people with diabetes around the world, and is largely the result of excess body weight and physical inactivity.this fatal disease becoming a major epidemic for the world community which is already the burden of epidemics of aids , hypertension related disorders etc.

But a new discovery in Japan might be boon for type 2 Diabetics where a  hormone produced  and secreted by liver previously known for insulin resistance is the new focus. The discovery may be a new target for the treatment of insulin resistance and type 2 diabetes."The current study sheds light on a previously underexplored function of the liver; the liver participates in the pathogenesis of insulin resistance through hormone secretion," said Hirofumi Misu of Kanazawa University in Japan.

The researchers had discovered earlier that genes encoding secretory proteins are abundantly expressed in the livers of people with Type 2 diabetes. Now, the researchers reported the results of comprehensive gene expression analyses, revealing that the liver expresses higher levels of the gene encoding selenoprotein P (SeP) in people with type 2 diabetes who are more insulin resistant.

Further studies in mice added support to the notion that the connection between SeP and insulin resistance is causal. When the researchers gave normal mice SeP, they became insulin resistant and their blood sugar levels rose. 

A treatment that blocked the activity of SeP in the livers of diabetic and obese mice improved their sensitivity to insulin and lowered blood sugar levels.