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).