Source: Massachusetts General Hospital
Date: 15 February 2009
Common gene variants increase risk of hypertension, may lead to new therapies
Mark Henderson and Sam Lister
A new study has identified the first common gene variants associated with an increased incidence of hypertension - a significant risk factor for heart attack, stroke and kidney failure. The report receiving early online release in the journal Nature Genetics identifies variants in genes for proteins involved with cardiovascular response to stress that also appear to influence blood pressure levels, an association previously seen in animals but not demonstrated in humans.
"It's well known that hypertension can run in families, and a few rare genetic syndromes that raise blood pressure 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," says Christopher Newton-Cheh, MD, MPH of the Massachusetts General Hospital (MGH) Center for Human Genetic Research and Cardiovascular Research Center, first author of the Nature Genetics report.
To search for hypertension-associated variants, the investigators focused on two genes called NPPA and NPPB that are involved in the production of atrial and B-type natriuretic peptides (ANP and BNP) - proteins known to relax blood vessels and to be involved in the excretion of dietary sodium. Animals in which both copies of NPPA have been knocked out are hypertensive, and even those with a single functional copy will develop hypertension on a high-sodium diet.
The overall study involved analyzing genetic data from almost 30,000 individuals. The researchers first screened 1,700 participants in the Framingham Heart Study for 13 common variations - called single-nucleotide polymorphisms (SNPs) - in the NPPA and NPPB genes, looking for any correlation with levels of ANP and BNP. SNPs identified in that first stage were validated in three other study groups, including participants from Sweden and Finland; and variants associated with changes in natriuretic peptide levels were then tested in the same individuals for any association with blood pressure levels.
Results of that third stage - which suggested two hypertension-associated SNPs - were validated in another study group. One identified variant, found in almost 90 percent of the population, was associated with a 20 percent reduction of ANP levels and an 18 percent greater incidence of hypertension. The other variant had a similar although less pronounced effect on ANP levels and blood pressure.
"Natriuretic peptides are known to be produced by the heart when it is stressed, and screening for peptide levels is widely used to diagnose heart failure, a condition in which they are sharply elevated," says senior author Thomas Wang, MD, of the MGH Cardiology Division. "It's currently premature to advocate screening natriuretic peptide levels or gene variants to diagnose hypertension risk, but someday it may be possible to treat natriuretic-peptide-deficient individuals with therapies that restore normal levels and reduce risk."
Newton-Cheh adds, "It's likely that many more genes will be found to contribute to changes in blood pressure, 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." He and Wang are both assistant professors of Medicine at Harvard Medical School and were co-corresponding authors on the paper.
“You wait till Larry comes and I tell him my theory!” The bids, duly sealed, were given into the keeping of the commissary officer to be put in his safe, and kept until the day of judgment, when all being opened in public and in the presence of the aspirants, the lowest would[Pg 188] get the contract. It was a simple plan, and gave no more opportunity for underhand work than could be avoided. But there were opportunities for all that. It was barely possible—the thing had been done—for a commissary clerk or sergeant, desirous of adding to his pittance of pay, or of favoring a friend among the bidders, to tamper with the bids. By the same token there was no real reason why the commissary officer could not do it himself. Landor had never heard, or known, of such a case, but undoubtedly the way was there. It was a question of having the will and the possession of the safe keys. "Well, I believe our boys 's all right. They're green, and they're friskier than colts in a clover field, but they're all good stuff, and I believe we kin stand off any ordinary gang o' guerrillas. I'll chance it, anyhow. This's a mighty valuable train to risk, but it ought to go through, for we don't know how badly they may need it. You tell your engineer to go ahead carefully and give two long whistles if he sees anything dangerous." "Fine-looking lot of youngsters," he remarked. "They'll make good soldiers." "That's just what he was, the little runt, and we had the devil's own time finding him. What in Sam Hill did the Captain take him for, I'd like to know? Co. Q aint no nursery. Well, the bugler up at Brigade Headquarters blowed some sort of a call, and Skidmore wanted to know what it meant. They told him that it was an order for the youngest man in each company to come up there and get some milk for his coffee tomorrow morning, and butter for his bread. There was only enough issued for the youngest boys, and if he wanted his share he'd have to get a big hustle on him, for the feller whose nose he'd put out o' joint 'd try hard to get there ahead o' him, and get his share. So Skidmore went off at a dead run toward the sound of the bugle, with the boys looking after him and snickering. But he didn't come back at roll-call, nor at tattoo, and the smart Alecks begun to get scared, and abuse each other for setting up a job on a poor, innocent little boy. Osc Brewster and Ol Perry, who had been foremost in the trick had a fight as to which had been to blame. Taps come, and he didn't get back, and then we all became scared. I'd sent Jim Hunter over to Brigade Headquarters to look for him, but he came back, and said they hadn't seen anything of him there. Then I turned out the whole company to look for him. Of course, them too-awfully smart galoots of Co. A had to get very funny over our trouble. They asked why we didn't get the right kind of nurses for our company, that wouldn't let the members stray out of their sight? Why we didn't call the children in when the chickens went to roost, undress 'em, and tuck 'em in their little beds, and sing to 'em after they'd said 'Now I lay me down to sleep?' I stood it all until that big, hulking Pete Nasmith came down with a camp-kettle, which he was making ring like a bell, as he yelled out, 'Child lost! Child lost!' Behind him was Tub Rawlings singing, 'Empty's the cradle, baby's gone.' Then I pulled off my blouse and slung it into my tent, and told 'em there went my chevrons, and I was simply Scott Ralston, and able to lick any man in Co. A. One o' their Lieutenants came out and ordered them back to their quarters, and I deployed the company in a skirmish-line, and started 'em through the brush toward Brigade Headquarters. About three-quarters o' the way Osc Brewster and Ol Perry, when going through a thicket, heard a boy boo-hooing. They made their way to him, and there was little Skidmore sitting on a stump, completely confused and fagged out. He'd lost his way, and the more he tried to find it the worse he got turned around. They called out to him, and he blubbered out: 'Yes, it's me; little Pete Skidmore. Them doddurned fools in my company 've lost me, just as I've bin tellin' 'em right along they would, durn 'em.' Osc and Ol were so tickled at finding him that they gathered him up, and come whooping back to camp, carrying him every step of the way." And the rush stopped. Cadnan waited for a second, but there was no more. "Dara is not to die," he said. Then he saw Orion hanging over him, very low in the windy sky, shaking with frost. His eyes fixed themselves on the constellation, then gradually he became aware of the sides of a cart, of the smell of straw, of the movement of other bodies that sighed and stirred beside him. The physical experience was now complete, and soon the emotional had shaped itself. Memory came, rather sick. He remembered the fight, his terror, the flaming straw, the crowd that constricted and crushed him like a snake. His rage and hate rekindled, but this time without focus—he hated just everyone and everything. He hated the wheels which jolted him, his body because it was bruised, the other bodies round him, the stars that danced above him, those unknown footsteps that tramped beside him on the road. Farewell to Jane and Caroline!" HoME大香蕉色人阁
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