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Gene for primary pulmonary hypertension identified
SCIENCE AND MEDICINE
Gene for primary pulmonary hypertension identified wo research groups report that they have identified the genetic cause for familial primary pulmonary hypertension (PPH) and have found evidence that the same gene is involved in many cases of the sporadic form of the disease. The reports will not appear in print until September, but have been posted on the internet because of the substantial interest in the findings. The cause of PPH has long been a mystery. It is thought to develop in response to injury when the endothelial and smooth muscle cells of the pulmonary precapillary arteries begin to proliferate abnormally, narrowing the vessels and gradually choking off blood flow. As the disease progresses, the vascular changes cause hypoxia and a rise in pulmonary vascular resistance, resulting in a fall in cardiac output. Patients typically die an average of 2–3 years after diagnosis, usually of right heart failure or sudden death. Current treatments can improve symptoms and extend life to a certain extent, but lung transplantation is the only cure.
T
injury normally “and they begin to In the new studies, investigators grow like a slow cancer”. William looked for the gene responsible for Nichols (Cincinnati, OH, USA), who the familial form of the disease, is a member of which accounts for the International about 6% of cases. Rights were not P r i m a r y Familial PPH Pulmonary disease is inherited granted to include this Hypertension in an autosomal image in electronic Consortium dominant pattern which did the secbut with incommedia. Please refer to ond study due to plete penetrance, the printed journal. b e meaning not all published in people who inherit September(Nat the gene develop Genet 2000, in disease. They Blocked precapillary artery in PPH press), says a folidentified a gene low-up study by his colleagues sugon chromosome 2 which codes for a gests that at least one in four patients receptor called bone morphogenetic with sporadic PPH also have mutaprotein receptor II (PMPR2), which tions in PMPR2. That study, to be belongs to the family of transforming published in October (J Med Genet growth factor  type-II receptors. 2000, in press), found that of 50 These inhibit cell growth and play a patients with sporadic forms of the crucial role in normal embryological disease, 13 had PMPR2 mutations. development. James Knowles (New “Many ‘sporadics’ are familial”, York, USA), an investigator of one of Nichols warns, “and others in their the studies (www.ajhg.org/journal/ families may be at risk”. rapid.html), says it appears the mutations in PMPR2 make pulmonary endothelial cells unable to respond to Michael McCarthy
“Infectious-fat” hypothesis gains weight
T
he team that published data linking human adenovirus-36 (Ad-36) with obesity have now reported that the same virus increases adiposity in animal models, sparking further controversy on whether fat can be an infectious issue. To date, four animal viruses have been linked with obesity in their hosts. Nikhil Dhurandhar (Wayne State University, Detroit, MI, USA) and colleagues reported previously that obese people are more likely to have antibodies against Ad-36, and that obese antibody-positive individuals have lower serum cholesterol and triglycerides compared
with obese antibody-negative individuals. Further studies showed that Ad-36 can induce differentiation in adipocytes. They now report the effect of Ad-36 inoculation on adiposity in four studies in chickens or mice compared with weightmatched controls . “Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue and paradoxically low levels of serum cholesterol and triglycerides”, write the investigators (Int J Obesity 2000; 24: 989–96). For example, chickens infected with AD-36 had 2·47% visceral fat and 7·8% total body fat, while a control group that received tissue
“First-born effect” may explain obesity in later life Obesity is a major public-health issue in the USA, yet the causes of it are still unclear. New research, however, has identified risk factors at birth that may predispose an individual to obesity later in life (Am J Clin Nut 2000; 71: 378–83). Nicolas Stettler and colleagues (The Children’s Hospital of Philadelphia, PA, USA) followed up a group of African American neonates to early adulthood. “Three variables measured at birth were independently associated with obesity in young adulthood”, explains Stettler. Of particular significance is the finding that the individuals who are first born in the family are more likely to become obese than their siblings; other risk factors were maternal obesity and female sex. “The reason for this ‘first-born effect’ is unclear”, says Stettler, but by knowing the risk factors involved, “there might be some room for intervention and prevention”.
culture media had mean proportions of 1·08% and 11·4%, respectively, despite equal food intakes. Ad-36 DNA persisted in adipose tissue but not skeletal muscle. Dhurandhar believes that “if the role of Ad-36 in human obesity is established, next steps would be to study the effect of antivirals on such obesity and/or to develop a vaccine to prevent Ad-36-induced obesity”. Some experts remain sceptical, however. Craig Pringle (University of Warwick, UK) comments in a Promed-MAIL internet posting (www.promedmail.org) that the observation “requires independent verification”, particularly as the choice of Ad-36 is “unusual”, he suggests. However, Johan Auwerx (Institut de Génétique et Biologie Moléculaire et Cellulaire, France) notes that evidence is accumulating that “adipose tissue has a function in the immune response . . . it is very well possible that particular viruses induce a response which instead of relying strictly on the classical immune system rather involves adipose tissue”.
Sally Hargreaves Kelly Morris
THE LANCET • Vol 356 • August 5, 2000
489
For personal use only. Not to be reproduced without permission of The Lancet.
Gene for primary pulmonary hypertension identified wo research groups report that they have identified the genetic cause for familial primary pulmonary hypertension (PPH) and have found evidence that the same gene is involved in many cases of the sporadic form of the disease. The reports will not appear in print until September, but have been posted on the internet because of the substantial interest in the findings. The cause of PPH has long been a mystery. It is thought to develop in response to injury when the endothelial and smooth muscle cells of the pulmonary precapillary arteries begin to proliferate abnormally, narrowing the vessels and gradually choking off blood flow. As the disease progresses, the vascular changes cause hypoxia and a rise in pulmonary vascular resistance, resulting in a fall in cardiac output. Patients typically die an average of 2–3 years after diagnosis, usually of right heart failure or sudden death. Current treatments can improve symptoms and extend life to a certain extent, but lung transplantation is the only cure.
T
injury normally “and they begin to In the new studies, investigators grow like a slow cancer”. William looked for the gene responsible for Nichols (Cincinnati, OH, USA), who the familial form of the disease, is a member of which accounts for the International about 6% of cases. Rights were not P r i m a r y Familial PPH Pulmonary disease is inherited granted to include this Hypertension in an autosomal image in electronic Consortium dominant pattern which did the secbut with incommedia. Please refer to ond study due to plete penetrance, the printed journal. b e meaning not all published in people who inherit September(Nat the gene develop Genet 2000, in disease. They Blocked precapillary artery in PPH press), says a folidentified a gene low-up study by his colleagues sugon chromosome 2 which codes for a gests that at least one in four patients receptor called bone morphogenetic with sporadic PPH also have mutaprotein receptor II (PMPR2), which tions in PMPR2. That study, to be belongs to the family of transforming published in October (J Med Genet growth factor  type-II receptors. 2000, in press), found that of 50 These inhibit cell growth and play a patients with sporadic forms of the crucial role in normal embryological disease, 13 had PMPR2 mutations. development. James Knowles (New “Many ‘sporadics’ are familial”, York, USA), an investigator of one of Nichols warns, “and others in their the studies (www.ajhg.org/journal/ families may be at risk”. rapid.html), says it appears the mutations in PMPR2 make pulmonary endothelial cells unable to respond to Michael McCarthy
“Infectious-fat” hypothesis gains weight
T
he team that published data linking human adenovirus-36 (Ad-36) with obesity have now reported that the same virus increases adiposity in animal models, sparking further controversy on whether fat can be an infectious issue. To date, four animal viruses have been linked with obesity in their hosts. Nikhil Dhurandhar (Wayne State University, Detroit, MI, USA) and colleagues reported previously that obese people are more likely to have antibodies against Ad-36, and that obese antibody-positive individuals have lower serum cholesterol and triglycerides compared
with obese antibody-negative individuals. Further studies showed that Ad-36 can induce differentiation in adipocytes. They now report the effect of Ad-36 inoculation on adiposity in four studies in chickens or mice compared with weightmatched controls . “Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue and paradoxically low levels of serum cholesterol and triglycerides”, write the investigators (Int J Obesity 2000; 24: 989–96). For example, chickens infected with AD-36 had 2·47% visceral fat and 7·8% total body fat, while a control group that received tissue
“First-born effect” may explain obesity in later life Obesity is a major public-health issue in the USA, yet the causes of it are still unclear. New research, however, has identified risk factors at birth that may predispose an individual to obesity later in life (Am J Clin Nut 2000; 71: 378–83). Nicolas Stettler and colleagues (The Children’s Hospital of Philadelphia, PA, USA) followed up a group of African American neonates to early adulthood. “Three variables measured at birth were independently associated with obesity in young adulthood”, explains Stettler. Of particular significance is the finding that the individuals who are first born in the family are more likely to become obese than their siblings; other risk factors were maternal obesity and female sex. “The reason for this ‘first-born effect’ is unclear”, says Stettler, but by knowing the risk factors involved, “there might be some room for intervention and prevention”.
culture media had mean proportions of 1·08% and 11·4%, respectively, despite equal food intakes. Ad-36 DNA persisted in adipose tissue but not skeletal muscle. Dhurandhar believes that “if the role of Ad-36 in human obesity is established, next steps would be to study the effect of antivirals on such obesity and/or to develop a vaccine to prevent Ad-36-induced obesity”. Some experts remain sceptical, however. Craig Pringle (University of Warwick, UK) comments in a Promed-MAIL internet posting (www.promedmail.org) that the observation “requires independent verification”, particularly as the choice of Ad-36 is “unusual”, he suggests. However, Johan Auwerx (Institut de Génétique et Biologie Moléculaire et Cellulaire, France) notes that evidence is accumulating that “adipose tissue has a function in the immune response . . . it is very well possible that particular viruses induce a response which instead of relying strictly on the classical immune system rather involves adipose tissue”.
Sally Hargreaves Kelly Morris
THE LANCET • Vol 356 • August 5, 2000
489
For personal use only. Not to be reproduced without permission of The Lancet.