Increased risk for hypertension associated with two gene variants

New data may lead to new therapies to treat hypertension.

Results of a study published in Nature Genetics showed that two common genetic variants at the NPPA-NPPB locus were associated with an increased incidence of hypertension.

The two genes are associated with circulating natriuretic peptide concentrations and may contribute to variations in blood pressure and hypertension.

“It’s well known that hypertension can run in families, and a few rare genetic syndromes that raise BP have been identified. But the common genetic basis for the type of hypertension that affects a billion individuals around the world has been very difficult to establish,” said Christopher Newton-Cheh, MD, MPH, assistant professor of medicine at Harvard Medical School and the Center for Human Genetic Research at Massachusetts General Hospital.

Search for variants

The researchers genotyped single nucleotide polymorphisms at the NPPA-NPPB locus in 14,743 individuals of European ancestry who participated in the Framingham Heart Study. They identified associations of both atrial and B-type natriuretic peptide with rs5068, rs198358 and rs632793. SNPs identified in this first stage were validated in additional Framingham individuals, the Malmö Diet and Cancer study and the Finrisk97 study, totaling 14,743 individuals, and variants associated with changes in natriuretic peptide levels were then tested in the same individuals for any association with BP levels.

The researchers reported that two hypertension-associated SNPs were validated in the Malmö Preventive Project. Two copies of one identified variant were found in almost 90% of the study population and were associated with a 20% reduction of atrial natriuretic peptides and an 18% greater incidence of hypertension. The other variant had a similar, although less pronounced, effect on atrial natriuretic peptide levels and BP.

“It’s likely that many more genes will be found to contribute to changes in BP, and the real challenge will be understanding the mechanism behind their effects. An advantage of these variants is that we know they act by influencing a well-studied pathway that may be modified with therapies that are currently being developed,” said Newton-Cheh.

While it is premature to advocate screening for natriuretic peptide levels or gene variants, the future holds the possibility for treating natriuretic peptide-deficient individuals with therapies to help restore normal levels and ultimately reduce the risk for hypertension, according to the study. – by Katie Kalvaitis

Newton-Cheh C. Nat Genet. 2009;doi:10.1038/ng.328.

The paper by Newton-Cheh and colleagues is a seminal observation linking genetic variance at the NPPA-NPPB locus with natriuretic peptide concentration and BP in the general population. Although the study is based on random Mendelian assortment of alleles, it is unique in identifying a feedback group between the biomarker (atrial natriuretic peptides) and the clinical trait (BP). An increase in systolic BP causes atrial natriuretic peptides release and, conversely, elevated atrial natriuretic peptides levels exert an antihypertensive effect. For many years, investigators have been looking for a single cause of essential hypertension. In the early 1950s, Irvine Page concluded that hypertension resulted from an interaction of multiple pathogenic mechanisms which he called the mosaic theory. Given this fascinating observation, we now have to ask ourselves whether it is merely a pebble (or if you prefer a tessera) in the mosaic or whether it ultimately will turn out to be the single stone replacing the whole mosaic. Provocative data, indeed.

– Franz Messerli, MD

Director, Hypertension Program, Division of Cardiology
St. Luke’s–Roosevelt Hospital, New York