Using genome-wide association for the first time to scan for genes implicated in high blood pressure, and studying both Amish and non-Amish people, US scientists have discovered a gene involved in regulating how kidneys process salt whose variant they suggest is linked to high blood pressure risk.
The study was the work of senior author, Dr Yen-Pei Christy Chang, an assistant professor of medicine and of epidemiology and preventive medicine at the University of Maryland School of Medicine, in Baltimore, US, and colleagues from other research centres in the US, and is published online before print on December 29 in the Proceedings of the National Academy of Sciences, PNAS.
In their background information the authors explained that while high blood pressure is an enormous public health concern, very little is known about the genetic basis of this complex condition.
About a quarter of Americans have high blood pressure, which puts them at higher risk of early death or diseases such as stroke and end-stage kidney disease. High blood pressure is usually treated with changes to diet and lifestyle plus medication like diuretics to help the kidneys remove Sodium ions (Na+) from the body. However, patients respond differently to treatments, so studies like this one may help to find out why.
Chang and colleagues conducted a genome wide association study of 542 members of the Old Order Amish community in Lancaster County, Pennsylvania. They analysed over 100,000 bits of each subject’s DNA (known as single nucleotide polymorphisms, or SNPs), and compared the results to their diastolic and systolic blood pressure.
They found what they described as “strong association signals” with common variants of STK39, the serine/threonine kinase gene, and they confirmed their findings via a meta-analysis that pooled the results of over 7,000 subjects that included another independent Amish group and four non-Amish Caucasian groups in the US and Europe.
They found that people who carried one variant of STK39 had slightly higher blood pressure compared to people with a more common version of the gene, and they were also more likely to develop high blood pressure.
Chang and colleagues estimated that about 20 per cent of Caucasians carry the STK39 variant.
STK39 occurs on chromosome 2 and codes for a protein that helps the kidneys to process Sodium ions (Na+), an element that is directly involved in blood pressure control.
The authors referred to studies that have looked at how STK39 interacts with certain proteins called WNK kinases and transporters of elements that combine with chlorine (such as Sodium ions) and found that certain variants are linked to poor regulation of blood pressure. In this study Chang and colleagues go some way to showing how STK39 is expressed in a part of the kidney where it may interact with these proteins.
They wrote that although none of the associated bits of DNA that they identified actually altered protein structure:
“Variants in STK39 may influence BP [blood pressure] by increasing STK39 expression and consequently altering renal Na+ excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.”
Speaking about the implications of their findings, Chang said that:
“This discovery has great potential for enhancing our ability to tailor treatments to the individual — what we call personalized medicine — and to more effectively manage patients with hypertension.”
“We hope that it will lead to new therapies to combat this serious public health problem worldwide,” she added.
However, the researchers said there is still a lot of work to be done before treatments can be developed. Blood pressure is not simple to understand, there are lots of factors involved, not just genetic but also environmental and lifestyle related.
“The STK39 gene is only one important piece of the puzzle,” said Chang.
“We want to determine how people with different variations of this gene respond to diuretics and other medications, or to lifestyle changes, such as reducing the amount of salt in their diet. This information might help us discover the most effective way to control an individual patient’s blood pressure,” she explained.
“Whole-genome association study identifies STK39 as a hypertension susceptibility gene.”
Ying Wang, Jeffrey R. O’Connell, Patrick F. McArdle, James B. Wade, Sarah E. Dorff, Sanjiv J. Shah, Xiaolian Shi, Lin Pan, Evadnie Rampersaud, Haiqing Shen, James D. Kim, Arohan R. Subramanya, Nanette I. Steinle, Afshin Parsa, Carole C. Ober, Paul A. Welling, Aravinda Chakravarti, Alan B. Weder, Richard S. Cooper, Braxton D. Mitchell, Alan R. Shuldiner, and Yen-Pei C. Chang.
PNAS published online before print December 29, 2008.
doi:10.1073/pnas.0808358106
Sources: Journal abstract, University of Maryland Medical Center.
Written by: Catharine Paddock, PhD