Highlights • DPN and CAN are common and disabling complications of diabetes. • Genetic and environmental factors could contribute to diabetic neuropathy susceptibility. • Genetic factors could be ...useful in identifying patients more prone to develop neuropathy.
Pharmacogenomics Novelli, G.; Borgiani, P.; Ciccacci, C. ...
Public health genomics,
01/2010, Letnik:
13, Številka:
5
Journal Article
Recenzirano
Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently defined by the regulatory authorities at an international level as ‘the investigation of variations of ...DNA and RNA characteristics as related to drug response’ (PGx), and the study of ‘the influence of variations in DNA sequence on drug efficacy and toxicity’ (PGt). In recent years a number of studies have in fact produced growing evidence that, besides the effects of age, sex, diseases, and different drugs interactions, genetic factors play a role in the inter-individual variability of drugs response. The increasing genomic knowledge has also raised the profile and role of the so called ‘genomic biomarkers’ (GBs) in drug development, approval, and clinical use. The aims of this review are to (a) revisit the general understanding of the role of genomics and genetics in drug response, (b) provide an update on the definition and classification criteria of GBs as recently defined at a global level by regulatory agencies such as the European Medicines Agency and the Food and Drug Administration, and (c) illustrate with some examples current and potential applications of biomarkers in clinical practice and in drug development.
Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and ...severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype–phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (OR
adj
= 4.89,
P
adj
= 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (OR
adj
= 0.49,
P
adj
= 0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (
p
< 0.001 and
p
= 0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (
p
= 0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (
P
adj
= 0.023 and OR
adj
= 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (
P
adj
= 0.052, OR
adj
= 0.32) and to confirmed CAN (
P
adj
= 0.041, OR
adj
= 0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (
p
= 0.002 and
p
= 0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility.
An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence ...variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.
It is known that warfarin treatment is problematic, due to its narrow therapeutic range and to the great interindividual variability. Numerous papers have shown the important contribution of CYP2C9 ...and VKORC1 genetic variants to this variability. Recently, a new SNP within the CYP4F2 gene was found associated with warfarin dose in the USA.
The aim of our work was to replicate this study in the Italian population and to assess the new CYP4F2 variant relative contribution in explaining warfarin dose variability with respect to CYP2C9 and VKORC1 genetic variants together with age and weight.
CYP4F2 rs2108622 genotyping was performed by allelic discrimination assay by TaqMan technology. Analysis of variance and multiple linear regression analyses were carried out to examine the contribution of genetic and nongenetic factors.
Our TT patients require 5.49 mg/day versus 2.93 mg/day of our CC patients. Analysis of variance indicates that about 7% of mean weekly warfarin dose variance is explained by CYP4F2 genotype. Our linear regression model including CYP4F2, CYP2C9 and VKORC1 genetic variants, age and weight, explains 60.5% of the interindividual variability.
Our data confirm and strengthen the role of this variant.
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