Gene Variants Linked to Hypertension

By Michael Smith

BALTIMORE, 12 jan 2009 -- Gene variants have been associated with essential hypertension, a step toward individualized treatment for high blood pressure, according to researchers here. The serine threonine kinase 39 gene, or STK39, encodes a protein that is thought to be involved in renal electrolyte transport, found Yen-Pei Christy Chang, Ph.D., of the University of Maryland, and colleagues. Common variants of STK39 are associated with increases in both systolic and diastolic pressures and might help clinicians predict response to salt reduction or diuretics, Dr. Chang and colleagues said online in the Proceedings of the National Academy of Sciences. "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," Dr. Chang said. "This information might help us discover the most effective way to control an individual patient's blood pressure," she added, although she cautioned that more research is needed. "Hypertension is a very complex condition, with numerous other genetic, environmental, and lifestyle factors involved," Dr. Chang said. "The STK39 gene is only one important piece of the puzzle." The finding emerged originally from a genome-wide association study of 542 members of a cohort of Old Order Amish volunteers, the Amish Family Diabetes Study. The researchers found clusters of single nucleotide polymorphisms (SNPs) -- single letter changes in the genetic code -- within the STK39 gene on chromosome two that were associated with systolic blood pressure. The associations were significant with values ranging from P=8.9x10-6 to P=9.1x10-5. Similar but slightly lower associations were found for diastolic pressure. SNPs within the two clusters appeared to be inherited together, so the researchers chose one from each group -- dubbed rs6749447 and rs3754777 -- as surrogates for use in replication studies. In the 557 remaining members of the Amish cohort, Dr. Chang and colleagues found, the associations with the two SNPs were also significant (at P=0 .003 for rs6749447 and P=0.02 for rs3754777). In an independently collected Amish cohort, the two SNPs were also significantly linked with systolic blood pressure, at P0.0001. When all three Amish groups were considered together, the researchers estimated that having one copy of the minor allele was associated with a 3.0 mmHg higher systolic blood pressure and a 1.0 mm Hg higher diastolic pressure. The researchers also looked at available genomic data from two large non-Amish cohorts -- the Framingham Heart Study and the Diabetes Genetics Initiative -- and found similar significant associations in the same direction. Data from two smaller studies showed a similar trend and effect size but did not reach significance, Dr. Chang and colleagues said. However, the researchers said, all six studies combined provided "compelling evidence of association" -- at P=1.6x10-7 for rs6749447 and P=2.3x10-6 for rs3754777 -- with an estimated effect size for the minor alleles of 2.0 mmHg for systolic and 1.0 mmHg for diastolic blood pressure. The identified variations do not appear to alter the structure of the protein -- dubbed SPAK -- that's encoded by STK39, the researchers said, but may affect how much of it is produced. Since emerging evidence indicates that SPAK is involved in renal electrolyte transport, more of it may increase intravascular volume and, therefore, blood pressure, they said. "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," Dr. Chang said. "We hope that it will lead to new therapies to combat this serious public health problem worldwide." The study was supported by the NIH. The researchers reported no conflicts.

Primary source: Proceedings of the National Academy of Sciences Source reference: Wang Y, et al "Whole-genome association study identifies STK39 as a novel hypertension susceptibility gene" PNAS 2008; DOI: 10.1073/pnas.0808358106.