Homozygous Carriers Of Wild-type Allele Research Articles

Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation

BackgroundIn renal tubular cells, cytochrome P4503A enzyme and adenosine triphosphate–binding cassette transporter activities result in intracellular drug or metabolite exposure variability, depending on genetic polymorphisms. Our aim was to establish whether long-term renal function is affected by genetic polymorphisms in biotransformation enzymes and drug transporters of the donor after kidney transplantation. Materials and methodsThe study was conducted in a selected cohort of 97 kidney recipients. Genotyping of donors was performed on renal biopsy samples obtained before transplantation. Serum creatinine levels and Cockcroft–Gault estimated glomerular filtration rate were considered 1 y after transplantation and at the last follow-up. ResultsLong-term function was significantly better in recipients of an organ from donors carrying the ABCB1 1199A mutated allele (median and range creatinine values were 1.1 mg/dL [0.8–1.5mg/dL] in case of at least one ABCB1 1199A allele versus 1.5 mg/dL [0.7–3.7 mg/dL] for homozygous carriers of wild-type allele, P < 0.01). ABCB1 1199G>A polymorphism and donor age had an independent impact on both serum creatinine and estimated glomerular filtration rate. Unlike donor age, the mutated ABCB1 1199A allele was found to have a protective effect on renal function. ConclusionsDonor age and ABCB1 1199G>A polymorphism affect long-term renal function after transplantation. Analysis of genetic factors offers a promising approach to calcineurin inhibitor toxicity risk assessment.

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.

Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy.

With the cytochrome P450 CYP2C19*2 (*2) allelic variant resulting in complete loss of enzyme function and the CYP2C19*17 (*17) variant being linked to increased transcriptional activity with extensive metabolism of CYP2C19 substrates, two common variants of the CYP2C19 gene have been explored recently. Currently, the isolated and interactive impacts of both variants on the antiplatelet effects of chronic clopidogrel therapy are unknown. The aim of this study was to assess the isolated and interactive impacts of *2 and *17 on clopidogrel responsiveness in patients under clopidogrel maintenance treatment. Patients (n=986) eligible for this study were under therapy with coronary stent-related chronic treatment with aspirin and clopidogrel. The ADP-induced platelet aggregation was measured on a Multiplate analyzer (in AU*min), and genotypes were determined with a TaqMan assay. Platelet aggregation values were significantly higher in carriers of at least one *2 allele than in homozygous wild-type allele carriers (P<0.001). For *17, platelet aggregation values were significantly lower in carriers of at least one *17 allele than in homozygous wild-type patients (P=0.01). A gene-dose effect was observed for both variants, with a pronounced effect of the mutant allele (*2 or *17) in homozygous patients being seen. For the interactive effect of both variants on platelet aggregation values, a gradual increase in platelet aggregation values was observed from (+)*17/(-)*2 patients, who exhibited the lowest values (median of 207 AU*min) to (-)*17/(-)*2, (+)*17/(+)*2 and (-)*17/(+)*2 patients, who exhibited the highest values (median of 309 AU*min) (P<0.001). *2 and *17 allele carriage are independent predictors for the antiplatelet effect of chronic clopidogrel therapy.

Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study

BackgroundThe xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness.The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.MethodsThe following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study.ResultsCarriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively).ConclusionTwo polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk.

Polymorphisms in genes involved in the inflammatory response and interaction with NSAID use or smoking in relation to lung cancer risk in a prospective study

Lung cancer risk was investigated in relation to single nucleotide polymorphisms in genes involved in the inflammatory response. The aim was to see if polymorphisms modifying the inflammatory response are associated with risk of lung cancer and if there were interactions between the same polymorphism and factors, which modify an inflammatory response, such as smoking status, duration, and intensity, and use of NSAID. The functional SNPs IL-1B T-31C, IL6 G-174C, IL8 T-251A, IL10 C-592T, COX2 C8473T, COX2 A-1195G and PPARγ2 Pro 12Ala were included. A case-cohort study including 428 lung cancer cases and a sub-cohort of 800 persons was nested within a population-based prospective study of 57,053 individuals. Variant allele carriers of IL-1B T-31C were at increased risk of lung cancer (IRR = 1.51, 95% CI = 1.08–2.12). There was interaction between the polymorphism COX-2 T8473C and smoking status. Thus, non-smoking variant allele carriers were at 5.75-fold (95% CI = 1.25–26.43) higher risk of lung cancer than for homozygous wild type allele carriers. Lung cancer risk was similar for all genotype carriers among past and current smokers. There were, however, very few non-smoking lung cancer cases. There was interaction between IL-1B T-31C, COX-2 A-1195G and PPARγ2 Pro 12Ala and NSAID use in relation to lung cancer risk. For the two latter, NSAID use was only associated with a lower cancer risk among homozygous wild type allele carriers. p for interaction was 3 × 10 −6 for COX-2 A-1195G and 9 × 10 −5 for PPARγ2 Pro 12Ala. The results suggest that NSAID use may modify risk of lung cancer differently depending on the genotype.

Prospective study of interaction between alcohol, NSAID use and polymorphisms in genes involved in the inflammatory response in relation to risk of colorectal cancer

Inflammatory bowl disease predisposes to cancer of the colorectum, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the risk; hence genetic variations that modify the inflammatory response may alter the risk of colorectal cancer (CRC). The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with colorectal cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We studied 355 adenocarcinoma cases and 753 control persons, nested within the prospective “Diet, Cancer and Health” study. None of the polymorphisms were associated with risk of colorectal cancer. A statistically significant interaction between PPARγ2 Pro 12Ala and alcohol was found, where alcohol use was associated with a 22% increased risk of CRC per 10 g alcohol/day among carriers of the variant allele but not among homozygous wild type allele carriers ( P for interaction = 0.02). Moreover, an interaction between DLG5 R30Q and NSAID use was found ( P for interaction = 0.02). Our results do not suggest that inborn variations in the inflammatory response play any major role in risk of colorectal cancer.

Polymorphisms in COX-2, NSAID use and risk of basal cell carcinoma in a prospective study of Danes

We investigated the risk of basal cell carcinoma (BCC) in relation to a number of single nucleotide polymorphisms in genes involved in the inflammatory response. A case–control study including 322 BCC cases and a similar number of controls was nested in a population-based prospective study of 57,053 individuals (aged 50–64 at inclusion) in Denmark. NSAID use was associated with a slightly decreased risk of BCC (IRR = 0.85, 95% CI = 0.66–1.10). We found that two polymorphisms in COX-2, COX-2 A-1195G and T8473C were associated with risk of BCC. Carriers of the variant allele of COX-2 A-1195G had lower risk of BCC than homozygous wild type carriers (IRR = 0.54, 95% CI = 0.47–0.89). Homozygous carriers of the variant allele of COX-2 T8473C were at 2.27-fold higher risk of BCC (95% CI = 1.31–3.92) than homozygous wild type allele carriers. The polymorphisms IL6 G-174C, IL8 T-251A, PPARγ2 Pro 12Ala, IL1β T-31C, and IL10 C-592A were not associated with risk of BCC. We found no statistically significant interaction between polymorphisms and NSAID use in relation to risk of BCC. While it cannot be ruled out that the present findings are due to chance, the results indicate that high COX-2 expression may increase risk of BCC while NSAID use may be protective.