Endothelial nitric oxide synthase gene polymorphism and ischemic heart disease

Background

Ischemic heart disease (IHD), the leading cause of death worldwide, is a multifactorial disease arising from the complex interplay of genetic and environmental factors. There is considerable evidence that nitric oxide (NO) plays an important role in protecting against atherosclerosis, the process underlying IHD. Endothelial NO is synthesized from the amino acid l-arginine by the endothelial isoform of NO synthase (eNOS). Thus, polymorphisms of the eNOS gene, by altering production of NO within the vascular endothelium, are potential risk factors for IHD. Several groups have investigated the role of the G894T polymorphism of the eNOS gene in IHD by using case-control association studies; however, its role is unclear because of contradictory results from these studies. We applied family-based association tests to investigate the role of this polymorphism in IHD in a well-defined Irish population.

Methods

A total of 1023 individuals from 388 families (discordant sibships and parent-offspring trios) were recruited. Linkage disequilibrium between the polymorphism and IHD was tested for by using the combined transmission disequilibrium test/sib-transmission disequilibrium test and pedigree disequilibrium test.

Results

Both the combined transmission disequilibrium test/sib-transmission disequilibrium test and pedigree disequilibrium test analyses found no statistically significant excess transmission of either allele to affected individuals (P = .57 and P = .38, respectively).

Conclusions

Using robust family-based association tests specifically designed for the study of complex diseases, we found no evidence that the G894T polymorphism of the eNOS gene has a significant role in the development of IHD in our population.     

The influence of surface modification on the cytotoxicity of PAMAM dendrimers

The influence of surface modification on the cytotoxicity of PAMAM dendrimers was examined using Caco-2 cells. Dendrimers were modified by conjugating either lauroyl chains or polyethylene glycol (PEG) 2000 onto the surface of cationic PAMAM dendrimers (G2, G3, G4).The cytotoxicity of unmodified dendrimers towards Caco-2 cells was appreciably higher for cationic (whole generation) compared with anionic (half generation) dendrimers and for both types increased with increasing size (generation) and concentration. A marked decrease in the cytotoxicity of cationic PAMAM dendrimers was noted when the surface was modified, with the addition of six lauroyl or four PEG chains being particularly effective in decreasing cytotoxicity. This decrease in cytotoxicity is thought to be due to a reduction/shielding of the positive charge on the dendrimer surface by the attached chains. The cytotoxicity of dendrimer-based delivery systems is likely to be very different from the parent dendrimer.