New Genes Associated with Blood Pressure and Hypertension

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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 [1]. 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. A new study in the journal Nature Genetics reports for the first time a number of genes showing significant associations with blood pressure and hypertension across the genome [2].

Although large-scale genome-wide association studies (GWAS) have been used successfully to identify genes associated with common diseases and traits, 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.

The 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 [4]. 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)

According to Dr. Aravinda Chakravarti, Ph.D., head of the Center for Complex Disease Genomics in the McKusick-Nathans Institute of Genetic Medicine at Hopkins [3]:

Strikingly, none of the genes we identified as having common variation are part of the system we know about that regulates blood pressure — the genes identified are not the ones targeted by current prescription drugs to control hypertension. If we can increase the number of genes implicated in blood pressure maintenance from the current 12 to the expected 50 in the next year, our understanding of the biology will change completely.

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).

Prevention

Consistently elevated blood pressure increases the risk of stroke, heart attack and kidney failure, among other conditions. Although genetics affects blood pressure, the environment — diet, physical activity, stress — also play a substantial role. You can take steps to prevent high blood pressure by adopting a healthy lifestyle. These steps include:

• Maintaining a healthy weight
• Being physically active
• Eating healthy (fruits, vegetables and lowfat dairy foods)
• Reducing salt and sodium in your diet
• If you drink alcohol, drink in moderation
• Quitting smoking

References

1. High Blood Pressure. The American Heart Association. Accessed 2009 May 25.
2. Levy et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009 May 10. [Epub ahead of print] DOI: 10.1038/ng.384
   View abstract
3. New genes implicated in high blood pressure. Johns Hopkins Medicine press release. 2009 May 10.
4. Newton-Cheh et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009 May 10. [Epub ahead of print]
   View abstract