Baltimore, MD - US researchers have identified a novel gene in a population of Amish that is associated with essential hypertension [1]. The serine/threonine gene, STK39, found on chromosome two, is expressed in the nephrons of the kidney, and Dr Ying Wang (University of Maryland School of Medicine, Baltimore) and colleagues believe that common variations in this gene may influence blood pressure by altering sodium excretion.

The report is published online December 29, 2008 in the Proceedings of the National Academy of Sciences.

Wang told heartwire that the research has two important implications. "First, the protein associated with the gene, SPAK (Ste20-related proline-alanine-rich kinase protein), could be a new drug target, and second, we know that SPAK regulates sodium transporters, specifically those targeted by thiazide diuretics. So identifying those with this common variation in STK39 could help predict who will best respond to thiazide diuretics and have the fewest side effects or those who will best respond to salt reduction."

Genomics expert Dr Eric Topol (Scripps Translational Research Institute, La Jolla, CA) told heartwire that this is the first genomewide-association study (GWAS) for blood pressure and hypertension to have come up with anything at all. "The current . . . study identifies a gene that has a modest effect on BP (3 mm Hg on systolic) [and is] the first time a common variant has been significantly associated, with independent replication, for blood pressure."

Wang et al first pinpointed the gene and variants—known as single nucleotide polymorphisms (SNPs)—using a GWAS of an Amish population in Pennsylvania. The Old Order Amish are a closed founder population who immigrated to the US from Switzerland during the early 1700s; its members are descendents of a small number of common founders, sharing a relatively homogeneous lifestyle, making it an ideal population in which to identify genes that underlie complex diseases, they explain.

In the Amish subjects, those with common variations in STK39 had a higher systolic blood pressure, by 3.3 mm Hg on average, and a slightly higher diastolic blood pressure—1.3 mm Hg—than those without the variants.

The findings were confirmed in an independent Amish and four non-Amish white subject samples, including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (a meta-analysis combining all studies: n=7125).

The finding may ultimately help guide some patients to more suitable therapy, in this case a specific type of diuretic.

Wang told heartwire that the effects of the variants "were stronger in the Amish than in the other populations, we don't know why," and also in older people compared with younger people. The average systolic BP in those non-Amish with the variant was around 2 mm Hg greater than those without it, she noted.

She estimates that around 20% of whites will have at least one copy of the variant, with only 1% to 2% being homozygous. As would be expected, homozygotes had an even higher systolic BP, on average around 6 to 7 mm Hg higher than those without the variant, she explained.

In conclusion, Wang said these results require further confirmation and replication, especially in nonwhite populations. "But this is a step toward personalized medicine," she noted.

Topol commented: "While the effect is small and the precise functional SNP is not clear, the authors correctly point out that the finding may ultimately help guide some patients to more suitable therapy, in this case a specific type of diuretic."