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At least 541 records · Page 30Linked to original sources
PubMed2004

Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.

OBJECTIVE: The adenosine triphosphate-binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan. METHODS: The drug was administered to 22 adult white patients with cancer as a 20-minute infusion (dose, 0.10-0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10-0.35 mg). RESULTS: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% (P =.015) of those in 15 patients with wild-type alleles, at mean values of 138 ng x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x mg(-1)), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, and CYP3A5 genes. CONCLUSION: These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2026

A de novo algorithm for allele reconstruction from Oxford nanopore amplicon reads, with application to CYP2D6.

MOTIVATION: The Oxford Nanopore Technologies' sequencing platform offers a path towards bedside genomics, producing long reads that can completely cover a gene of interest, and detect any known or novel variant the gene contains. However, the analysis of these long reads to identify actionable genotypes remains challenging and typically requires customization depending on the target gene. RESULTS: Here, we describe a generic algorithm to accurately reconstruct allele sequences derived from long-reads of amplicon-based data. Rather than calling variants directly from these long-reads, our method takes a "sequence-first" approach, performing an unbiased reconstruction of the underlying amplicon sequences to generate high-confidence reconstructed allele sequences. This is done without user input of the target gene, allowing for any source amplicon to be reconstructed. These high-confidence reconstructed allele sequences are then compared to the genomic reference sequence of the gene to infer the specific diplotype present in the sample. This approach is agnostic towards the number of genes and alleles present and readily detects novel variants. We demonstrate our approach using three independent data sets for CYP2D6, a diverse and complex gene with over 175 known alleles of clinical significance. We show how our approach can accurately recover validated CYP2D6 diplotypes from 20 Coriell samples covering 14 distinct alleles, using different amplicons, flow cell versions, and depths. This includes inferring occurrences of allele duplication events from relative abundances of each allele, a critical factor for ascribing functional effects to a diplotype. Further, we demonstrate our approach's utility for other genomic regions, including HLA. AVAILABILITY: Custom code is available at the following GitHub repository, along with instructions for use and test data: https://github.com/scottdbrown/allele-reconstruction-long-read-amplicon-data. A snapshot of the code at the time of publication is available on Zenodo.org; doi 10.5281/zenodo.19716004. Raw .fastq sequence data for our three sequencing runs is available at the SRA under Bioproject PRJNA1357883 (https://www.ncbi.nlm.nih.gov/bioproject/1357883).

Alleles↗
PubMed1998

Role of CCR2 genotype in the clinical course of syncytium-inducing (SI) or non-SI human immunodeficiency virus type 1 infection and in the time to conversion to SI virus variants.

The effect of a valine to isoleucine switch in the CCR2 first transmembrane domain (CCR2 64I) on the clinical course of human immunodeficiency virus type 1 (HIV-1) infection was analyzed in relation to the presence or absence of syncytium-inducing (SI) HIV-1 variants. Compared with persons with a wild-type genotype for CCR2 and CCR5, subjects with a CCR2-64I/+ or 64I/64I (but CCR5 wild-type homozygous genotype) had significantly delayed disease progression (relative hazard, 0.66; 95% confidence interval, 0.44-0.99) with a 1. 5-fold slower CD4 T lymphocyte decline and a 1.2-fold lower RNA virus load. The delay in disease progression was more pronounced when only non-SI (NSI) HIV-1 variants were present and was not observed after conversion to SI HIV-1 in CCR2-64I/+ persons. In CCR2-64I/+ subjects, a higher conversion rate to and a higher prevalence of SI HIV-1 was observed. These findings suggest that the mechanism of action of the CCR2 polymorphism is mediated via CCR5-restricted NSI HIV-1 variants.

Cells, Cultured↗
PubMed2026

Longitudinal characterization of mixed-genotype SARS-CoV-2 infections in a military cohort reveals compartmentalized viral populations.

UNLABELLED: Mixed-genotype severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a concern due to the potential generation of novel recombinants that give rise to new variants. To better understand intra-host viral dynamics, we analyzed specimens from 24 participants from the U.S. Military Health System's Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential COVID-19 cohort with suspected mixed-genotype SARS-CoV-2 infections. From an initial 24 suspected cases, we confirmed 17 as genuine coinfections and graded them by evidence: 7 were "strong"; 4 were "moderate"; 6 were "weak"; and 7 were deemed unlikely to be true mixed-genotype infections. Access to swabs from multiple body sites across the course of infection allowed us to observe compartmentalization and shifts in variant dominance that would have been missed by a single-timepoint analysis, as well as one recombinant Omicron BA.1/BA.2 genome. By using an evidence-based bioinformatic framework to assess sequencing data from well-characterized clinical cases, we distinguished genuine coinfections from bioinformatic artifacts. Our findings emphasize the importance of both extensive specimen collection and careful bioinformatic approaches in ascertaining dual genotype infections. IMPORTANCE: Novel recombinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) arise from coinfections with different lineages, but mixed infections are not screened for despite risk to public health, and most surveillance relies on single swabs. We analyzed a longitudinal data set with specimens from multiple body sites, providing an opportunity to assess intra-host dynamics. To distinguish true coinfection from bioinformatic artifacts with confidence, we applied a framework that grades evidence for mixed genotypes by incorporating lineage and clade with manually validated variant calls. This allowed investigation beyond abundance levels of mixed genotypes within a single specimen, including observations of compartmentalization and a recombinant virus. This work enables further study of evolutionary, immunological, and clinical implications of mixed SARS-CoV-2 genotypes. Detecting dual-genotype infections and discriminating between true dual-genotype infection vs potential bioinformatics-based artifacts support public health and military readiness. These efforts provide evidence to bolster decision-making in molecular epidemiological studies to track transmission and for the choice of effective countermeasures.

SARS-CoV-2↗
PubMed2005

Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity.

Genetic polymorphism of the UDP-glucuronosyltransferase (UGT) 1A1 gene is associated with the decreased glucuronidation activity of an active metabolite of irinotecan, SN-38, and UGT1A1*28 has been shown as a predictive factor for irinotecan toxicity. The phenobarbital-responsive enhancer module (PBREM) of the UGT1A1 promoter region has been reportedly associated with the transcriptional activity of the gene. We investigated whether the polymorphism of PBREM (T-3279G) would affect inter-patient variations in sensitivity to irinotecan toxicity. The study population comprised 119 cancer patients who had received irinotecan. We reviewed their clinical records, including patient characteristics, and observed their toxicity levels following irinotecan infusion. Genotyping was performed by sequencing analyses. Logistic regression analyses were performed to assess the relationship between genotypes and irinotecan toxicity. We identified the homozygotes of the reference allele for T-3279G in 68 patients, the heterozygotes in 37, and the homozygotes for the variant in 14. Logistic regression analysis indicated a significant association between the homozygotes for T-3279G and the severe toxicity (odds ratio 5.80; 95% confidence interval 1.67-20.1). However, multivariate analysis, including the data of UGT1A1*28 polymorphism, revealed a diminution of the association due to a highly significant linkage disequilibrium between these polymorphisms. Our results suggest that a highly significant linkage disequilibrium exists between T-3279G and UGT1A1*28 polymorphisms, and that the variants of T-3279G and UGT1A1*28 cooperatively decrease transcriptional activity of the UGT1A1 promoter. The determination of T-3279G and UGT1A1*28 genotypes might be clinically useful in predicting severe irinotecan toxicity in cancer patients.

Adult↗
PubMed2001

Prevalence of the methylenetetrahydrofolate reductase 677C > T mutation in the Mediterranean Spanish population. Association with cardiovascular risk factors.

Methylenetetrahydrofolate reductase (MT-HFR) is a key enzyme involved in folate metabolism. A common cytosine (C) to a thymine (T) mutation at nucleotide 677 (677C > T) in the MTHFR gene which converts an alanine residue to a valine, has been related with several biochemical phenotypes and with cardiovascular risk, depending on the population studied. Our objective was to estimate the prevalence of the 677C > T mutation in a large and randomly selected sample (289 men and 427 women) from the Mediterranean Spanish population, and to test the association between this genetic variant and some cardiovascular risk factors. For both genders, the prevalence of CC, CT and TT subjects was 32.0, 52.2 and 15.8%, respectively. The frequency (95% confidence interval) of the 677T allele was 0.44 (0.40-0.48) in men and 0.40 (0.37-0.44) in women. This prevalence was significantly different from other European countries, and among the highest reported in the world for any healthy population. We found no association between the 677C > T gene variants and age, body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or diastolic blood pressure in men and women. However, in men, a statistically significant increase of systolic blood pressure with the number of mutant alleles was found (122.2 mmHg in CC, 125.1 mmHg in CT and 128.5 mmHg in TT subjects; p for trend = 0.030). This association remained significant (p = 0.047) even after adjustment for age, BMI, alcohol consumption, tobacco smoking, education and physical activity.

Adult↗
PubMed2006

Matrix metalloproteinase polymorphisms and survival in stage I non-small cell lung cancer.

PURPOSE: The matrix metalloproteinases (MMP) are a family of enzymes that can degrade extracellular matrix and facilitate invasion through the basement membrane. Several polymorphisms in MMP-1, MMP-2, MMP-3, and MMP-12 have been described, some of which lead to differential transcription. We hypothesized that polymorphisms in these MMP genes may be associated with survival outcomes in early-stage non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We evaluated the relationship between MMP-1, MMP-2, MMP-3, and MMP-12 polymorphisms and both recurrence-free survival (RFS) and overall survival (OS) among 382 patients with stage I NSCLC. Analyses of genotype associations with survival outcomes were done using Cox proportional hazards models and Kaplan-Meier methods and the log-rank test. RESULTS: Patients carrying the variant G allele of the MMP-12 1082A/G polymorphism had significantly worse outcomes [crude hazard ratio (HR) for OS 1.74; 95% confidence interval (95% CI), 1.18-2.58, P=0.006; crude HR for RFS, 1.53; 95% CI, 1.05-2.23, P=0.03]. After adjusting for age, sex, stage, pack-years of smoking, and histologic subtype, the MMP-12 1082A/G polymorphism remained significantly associated with survival outcomes [adjusted HR (AHR) for OS, 1.94; 95% CI, 1.28-2.97, P=0.002; AHR for RFS, 1.61; 95% CI, 1.07-2.41, P=0.02]. None of the other MMP polymorphisms was significantly associated with survival. CONCLUSIONS: Our results show that patients with stage I NSCLC carrying the variant G allele of the MMP-12 1082A/G polymorphism have worse survival.

Adult↗
PubMed2006

Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer.

BACKGROUND: P-glycoprotein (P-gp) is a transmembrane transporter that is encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) gene, which plays a role in cell defense against environmental attacks, like those generated by xenobiotics. P-gp is expressed in the lung, where it has been suggested to transport these compounds from the interstitium into the lumen. METHODS: Two functional ABCB1 polymorphisms were examined, G2677T/A (in exon 21) and C3435T (in exon 26), in a group of lung cancer patients and in a control group. RESULTS: Whereas 3435T allelic and genotype frequencies were unchanged between both study groups, lung cancer patients showed higher frequency of the 2677T variant allele compared with the control group (0.67 vs. 0.43; P < .001; odds ratio, [OR], 2.6; 95% confidence interval [95% CI], 1.7-4.0). Among the histologic tumor types that were included in the study, squamous cell carcinoma was associated most strongly with the presence of the 2677T allele (OR, 3.92; 95% CI, 2.2-6.9) and especially was associated with the 2677 TT genotype (OR, 6.75; 95% CI, 3.0-15.2). In a haplotype analysis, homozygous wild-type alleles were classified as genotype A, heterozygous alleles were classified as genotype B, and homozygous mutant allele were classified as genotype C both in exon 21 (first letter) and in exon 26 (second letter) loci. The haplotype CB displayed the highest association with lung cancer (OR, 18.09; 95% CI, 2.4-139.2). CONCLUSIONS: The current results taken together suggest that, aside from other known causes of lung cancer, such as tobacco smoke, the existence of polymorphisms in the ABCB1 gene and, specifically, the presence of the G2677T mutation can be crucial in conferring susceptibility to lung cancer. Further studies comprising larger populations are needed to confirm these preliminary findings.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

CYP1A1 T3801 C polymorphism and lung cancer: a pooled analysis of 2451 cases and 3358 controls.

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

Age Factors↗
PubMed2000

The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression.

A gene family of small membrane proteins, represented by phospholemman and the gamma subunit of Na,K-ATPase, was defined and characterized by the analysis of more than 1000 related ESTs (expressed sequence tags). In addition to new and more complete cDNA sequence for known family members (including MAT-8, CHIF, and RIC), the findings included two new family members and new splicing variants. A large number of EST replicates made it possible to derive curated DNA sequence with higher confidence and accuracy than from the sequencing of individual clones. The family has a core motif of 35 invariant and conserved amino acids centered on a single transmembrane span. Features of each predicted protein product were compared, and tissue distributions were determined. The gene family was named FXYD (pronounced fix-id) in recognition of invariant amino acids in its signature motif. The abundant proteins are involved in the control of ion transport.

Amino Acid Sequence↗
PubMed2006

O6-methylguanine-DNA methyltransferase Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in the Nurses' Health Study and Physicians' Health Study (United States).

OBJECTIVE: O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6-position of guanine in DNA. Unrepaired O6-methylguanines result in G:C to A:T transitions in mutated K-ras and p53 in colorectal tumors. Two non-synonymous MGMT coding region variants, Leu84Phe and Ile143Val, lie in close proximity to the reactive 145Cys residue and to a conserved estrogen receptor interacting helix. METHODS: We assessed the association between the MGMT Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in two nested case-control studies: one each in the Nurses' Health Study (NHS) and the Physicians' Health Study (PHS) cohorts. RESULTS: Among 197 female cases and 2,500 controls from the NHS, the variant 143Val allele was significantly associated with reduced risk of colorectal cancer [odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.33-0.80]. In women, statistically significant gene-environment interactions were found between the Leu84Phe polymorphism and alcohol intake (P = 0.03), BMI (P = 0.04) and postmenopausal hormone use (P = 0.03). The Leu84Phe and Ile143Val polymorphisms were not significantly associated with risk of colorectal cancer among 271 male cases and 451 controls from the PHS. CONCLUSIONS: Our results suggest that the common Leu84Phe and Ile143Val polymorphisms in MGMT influence risk of colorectal cancer in women possibly through modulating estrogen receptor-dependent transcriptional activation, which has previously been shown to occur in response to DNA alkylation damage.

Adult↗
PubMed2026

Eribulin versus taxane as first-line chemotherapy combined with dual HER2 blockade in patients with HER2-positive locally advanced or metastatic breast cancer: final survival outcomes of the JBCRG-M06/EMERALD study.

BACKGROUND: The phase III JBCRG-M06/EMERALD study was the first to show noninferior progression-free survival (PFS) of eribulin to taxane, combined with dual human epidermal growth factor receptor 2 (HER2) blockade (trastuzumab plus pertuzumab), as a first-line treatment for HER2-positive locally advanced breast cancer or metastatic breast cancer (LABC/MBC). We report final survival outcomes and biomarker analyses of the EMERALD trial. PATIENTS AND METHODS: Patients with HER2-positive LABC/MBC were randomly assigned 1:1 to either eribulin or physician-choice taxane (docetaxel or paclitaxel), both combined with trastuzumab plus pertuzumab, as first-line chemotherapy. PFS and overall survival (OS) were assessed through 30 June 2023 for PFS and 31 December 2024 for OS. Survival outcomes were compared between the eribulin and taxane groups and according to circulating tumor DNA (ctDNA) detection of PIK3CA mutations (PIK3CAm+; E542K, E545K, H1047R, and N345K single nucleotide variants) or HER2 amplification (HER2 amp+; ERBB2 copy number >2.5). RESULTS: Median OS was 78.5 months [95% confidence interval (CI) 64.3-not reached (NR)] for eribulin and was NR for taxane, with a hazard ratio of 1.25 (95% CI 0.92-1.71, log-rank P = 0.19). The 60-month OS rates were 59.7% and 65.2% for eribulin and taxane, respectively. Median OS and 60-month OS rates were numerically lower in ctDNA PIK3CAm+ patients, and greater in ctDNA HER2 amp+ patients for all patients and with stratification by treatment group. There were no statistical interactions between treatment group with either ctDNA PIK3CAm or ctDNA HER2 amp status. Similar patterns were observed for PFS. CONCLUSION: Final survival analysis revealed that median OS exceeded 6 years with eribulin or physician-choice taxane, combined with trastuzumab plus pertuzumab, as first-line chemotherapy for HER2-positive LABC/MBC, with no significant differences between the two groups. ctDNA PIK3CAm+ status was a poor prognostic factor. ctDNA HER2 amp+ was associated with longer survival.

Aged↗
PubMed2003

Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan.

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.

Adenocarcinoma↗
PubMed2004

The E237G polymorphism of the high-affinity IgE receptor beta chain and asthma.

BACKGROUND: The beta chain of high-affinity IgE receptor (FcepsilonRI beta) has been proposed as a candidate gene for asthma and atopic diseases. OBJECTIVES: To determine the prevalence of the E237G polymorphism of the FcepsilonRI beta gene and to investigate its association with asthma and total IgE levels in 3 Asian populations. METHODS: A total of 291 asthmatic patients (141 Chinese, 68 Malay, and 82 Indian) and 355 asymptomatic blood donors (157 Chinese, 100 Malay, and 98 Indian) were recruited. The E237G genotype was determined by allele-specific polymerase chain reaction. Total serum IgE level was measured by enzyme-linked immunosorbent assay. RESULTS: The G allele was more common in Chinese controls (17.9%) than in Malay (11.5%) (P = .05) and Indian (9.2%) (P = .01) controls. Genotypes with the G allele were more prevalent in asthmatic patients in the Chinese population (odds ratio, 1.97; 95% confidence interval, 1.05-3.77; P = .04). CONCLUSIONS: There were interethnic differences in the frequencies of the G variant among Chinese, Malay, and Indian populations. The E237G polymorphism of FcsRI beta may be a risk factor for asthma in the Chinese population.

Adult↗
PubMed1999

Imaging of Soft Tissue Neoplasms in the Adult: Benign Tumors.

This discussion reviews the spectrum of benign soft tissue tumors usually found in adults. Lesions most commonly identified in the pediatric population, tumorlike masses, and malignant tumors are discussed in other articles in this issue. Rather than presenting a complete review, the focus of this article is on benign tumors in which the diagnosis may be confidently made or strongly suggested on the basis of imaging. Diagnoses presented include those for lipoma, lipoma variants, giant cell tumor of the tendon sheath, pigmented villonodular synovitis, superficial and deep fibromatoses, elastofibroma, and peripheral nerve sheath tumors.

Journal Article↗
PubMed2002

Heritability of mammographic density, a risk factor for breast cancer.

BACKGROUND: Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30 percent of the age-adjusted variation in the percentage of dense tissue. METHODS: We undertook two studies of twins to determine the proportion of the residual variation in the percentage of density measured by mammography that can be explained by unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. Information on putative determinants of breast density was obtained by questionnaire. Mammograms were digitized, randomly ordered, and read by a blinded investigator. RESULTS: After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in North America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variants attributable to additive genetic factors) accounted for 60 percent of the variation in density (95 percent confidence interval, 54 to 66) in Australian twins, 67 percent (95 percent confidence interval, 59 to 75) in North American twins, and 63 percent (95 percent confidence interval, 59 to 67) in all twins studied. CONCLUSIONS: These results show that the population variation in the percentage of dense tissue on mammography at a given age has high heritability. Because mammographic density is associated with an increased risk of breast cancer, finding the genes responsible for this phenotype could be important for understanding the causes of the disease.

Adipose Tissue↗
PubMed2003

Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility.

Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.

Adult↗
PubMed2007

Association of the C-344T aldosterone synthase gene variant with essential hypertension: a meta-analysis.

BACKGROUND: The CYP11B2 gene (CYP11B2) encoding aldosterone synthase has been associated with essential hypertension and some, but not all, studies have reported that the C-344T variant may influence the risk of the disease. OBJECTIVE: We performed a systematic review of the literature by means of a meta-analysis to evaluate the influence of the C-344T CYP11B2 polymorphism on arterial hypertension and intermediate phenotypes. METHODS: From 485 reports, we included 42 observational studies, case-control and cohort at baseline. Fixed and random effect models were used to pool data from individual studies. RESULTS: From 19 heterogeneous studies including 5343 essential hypertensive and 5882 control subjects, we found a significant association between hypertension and the C-344T variant in fixed but not in random effect models [for homozygous CC: odds ratio (OR), 0.834; 95% confidence interval (CI), 0.760-0.914; P < 0.0001, n = 11 225]. Besides, homozygous CC subjects had lower plasma renin activity (D, -0.161; 95% CI, -0.279 to -0.043; P < 0.01, n = 1428) but no difference in plasma aldosterone levels (D, -0.006; 95% CI, -0.081 to 0.07; P = 0.88, n = 2872). Limiting the quantitative analysis of blood pressure to 13 studies including only untreated individuals, no significant association was found for systolic arterial blood pressure (D, 0.042; 95% CI, -0.057 to 0.141; P = 0.41, n = 1775) and diastolic arterial blood pressure (D, 0.026; 95% CI, -0.073 to 0.125; P = 0.61, n = 1775). CONCLUSION: Homozygous individuals for the -344C CYP11B2 allele are at 17% lower risk of hypertension with respect to homozygous TT subjects.

Aldosterone↗