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David E C Cole

Publications and source records attributed to David E C Cole.

At least 19 recordsLinked to original sources
PubMed2006

Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.

BACKGROUND: BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. METHODS: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 first-degree relatives. Population allele frequencies and relative risks (RRs) were derived from the regression results by an extension of Saunders-Begg methods. Age-specific Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. RESULTS: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confidence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR = 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation's position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%). CONCLUSIONS: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.

Breast Neoplasms↗
PubMed2006

Relationship of the human growth hormone receptor exon 3 genotype with final adult height and bone mineral density.

CONTEXT: Three recent clinical studies have reported that two of the most common isoforms of the human GH (hGH) receptor (hGHR), exon 3 full-length (3+) and exon 3 deleted (3-), may have differential effects on the growth response of children receiving hGH therapy, whereas others refute this. However, none of the investigations has explored the relationship between these hGHR isoforms and final adult height (FAH) or measures of bone mineral density (BMD) within a healthy adult population. OBJECTIVE: The aim of this study was to investigate the possible influences of hGHR exon 3 isoforms on FAH and BMD measures of a normal population. DESIGN: The study was designed to correlate the hGHR exon 3 genotype of a cohort of healthy adults with FAH, BMDs [spine (L2-L4) and hip (femoral neck)], and quantitative ultrasound (QUS) of the heel. PATIENTS: Participants were 368 unrelated healthy adult white women, aged 18-35 yr. MAIN OUTCOME MEASURES: We analyzed association of hGHR exon 3 genotypes with FAH, BMD, and QUS. Heights were measured using a stadiometer, BMDs using dual-energy x-ray absorptiometry, and QUS by standard technique. Detailed medical histories, including lifestyle factors, were obtained using a standardized interview. RESULTS: The distribution of hGHR genotypes in the 368 samples was 53.3% for 3+/3+, 35.6% for 3+/3-, and 11.1% for 3-/3-. There was no correlation between the hGHR exon 3 genotypes and FAH, BMD, or QUS in this cohort. CONCLUSION: The hGHR 3+ and 3- isoforms appear not to have differential effects on two major growth outcomes of hGH action, FAH, and BMD in a population of healthy adult women.

Adolescent↗
PubMed2006

Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor.

INTRODUCTION: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. RESULTS: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. CONCLUSION: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.

Adult↗
PubMed2006

Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy.

PURPOSE: This study evaluated whether additional palliative benefits could be derived from the second-line use of the more potent bisphosphonate zoledronic acid in metastatic breast cancer patients with either progressive bone metastases or skeletal-related events (SRE), despite first-line therapy with either pamidronate or clodronate. PATIENTS AND METHODS: This prospective study evaluated the impact of second-line zoledronic acid on pain, quality of life, and markers of bone turnover (for example, urinary N-telopeptide [NTX]). Patients received monthly zoledronic acid (4 mg) for 3 months. Study evaluations were made weekly during the first month and again at week 8. No changes in chemotherapy or endocrine therapy were allowed in the month before or after commencing study treatment. RESULTS: Thirty-one women completed this study. By week 8, patients had experienced significant improvements in pain control (P < .001). There was a downward trend in urinary NTX levels over the same time period (P = .008). Overall, there was a trend towards a positive correlation between improvement in pain control and reduction in week one urinary NTX relative to baseline (Spearman's rho r = 0.27; P = .15). CONCLUSION: This is the first study to demonstrate that patients with either progressive bone metastases or SREs while on clodronate or pamidronate can have relevant palliative benefits with a switch to the more potent bisphosphonate zoledronic acid. This is reflected by significant improvements in pain control and bone turnover markers. If confirmed in randomized trials, these findings have major implications to the use of bisphosphonates in both the metastatic and adjuvant settings.

Adult↗
PubMed2006

Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance.

CONTEXT: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma. OBJECTIVE: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation. PATIENTS, METHODS, AND RESULTS: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767-769. Nine family members (age, 33.9 +/- 19.8 yr, mean +/- SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma. CONCLUSIONS: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.

Adenoma↗
PubMed2006

Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort.

OBJECTIVES: To assess allele frequency and genotype distribution of CYP2C9 polymorphisms in patients (n = 189) attending an anticoagulant clinic in comparison to control patients (n = 177) and also to assess if the patients with variant genotypes require lower doses of warfarin. METHODS: Genotyping of the common CYP2C9 variants *2 and *3 was carried out by multiplexed PCR-RFLP while the *5 and *6 allele variants were genotyped by singleton PCR-RFLP. DNA sequencing was used to confirm genotype in all specimens with *3, *4 and *6 alleles. RESULTS: CYP2C9 allele frequencies in patients were 0.81 for *1, 0.11 for *2 and 0.08 for *3, compared to 0.88, 0.08 and 0.04, respectively, in controls. Patients with *1/*3 and *X/*X (where *X is *2 or *3) genotypes required 32 to 67% less warfarin in comparison to patients with the normal *1/*1 genotype. Other alleles were observed in less than 1% of subjects. CONCLUSIONS: Allele frequencies and genotypes for CYP2C9*2 and *3 variants in patients on warfarin are not statistically different from controls whether or not they are stratified for ethnicity. Less common genotypes (*4, *5, *6) do not contribute significantly to warfarin sensitivity among patients attending a routine anticoagulation clinic. CYP2C9 genotype predicts warfarin dosage even in an uncontrolled, retrospective survey of unselected patients on warfarin therapy.

Aged↗
PubMed2006

A hypocalcemic child with a novel activating mutation of the calcium-sensing receptor gene: successful treatment with recombinant human parathyroid hormone.

CONTEXT: Persistent hypercalciuria, with the attendant risk of nephrocalcinosis and eventual renal failure, is common in hypoparathyroid patients, especially those with activating mutations of the calcium-sensing receptor (CASR) gene, being treated with oral calcium and calcitriol. Treatment with replacement PTH may be warranted, although this has yet to be evaluated in children. OBJECTIVES: The objectives of this study were to identify the cause of the disorder in a young hypocalcemic patient and to assess the efficacy of treatment of the patient with recombinant human PTH(1-34). SUBJECT: An infant presenting with hypocalcemia at 3 wk of age was studied. METHODS: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The patient was treated with twice-daily administration of recombinant human PTH(1-34) over a 17-month period. RESULTS: The proband was heterozygous for a de novo novel missense mutation (L727Q), on the border between transmembrane helix 4 and intracellular loop 2 of the CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve vs. that for the wild-type receptor [EC(50); mutant, 2.59 +/- 0.11 mm (mean +/- se) vs. wild-type, 3.78 +/- 0.12 mm, P < 0.001]. During treatment with PTH(1-34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably. CONCLUSION: PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients.

Calcium↗
PubMed2006

A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young caucasian women.

The parathyroid hormone type 1 receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHRP). Interacting with this receptor, PTHRP contributes to skeletal development through the regulation of chondrocyte proliferation and differentiation. Recently, a tetranucleotide repeat-(AAAG)( n )-in the P3 promoter of the PTHR1 gene has been shown to have functional activity in vitro, and homozygosity for (AAAG)(6), or the 6/6 genotype, has been associated with greater adult height compared to the 5/5 genotype. In this study, we evaluated the association of (AAAG)( n ) with height and bone mineral density (BMD) measured at lumbar spine (LS) and femoral neck (FN) in a cohort of 677 young caucasian women 18-35 years of age. Genomic DNA was amplified and genotyped by comparison with sequenced controls following electrophoretic separation through high-resolution polyacrylamide gels. Allele frequencies for (AAAG)( n ) were: 76.8% (n=5); 20.9% (n=6); 1.8% (n=7); 0.18% (n=8); 0.27% (n=9); 0.08% (n=2), and there was no evidence for Hardy-Weinberg disequilibrium. Analysis of variance showed that subjects bearing one or two (AAAG)(6) alleles (6/X & 6/6) were significantly taller (165.7+/-0.5 cm) than the others (X/X, 164.5+/-0.3 cm; P=0.034). This association was significant after adjusting for multiple covariates-current age, age at menarche, physical activity, smoking status, and intakes of caffeine and calcium. Comparison of genotype groups for BMD was not significant at LS, but BMD was significantly higher at FN in the group with at least one (AAAG)(6) allele (adjusted means: 1.021+/-0.008 vs. 0.999+/-0.006 g/cm(2), P=0.032). In conclusion, our data show that subjects bearing one or two (AAAG)(6) alleles are taller than subjects without, reinforcing the notion that in vivo variation in promoter activity of the PTHR1 gene may be a relevant genetic influence on final adult height and BMD.

Adult↗
PubMed2006

G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective.

Genetic variation in specific G-protein coupled receptors (GPCRs) is associated with a spectrum of respiratory disease predispositions and drug response phenotypes. Although certain GPCR gene variants can be disease-causing through the expression of inactive, overactive, or constitutively active receptor proteins, many more GPCR gene variants confer risk for potentially deleterious endophenotypes. Endophenotypes are traits, such as bronchiole hyperactivity, atopy, and aspirin intolerant asthma, which have a strong genetic component and are risk factors for a variety of more complex outcomes that may include disease states. GPCR genes implicated in asthma endophenotypes include variants of the cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2), and prostaglandin D2 receptors (PTGDR and CRTH2), thromboxane A2 receptor (TBXA2R), beta2-adrenergic receptor (ADRB2), chemokine receptor 5 (CCR5), and the G protein-coupled receptor associated with asthma (GPRA). This review of the contribution of variability in these genes places the contribution of the cysteinyl leukotriene system to respiratory endophenotypes in perspective. The genetic variant(s) of receptors that are associated with endophenotypes are discussed in the context of the extent to which they contribute to a disease phenotype or altered drug efficacy.

Aspirin↗
PubMed2006

Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder?

This report describes the case of a 4 1/2-year-old female with developmental delay and tonic-clonic seizures, persistently elevated serum alkaline phosphatase activity, and low serum pyridoxal 5'-phosphate. Born at term to consanguineous parents, she was dysmorphic and delayed at 5 months. At 11 months, seizures and microcephaly were evident but skeletal and cerebral imaging, karyotyping, and genetic metabolic tests were unremarkable. Serum alkaline phosphatase activity, however, was elevated (1.3 +/- 0.6 times greater than the upper limit of normal) on seven occasions between 5 months and 4(1/2) years of age. Hyperphosphatasia with neurologic deficit (MIM #239300), a rare autosomal recessive disorder, was diagnosed. The low serum levels of pyridoxal 5'-phosphate (6 nmol/L; normal >20 nmol/L) prompted a pyridoxine challenge. A clinically significant but paradoxical response was observed. On electroencephalography, diffuse delta slow waves (1-2 Hz) were observed, suggestive of stage 3 or 4 slow-wave sleep. With daily administration of 100 mg pyridoxine and withdrawal of phenobarbital, seizures were not evident. We suggest that serum alkaline phosphatase should be measured in cases of seizures with paradoxical electroencephalographic response to pyridoxine. Conversely, pyridoxine challenge should be considered in cases of hyperphosphatasia with seizures and neurologic deficit.

Alkaline Phosphatase↗
PubMed2005

Can bone markers guide more effective treatment of bone metastases from breast cancer?

Bone metastases are a common problem for breast cancer patients, causing significant disease-related morbidity and mortality. Bisphosphonates and other cancer therapies can assist in managing these patients. However, assessing treatment efficacy in bone metastases is hampered by the inability to accurately measure disease response within a clinically desirable time frame. Bone-specific biochemical markers, notably type I collagen telopeptide cross-link by-products such as N-telopeptide (NTx) and C-telopeptide (CTx), have been shown to be effective tools for assessing the severity and extent of bone metastases, and the response to bisphosphonates. Elevated NTx levels correlate with adverse clinical outcomes. Normalization of NTx and CTx excretion rates are associated with relief of symptoms and a reduced incidence of skeletal-related events (SRE). This review discusses the expanding role of these bone markers in guiding treatment of bone metastases from breast cancer.

Biomarkers, Tumor↗
PubMed2005

Thromboembolism in heart transplantation: role of prothrombin G20210A and factor V Leiden.

BACKGROUND: Thromboembolism has been reported as a frequent complication after cardiac transplantation. Many risk factors for thrombosis may explain this, such as metabolic alterations and the use of cyclosporine. In the general population, two single nucleotide polymorphisms (SNPs), factor V Leiden and prothrombin G20210A (PT G20210A), have been associated with a significant increase in the risk of thrombosis. However, these mutations have not been analyzed in cardiac transplant patients. We describe the protracted history of recurrent thromboembolism in a rare case of homozygosity for the PT G20210A variant. This prompted us to analyze the entire cardiac transplant cohort for the incidence of thromboembolic events and their association with these genetic polymorphisms. METHODS: We report the study of 84 cardiac transplant recipients. We retrospectively analyzed the frequency of thromboembolic episodes. The genotypes for FVL and PT G20210A were determined and correlated with those episodes. RESULTS: Our results confirm a very high incidence of thromboembolism in this population. We also found a significant increase in the likelihood of thromboembolism in subjects with the PTB G20210A variant (odds ratio 3.08; 95% confidence interval: 1.7-5.5). CONCLUSIONS: The incidence of thromboembolic complications after heart transplantation is increased and may be related in part to genetic predisposition.

Adult↗
PubMed2005

Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia.

Primary hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia. Pathophysiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the distal convoluted tubule. Recently, mutations in the TRPM6 gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, were identified as the underlying genetic defect. Here, the results of a TRPM6 mutational analysis of 21 families with 28 affected individuals are presented. In this large patient cohort, a retrospective clinical evaluation based on a standardized questionnaire was also performed. Genotype analysis revealed TRPM6 mutations in 37 of 42 expected mutant alleles. Sixteen new TRPM6 mutations were identified, including stop mutations, frame-shift mutations, splice-site mutations, and deletions of exons. Electrophysiologic analysis of mutated ion channels after heterologous expression in Xenopus oocytes proved complete loss of function of TRPM6. Clinical evaluation revealed a homogeneous clinical picture at manifestation with onset in early infancy with generalized cerebral convulsions. Initial laboratory evaluation yielded extremely low serum magnesium levels, low serum calcium levels, and inadequately low parathyroid hormone levels. Treatment usually consisted of acute intravenous magnesium supplementation leading to relief of clinical symptoms and normocalcemia, followed by lifelong oral magnesium supplementation. Serum magnesium levels remained in the subnormal range despite adequate therapy. This is best explained by a disturbed magnesium conservation in the distal convoluted tubule, which emerged in all patients upon magnesium supplementation. Delay of diagnosis resulted in permanent neurologic damage in three patients.

DNA Mutational Analysis↗
PubMed2005

Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel.

BACKGROUND: Variance of peak bone mass has a substantial genetic component, as has been shown with twin studies examining quantitative measures such as bone mineral density (BMD) and quantitative ultrasound (QUS). Evidence implicating single nucleotide polymorphisms (SNPs) of the transforming growth factor beta-1 (TGFB1) gene is steadily accumulating. However, a comprehensive look at multiple SNPs at this locus for their association with indices of peak bone mass has not been reported. METHODS: A cohort of 653 healthy Caucasian females 18 to 35 years old was genotyped for seven TGFB1 SNPs. Polymorphisms were detected by restriction endonuclease digestion of amplified DNA segments. RESULTS: The frequencies of the least common allele at G-800A, C-509T, codon 10 (L10P), codon 25 (R25P), codon 263 (T263I), C861-20T, and 713-8 delC loci were 0.07, 0.33, 0.41, 0.08, 0.04, 0.25 and 0.01, respectively. A significant association was seen between QUS Stiffness Index (QUS-SI) and the SNP at codon 10 and the linked promoter SNP, C-509T. This association remained significant after multiple regression was used to incorporate important clinical covariates--age, BMI, level of activity, family history, and caffeine intake--into the model. CONCLUSION: The association of QUS-SI with -509T is consistent with a gene-dose effect, while only individuals homozygous for the codon 10P allele showed a significant increase. In this cohort of young healthy Caucasian females, the T allele at position -509 is associated with greater bone mass as measured by calcaneal ultrasound.

Adult↗