//////////////////////////////Risk Factors for Pulmonary Hypertension in Sickle Cell Patients

Genetic variants in SCD patients were associated with PH.

People with sickle cell disease (SCD) are homozygous for the glutamic-acid-to-valine substitution in the ß-globin chain of hemoglobin. But the variability in clinical severity of SCD suggests the presence of modifier genes that contribute to disease complications. In fact, one such complication, pulmonary hypertension (PH) — present in up to 30% of adult sickle cell disease patients and linked with considerable morbidity and mortality — has been associated with specific genetic polymorphisms in PH patients (Eur Respir J 2004; 24:371).

To investigate genetic risk factors for PH in SCD patients, investigators collected genotyping samples from 518 unrelated adult patients with sickle cell anemia, SCD, or sickle-thalassemia. PH was defined by echocardiographic demonstration of a tricuspid regurgitation jet velocity >2.5 m/sec or by right-heart catheterization and was present in 44 patients (40%) who underwent one of these procedures. Patients with PH were more likely to be older (P<0.001) and, even after adjustments for age, to have lower hemoglobin concentrations (P=0.03). Single nucleotide polymorphisms (SNPs) were identified using the National Center for Biotechnology Information database and by review of the medical literature. A total of 297 SNPs were identified in 49 candidate genes, including those involved in cell adhesion, signal transduction, coagulation, and nitric oxide biology, as well as those encoding transporters, ion channels, and cytokine receptors. Some of these genes are in the transforming growth factor ß (TGF-ß) superfamily.

A significant association was found between PH and genes predominantly in the TGF-ß family, including the ACVRL1 (activin A receptor-like kinase) and BMP6 (bone morphogenetic protein) genes; a marginally significant association was found for two other TGF-ß genes known as BMPR2 and TGFBR3. A significant association was also found for polymorphisms in the ADRB1 (ß-1 adrenergic receptor) gene. Previous studies have shown that genes in the TGF-ß pathway are associated with stroke, leg ulcers, bacteremia, and priapism in patients with sickle cell disease. Mutations in BMPR2 have been described in persons with primary PH (J Am Coll Cardiol 2004; 43:33S). Polymorphisms in the ACVRL1 gene have been associated with primary PH in families with hereditary hemorrhagic telangiectasia (N Engl J Med 2001; 345:325).

Comment: In many patients, sickle cell disease is a devastating disorder that can lead to frequent hospitalizations and life-threatening complications such as acute chest syndrome. In others, disease is relatively mild (N Engl J Med 2007; 356:642) and is modulated by high levels of hemoglobin F or other hemoglobins. Researchers recently have identified a number of genes, such as those involved in inflammation, that also seem to modify the course of sickle cell disease. PH is a particularly serious complication that has been associated with an increased risk for death in sickle cell patients (N Engl J Med 2004; 350:886). Genetic analyses to identify sickle cell patients at risk for such complications as well as strategies to raise hemoglobin F, prevent cell leakiness, and combat inflammation might improve survival for patients with this disorder.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology July 8, 2008

////////////////////////////////sw=A Moderate Man

Posted: 14 Jul 2008 12:14 PM CDT

The mark of a moderate man
is freedom from his own ideas.
Tolerant like the sky,
all-pervading like sunlight,
firm like a mountain,
supple like a tree in the wind,
he has no destination in view
and makes use of anything
life happens to bring his way.

/////////////////////////////Dr P

Hand on my heart, i could not have been like her. You are absolutely right, we should be contained with what we have. Infact i have seen a similar situation few years ago and have realised that me not having a job i am no way near as unfortunate as the lady caring for her disabled children. Belive me or not i stopped caring about my job since then i just did my best and left the rest. I have been happy since then.

S

////////////////////////////////////////////////////'happiness' is not a destination its a journey