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PubMed2005

Mannose-binding lectin 2 (MBL2) gene polymorphism in asthma and atopy among adults.

Mannose-binding lectin (MBL) insufficiency due to polymorphisms in the MBL2 gene causes an opsonization defect, which has been connected to infections and atopy. We investigated the significance of MBL2 genotypes with regard to persistent asthma and atopy among adults. The genotypes were determined in 243 adults with persistent asthma and 400 controls. Atopy was determined by skin-prick test. As a result, the carriage of -221 base pairs (bp) promoter region variant allele X (nucleotide change G-->C; alleles Y-->X, respectively) causing low MBL expression proved to be a significant risk factor for asthma in non-atopic males [odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23-5.15; P = 0.01]. Furthermore, the X-allele carriage was associated with the decrease in lung function (forced expiratory volume at 1 s, FEV(1)) during follow-up in the patients with asthma (P = 0.033), the effect being strongest for non-atopic asthmatics (P = 0.042). The MBL2 genotype had no clear effect on the occurrence of atopy in adults. In conclusion, our results abrogate the previously suggested predisposing effect of MBL insufficiency on atopy at least in adults. However, as MBL is a complement component participating in immune defence against microbes, and as in the pathogenesis of non-atopic asthma infectious agents are probably involved, the gene-environment interactions between MBL and infections should be assessed further with regard to asthma.

Adult↗

PubMed2005

Delta-aminolevulinic acid dehydratase polymorphism and risk of brain tumors in adults.

The enzyme delta-aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme synthesis, can be inhibited by several chemicals, including lead, a potential risk factor for brain tumors, particularly meningioma. In this study we examined whether the ALAD G177C polymorphism in the gene coding for ALAD is associated with risk of intracranial tumors of the brain and nervous system. We use data from a case-control study with 782 incident brain tumor cases and 799 controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to the hospital. Blood samples were drawn and DNA subsequently sent for genotyping for 73% of subjects. ALAD genotype was determined for 94% of these samples (355 glioma, 151 meningioma, 67 acoustic neuroma, and 505 controls). Having one or more copy of the ALAD2 allele was associated with increased risk for meningioma [odds ratio (OR) = 1.6; 95% confidence interval (CI), 1.0-2.6], with the association appearing stronger in males (OR = 3.5; 95% CI, 1.3-9.2) than in females (OR = 1.2; 95% CI, 0.7-2.2). No increased risk associated with the ALAD2 variant was observed for glioma or acoustic neuroma. These findings suggest that the ALAD2 allele may increase genetic susceptibility to meningioma.

Adult↗

PubMed2000

Association of the myeloperoxidase -463G-->a polymorphism with lung cancer risk.

Myeloperoxidase, which is released from neutrophils in response to various pulmonary insults including tobacco smoke, is suspected to play a carcinogenic role in the lung. A G-to-A substitution polymorphism in the promoter region of the MPO gene has been suggested in in vitro studies to decrease gene transcription. We tested the association of this polymorphism with lung cancer in a population-based case-control study of 323 cases and 437 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. We found a marked difference in the frequency of the variant A allele among Caucasians (26%), Japanese (17%), and Hawaiians (13%). Overall, the variant allele was somewhat less frequent in cases than controls (P = 0.13). Individuals with the A/A genotype were found to be at a 50% decreased risk compared to those with two G alleles (95% confidence interval, 0.2-1.3). Although not statistically significant, this inverse association was suggested in both sexes and two of the three ethnic groups studied. Heterozygotes were at no decreased risk. Further work needs to clarify the functional relevance of the A allele in vivo and to confirm the inverse association of the A/A genotype with lung cancer in large epidemiological studies.

Adolescent↗

PubMed1983

Chromosome abnormalities and spontaneous fetal death following amniocentesis: further data and associations with maternal age.

The pooled results are presented of two North American surveys concerning spontaneous fetal deaths of conceptuses with cytogenetic abnormalities diagnosed prenatally whose mothers had declined elective abortion. The rate of fetal death of those with nonmosaic genotypes associated with Down syndrome was 30.1% (95% confidence interval of 19.0%-42.0%), which is almost identical with the difference of 30% previously estimated between rates observed at amniocentesis and in live births. The fetal death rate for (nonmosaic) 47,+18 was 68.0% (95% confidence interval of 46.5%-85.1%), close to the estimated difference of 75% between rates at amniocentesis and in live births for this genotype. For other nonmosaic genotypes, the rates (and 95% confidence intervals) were: 47,+13, 42.9% (9.9%-81.6%); 47,XXX, 0% (0%-9.0%); 47,XXY, 8.1% (0.8%-11.0%); 47,XYY, 3.0% (.08%-15.8%); for balanced translocations and inversions, 2.8% (0.3%-9.8%); and for markers, variants, and fragments, 0% (0%-12.8%). For 45,X, the rate was 75.0% (42.8%-94.5%), in contrast to the rate for 46,XX/45,X of 10.5% (1.3%-33.1%) and for structural X abnormalities associated with Turner syndrome of 0% (0%-60.2%). The rate for nonmosaic 45,X is significantly different from that for either of the other two categories associated with Turner syndrome. The maternal age of nonmosaic 47,+21 fetuses that survived to live birth was 39.1 +/- 6.2, not significantly different from the rate for fetal deaths: 39.5 +/- 3.8. The observations provide no support for opposing hypotheses by other groups that maternal age is positively or negatively associated with fetal death of 47,+21 conceptuses. For other chromosome abnormalities, maternal ages of fetal deaths are slightly lower than for live births, but none of the differences are significant. The rates of spontaneous fetal deaths derived here are likely to be pertinent to genetic counseling. Their use in adjusting the rates of abnormalities diagnosed at amniocentesis will enable derivation of predicted contemporary live-birth prevalence rates of abnormalities that would be observed in absence of selective abortion.

Adult↗

PubMed2005

TP53-binding protein variants and breast cancer risk: a case-control study.

INTRODUCTION: The TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk. METHODS: Allelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals. RESULTS: No significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34). CONCLUSION: The lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing.

Adult↗

PubMed2005

The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects.

AIMS: To study the effect of CYP2C8*3, the most common CYP2C8 variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C8*3 with variant CYP2C9 alleles. METHODS: Three hundred and fifty-five randomly selected Spanish Caucasians were screened for the common CYP2C8 and CYP2C9 mutations. The pharmacokinetics of (R)-ibuprofen were studied in 25 individuals grouped into different CYP2C8 genotypes. RESULTS: The allele frequency of CYP2C8*3 (0.17) was found to be higher than that reported for other Caucasian populations (P = 0.0001). The frequencies of CYP2C9*2 and CYP2C9*3 were 0.19 (0.16-0.21) and 0.10 (0.08-0.12), respectively. An association between CYP2C8*3 and CYP2C9*2 alleles was observed, occurring together at a frequency 2.4-fold higher than expected for a random association of alleles (P = 0.0001). The presence of the CYP2C8*3 allele was found to influence the pharmacokinetics of (R)-ibuprofen in a gene-dose effect manner. Thus, after administration of 400 mg ibuprofen, the plasma half-life (95% confidence intervals) for individuals with genotypes CYP2C8*1/*1, CYP2C8*1/*3 and CYP2C8*3/*3, was 2.0 h (1.8-2.2), 4.2 h (1.9-6.5; P < 0.05) and 9.0 h (7.8-10.2; P < 0.002), respectively. A statistically significant trend with respect to the number of variant CYP2C8*3 alleles was also observed for the area under the concentration-time curve (P < 0.025), and drug clearance (P < 0.03). CONCLUSION: Polymorphism of the CYP2C8 gene was found to be common, with nearly 30% of the population studied carrying the variant CYP2C8*3 allele. The presence of the latter caused a significant effect on the disposition of (R)-ibuprofen. This suggests that a substantial proportion of Caucasian subjects may show alterations in the disposition of drugs that are CYP2C8 substrates.

Aryl Hydrocarbon Hydroxylases↗

PubMed2006

Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA.

An A to G substitution, rs925013, in the promoter of the prostate-specific antigen gene (PSA) was recently found to be associated with promoter activity and circulating PSA levels. The objective of this study was to test the associations between rs925013 and another A to G substitution, rs266882, in the PSA gene with prostate cancer risk using a population-based case-control study of 821 prostate cancer cases and 734 controls carried out in Perth and Melbourne, Australia. The study focused on young (i.e., < 70 years) and aggressive cases (i.e., well-differentiated tumors were excluded). Cases in the Melbourne arm of the study (N = 638) were followed up prospectively for an average period of 8.2 years and deaths from prostate cancer ascertained through record linkage to study the possible association between genetic variants and disease-specific survival. PSA-circulating levels were measured in controls to test the association with the genetic variants using a cross-sectional design. Linear regression of log PSA levels, unconditional logistic regression, Cox regression, and haplotype analyses were undertaken. For rs925013, the G allele was associated with an increased risk of prostate cancer [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-1.7; P = 0.001], and the hazard ratio for survival for cases homozygous for the G allele compared with cases homozygous for the A allele was increased but not statistically significant (hazard ratio, 2.3; 95% CI, 1-5.6; P = 0.06). For rs266882, there was no association with overall prostate cancer risk and survival (all P > 0.1). Men homozygous or heterozygous for the G/G (rs925013/rs266882) haplotype were at higher risk of prostate cancer than men homozygous for the A/A haplotype (odds ratio, 1.3; 95% CI, 1.1-1.7; P = 0.009). Adjusted geometric means of circulating PSA levels in controls were similar in men with zero, one, and two copies of the G allele in rs266882 (1.2, 1.1, and 1.3 ng/mL, respectively; all P > or = 0.2) and rs925013 (1.1, 1.2, and 1.5 ng/mL, respectively; all P > 0.1). For rs925013, our study provides good evidence of association with prostate cancer risk, marginal evidence of association with survival, and little evidence of detectable association with circulating PSA levels in controls. We found no evidence of an independent association between rs266882 and any of the outcomes. The genotypes and haplotypes studied might be associated with the PSA gene function or be in linkage disequilibrium with other unmeasured and functional variants in the PSA or other genes.

Aged↗

PubMed2004

NOD2 3020insC alone is not sufficient for colorectal cancer predisposition.

Mutations in NOD2 have been shown to associate with increased susceptibility to Crohn's disease. A recent Polish study linked the truncating NOD2 3020insC variant with an increased risk of colorectal cancer (CRC) at an older age (>50 years) of disease onset, with an odds ratio of 2.23. We studied the possible contribution of the 3020insC variant to CRC risk in a series of 1,042 Finnish population-based patients from which 926 samples were successfully analyzed and in 348 anonymous cancer-free controls. The frequency of the 3020insC mutation was 3.7% in both CRC patients (34 of 926, including 1 homozygote) and cancer-free controls (13 of 348; odds ratio, 0.98; confidence interval, 0.51-1.88). Contrary to the Polish study, there was no significant difference in the mutation rates between CRC patients > 50 years of age (25 of 576; 4.3%) and controls in the present series. We studied respective tumor tissue DNAs of all patients displaying heterozygous 3020insC changes for loss of heterozygosity. Loss of heterozygosity at NOD2 was observed in only 1 of the 33 CRC samples. Our results suggest that NOD2 3020insC alone does not contribute to CRC risk. If this variant predisposes to CRC, additional factors not present in the Finnish population need to be involved.

Alleles↗

PubMed2006

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Aged↗

PubMed2001

Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype.

Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometrial cancer. We examined the association between endometrial cancer risk and estrogen replacement therapy (ERT) by CYP17 genotype using 51 incident cases and 391 randomly selected controls from a multiethnic cohort in Hawaii and Los Angeles, California. The relative risk of endometrial cancer was calculated for ever use versus never use of ERT by CYP17 genotype (TT, TC, and CC). We found that women who reported ever taking ERT were more than twice as likely to develop endometrial cancer as women who never took ERT [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.19-4.23]. Among these women, the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR, 4.10; 95% CI, 1.64-10.3), but not for women with the C allele (OR, 1.31; 95% CI, 0.53-3.21). These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be potential markers of endometrial cancer susceptibility due to ERT.

Aged↗

PubMed1999

Determinants of chronic infection with Staphylococcus aureus in patients with bronchiectasis.

Staphylococcus aureus is an uncommon pathogen in bronchiectasis not caused by cystic fibrosis (CF). The object of this study was to identify characteristics that cause patients to be prone to infection with S. aureus. The study population consisted of patients with bronchiectasis attending the authors' unit, excluding those with a diagnosis of overt CF. All patients had a high resolution computer tomographic scan (HRCT) of the thorax which demonstrated bronchiectasis. Cases that were currently chronically infected with S. aureus (isolated consecutively on more than two occasions >3 months apart) were identified (n = 12) and compared with 74 control patients who had not been chronically infected with S. aureus. Patients were carefully evaluated to determine the aetiology of their disease. Odds ratios (OR) and 95% confidence intervals (CI) as measures of the association between disease characteristics and chronic infection with S. aureus were calculated. The results for patients chronically infected by S. aureus demonstrated significant associations with allergic bronchopulmonary aspergillosis (ABPA; OR = 8.8, 95% CI 1.8-41.9), atypical variants of CF (OR = 12.0, 95% CI 1.8-81.7) or equivocal sweat sodium values (OR = 4.0, 95% CI 1.0-15.3). The associations persisted when the analysis was based on cases (n = 28) in whom S. aureus had ever been isolated from sputum. In the latter analysis there was also a significant association with predominant upper zone disease on HRCT. These results suggest that patients with bronchiectasis in whom S. aureus is isolated from sputum should be carefully evaluated to exclude allergic bronchopulmonary aspergillosis or atypical cystic fibrosis.

Adult↗

PubMed2006

KLF6 IVS1 -27G>A variant and the risk of prostate cancer in Finland.

OBJECTIVES: A recent report demonstrated that KLF6 IVS1 -27G>A substitution increases the transcription of alternatively spliced isoforms; this action was suggested to be associated with prostate cancer (pCA). To evaluate these findings among the Finnish population, a total of 3348 samples were analysed. METHODS: The variant was genotyped in 164 patients with familial pCA, 852 patients with unselected pCA, 459 patients with benign prostate hyperplasia (BPH), 923 male population controls, and 950 men from a Finnish prostate-specific antigen (PSA) screening trial with PSA levels less than 1.0ng/ml. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated by using logistic regression to estimate pCA risk. RESULTS: Association testing revealed no significant differences between familial prostate cancer patients and population controls (OR: 0.84; 95%CI, 0.56-1.28; p=0.42), unselected cases and controls (OR: 0.95; 95%CI, 0.76-1.19; p=0.63), or BPH cases and controls (OR: 1.12; 95%CI, 0.86-1.46; p=0.39). pCA and BPH cases were also compared with PSA-screened controls. None of these analyses revealed any significant associations. CONCLUSIONS: Our results do not support the suggested association of KLF6 IVS1 -27G>A germline polymorphism with pCA risk and also suggest that the variant is not a risk allele for BPH in the Finnish population.

Adenine↗

PubMed2002

Hand grip strength: a phenotype suitable for identifying genetic variants affecting mid- and late-life physical functioning.

Physical functioning late in life has been shown to be affected by genetic factors. Only a few genetic variants have been suggested to be associated with physical functioning, and this only in selected populations (e.g., young healthy males and elite athletes). Declining physical functioning late in life is a major problem in terms of prevalence, morbidity, functional limitations, and quality of life. It is therefore of interest to find a phenotype reflecting physical functioning which has a relatively high heritability and which can be measured in large samples. Hand grip strength is known to be associated with muscular functioning in other muscle groups and with activities of daily living (ADL) functioning, and it predicts incident disability. We studied 1,757 Danish twin pairs aged 45-96 years, and found that this phenotype has a heritability of 52% (95% confidence interval (CI), 48-55%). A powerful design to detect genes associated with a phenotype is obtained using the extreme discordant and concordant sib pairs, of whom 28 and 77 dizygotic twin pairs, respectively, were found in this study. Hence grip strength is a suitable phenotype for identifying genetic variants of importance to mid- and late-life physical functioning.

Activities of Daily Living↗

PubMed2000

Screening a human population sample for DNA repair gene deficiencies utilizing the protein truncation test.

A significant fraction of human cancers are thought to have a genetic component and several lines of evidence suggest that deficiencies in DNA repair may be a contributing factor. Little is known, however, about the frequency and distribution of variants of DNA repair genes in the general human population. The protein truncation test (PTT) was used to screen 136 healthy volunteers for protein-truncating variants of 10 DNA repair genes: APE, CDK7, ERCC1, WAF1, HOGG1, MGMT, POLB, UNG, HAAG, and CCNH. This sample consisted of 41males (30%) and 95 females (70%) with an average age of 25.3 years, ranging from 17 to 60 years of age. No truncating mutations were found in the 10 genes examined in any of the subjects. The 95% confidence interval for a proportion of 0 over the 272 alleles examined per locus is 0-0.01. The calculated frequency of truncating mutations in each of these genes, among the general population, is thus less than 1%. Among the 10 genes tested in 136 people, a single sample had no PCR product for HAAG, even though PCR products were obtained on all other genes. Total RNA dot hybridization confirmed the presence of HAAG mRNA transcripts in this sample. Despite identification of this single DNA repair variant, these results indicate a low frequency of truncating mutations in DNA repair genes in the general population.

Base Sequence↗

PubMed2025

Protective Effects of Genetic Proxies of Cognitive Reserve in Parkinson's Disease: A Longitudinal Multi-Cohort Study.

BACKGROUND: Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD. METHODS: Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage ≥3, progression to a Montreal Cognitive Assessment score ≤24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs. RESULTS: All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P < 0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P = 0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P = 0.029). CONCLUSIONS: Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Humans↗

PubMed2005

HTERT mRNA partially regulates telomerase activity in gastric adenocarcinoma and adjacent normal gastric mucosa.

The extent to which human telomerase reverse transcriptase (hTERT) mRNA and its splice variants control telomerase activity in human cancers is controversial. Telomerase and hTERT mRNA were assessed quantitatively in paired samples of gastric adenocarcinoma and adjacent normal tissue. Splice variants within the hTERT reverse transcriptase domain (alpha, beta, alphabeta) were detected by RT-PCR. In gastric adenocarcinoma, compared to normal tissue, median telomerase activity increased significantly (from 0 total product generated [tpg; 95% confidence interval CI, 0-2.3] to 16.1 tpg [95% CI, 3.7-97]; P = 0.008) and median hTERT mRNA levels also increased (from 2.21 [95% CI, 1.40-4.62] to 7.08 [95% CI, 3.26-10.8]; P = 0.0054). hTERT mRNA and telomerase activity correlated in normal gastric mucosa (r = 0.819, P = 0.0002). Alpha, beta, and alphabeta deletions were similar in both groups. We conclude that hTERT mRNA partially regulates telomerase activity in normal gastric mucosa and gastric adenocarcinoma. In contrast, hTERT mRNA splicing is not involved in the regulation of enzyme activity.

Adenocarcinoma↗

PubMed2004

Recurrent pregnancy failure is associated with a polymorphism in the p53 tumour suppressor gene.

BACKGROUND: The p53 tumour suppressor gene is a well-known factor regulating apoptosis in a wide variety of cells and tissues. Alterations in the p53 gene are among the most common genetic changes in human cancers. In addition, recent data provide evidence that p53 plays a critical role in mediating pregnancy by regulating steroid hormone activation. In idiopathic recurrent miscarriages (IRM), causes and associations are much debated as the exact pathophysiological mechanisms are unknown. In this study, we assess whether an established polymorphism in the p53 gene is associated with the occurrence of IRM. METHODS: Genotyping was performed by PCR-based amplification of the p53 Arg and Pro variants at codon 72 in 175 cases of IRM and 143 controls. RESULTS: We observed a statistically significant association between carriage of the Pro allele and the occurrence of IRM (P = 0.03, odds ratio 1.49, confidence interval 1.04-2.14). Distribution of genotypes was in Hardy-Weinberg equilibrium. CONCLUSIONS: Our results indicate an over-representation of the Pro allele of the p53 gene in women with IRM, giving support to the theory that p53 has a potential role during pregnancy.

Abortion, Habitual↗

PubMed2005

The role of cytokine gene polymorphisms in colorectal cancer and their interaction with aspirin use in the northeast of Scotland.

The reduced risk of colorectal cancer associated with cyclooxygenase enzyme inhibitors, such as aspirin and other nonsteroidal anti-inflammatory drugs, strongly suggests that chronic inflammation is a key mediator in the development of colorectal cancer. This complements recent molecular evidence demonstrating an association between a number of proinflammatory genetic polymorphisms and risk of colorectal cancer. We assessed polymorphisms in the IL-1, IL-10, TNF-A, and TGF-B genes in a population-based case-control study of colorectal cancer cases (n = 264) and frequency-matched controls (n = 408) in the Northeast of Scotland and analyzed their interaction with regular aspirin use. There was no evidence of a relation between any of the individual polymorphisms, or pairs of polymorphisms, and risk of colorectal cancer. There was a significant interaction between the IL-10-592 C/A polymorphism and aspirin use (Pinteraction = 0.03). Carriers of the variant IL-10-592 (A) allele, who produce less of the anti-inflammatory cytokine interleukin-10, had a statistically significant 50% reduced risk of colorectal cancer when taking regular aspirin (odds ratio, 0.5; 95% confidence interval, 0.25-0.97), whereas risk was not reduced in carriers of the A allele who did not use aspirin, or among aspirin users with the CC genotype. It is possible that carriers of the mutant IL-10-592 allele are more likely to derive anti-inflammatory and chemopreventive benefits from aspirin in the presence of a lower production of their own endogenous anti-inflammatory interleukin-10. These results suggest that host genetics may play a role in predicting response to chemopreventive strategies. Confirmation of these findings in other populations is required.

Aged↗