Wild-type CC Genotype Research Articles

BCRP gene polymorphisms are associated with susceptibility and survival of diffuse large B-cell lymphoma

To date, the biological significance of breast cancer resistance protein (BCRP) G34A and C421A polymorphisms is largely unknown. Analysis of these two polymorphisms in 156 diffuse large B-cell lymphoma (DLBCL) patients and 376 control subjects revealed an increased risk of DLBCL associated with variant BCRP 421 genotypes (CA and AA), when compared with the wild-type CC genotype [odds ratio = 1.49, 95% confidence interval (CI) 1.02-2.17, P = 0.042]. Moreover, the increased risk was more evident in younger patients (<or=50 years, odds ratio = 2.14, 95% CI 1.25-3.68, P = 0.006). Further evaluation for the association of these polymorphisms with overall survival of DLBCL showed that patients with 34AA alleles displayed worse survival compared with those carrying GG/GA genotypes [hazard ratio (HR) = 3.69, 95% CI 1.56-8.71, P = 0.001]. Significant association between 421CC genotypes and poorer survival of DLBCL was observed in patients younger at diagnosis (<or=50 years, HR = 5.80, 95% CI 1.16-28.90, P = 0.015) or with bulky tumor (HR = 4.36, 95% CI 1.04-18.31, P = 0.027). Furthermore, we found the combined effects of BCRP G34A and C421A on the overall survival. Compared with patients carrying BCRP 34(GG + GA)421(AA + CA) genotype, the individual with 34AA421CC displayed the worst survival (HR = 7.55, 95% CI 2.36-24.17, P = 0.001), while those with 34(GG + GA)421CC and 34AA421(AA + CA) combinations showed the intermediate survival. These results suggest that the BCRP G34A and C421A polymorphisms are associated with the risk and survival of DLBCL. Our finding warrants further investigations on the association of BCRP polymorphisms with susceptibility and clinical outcome of cancer.

A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus

Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G > T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARG-coactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 -512C > T) and beta3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p = 3.7 x 10(-6), corrected p value [Pc] for multiple testing Pc = 2.2 x 10(-5)). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28-1.75], p = 4.9 x 10(-7) [Pc = 2.8 x 10(-6)]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26-1.93, p = 3.7 x 10(-5) [Pc = 0.0002]) and a 2.1-fold (95% CI 1.41-2.99, p = 0.0001 [Pc = 0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G > T: 1.17 [1.01-1.36], p = 0.039 [Pc = 0.23]; PPARG Pro12Ala: 1.06 [0.87-1.29], p = 0.53; PPARGC1A Gly482Ser: 0.96 [0.83-1.10], p = 0.54; FOXC2 -512C > T: 1.01 [0.87-1.16], p = 0.94; and ADRB3 Trp64Arg: 1.22 [0.95-1.56], p = 0.12). The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.

Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives.

The promise of pharmacogenetics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. Genetic polymorphisms are implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs. The first pharmacogenetic trait identified was monogenic, and concerned the prototypic example of thiopurine methyltransferase (TPMT) implicated in azathioprine metabolism. Individuals with low TPMT activity, inherited in an autosomal codominant fashion, are at risk of drug-induced myelosuppression. TPMT activity determination and DNA-based tests are now used in clinical practice. It has been also demonstrated that there is a link between the polymorphisms of the cytochrome P450 3A5, 3A4 and the multidrug resistance-1 (MDR1) genes, and the daily dose necessary to achieve adequate blood tacrolimus levels. Analysis of MDR1 haplotypes or using the association of the different genes might further improve predictions. Since genotyping methods improve rapidly, it will soon be easy to test for thousands of single nucleotide polymorphisms in one assay. Present challenges are to determine the genes of interest and to validate such determination prospectively in clinical practice.