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PubMed2002

Polygenic susceptibility to breast cancer and implications for prevention.

The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases.

Breast Neoplasms↗
PubMed1997

beta-Glucuronidase in common duct bile, methodological aspects, variation of pH optima and relation to gallstones.

beta-Glucuronidase of human or bacterial origin may deconjugate bilirubin diglucuronide, causing pigment gallstones. Intrinsic interference by biliary compounds must be minimized for accurate assay of beta-glucuronidase. We report a modified ion-pair extraction of interfering substances by tetrahexylammonium chloride (THAC) in ethyl acetate in the presence of albumin, and a microtitre plate assay for biliary beta-glucuronidase activity in bile with the substrate p-nitrophenol-glucuronide. Adding albumin improved the recovery of beta-glucuronidase activity to 99.8% (CV 1.9%), and 92.2% of the bilirubin in bile samples was extracted in one step. Competitive inhibition was overcome by increasing the substrate concentration. In endoscopically obtained common duct bile from 44 patients, five different beta-glucuronidase activity peaks were identified, at pH 3.9, 4.8, 5.3, 5.8 and 7.2. The pH profiles were classified into one bacterial pattern and five patterns for presumed human beta-glucuronidase. Of the latter patterns, four displayed dual activity peaks. In a second sample, obtained at follow up in four patients, their original pH profile was maintained. In conclusion, using the modified purification and assay system, we found functionally diverse subcategories of human beta-glucuronidase with respect to activity at variable pH. Our results indicate that several pH optima have to be taken into consideration in order to clarify the role of human biliary beta-glucuronidase in the pathogenesis of pigment gallstones. Bacterial beta-glucuronidase activity was associated with duodenal diverticula (p < 0.05) and common duct stones (p < 0.05).

Adult↗
PubMed1991

Theophylline in asthma and COPD: changing perspectives and controversies.

Theophylline's role in the treatment of airway obstruction has been challenged, yet it remains a useful agent in the management of obstructive lung disease. It has a narrow therapeutic range and frequent side effects. Drug interactions are common, and variations in theophylline clearance among patients arise from individual differences in its absorption, metabolism, and elimination. Acute bronchospasm is best treated with inhaled sympathomimetic agents, but the nonbronchodilator effects of theophylline offer therapeutic benefits for the patient with non-reversible disease. When properly monitored by serum level determinations, theophylline may be used as an adjunct to aerosol therapy and corticosteroids in asthma. However, the patient with COPD may benefit the most from an empiric trial of the drug, using lower doses than were commonly employed in the past.

Asthma↗
PubMed2001

Catalog of 434 single-nucleotide polymorphisms (SNPs) in genes of the alcohol dehydrogenase, glutathione S-transferase, and nicotinamide adenine dinucleotide, reduced (NADH) ubiquinone oxidoreductase families.

An approach based on development of a large archive of single-nucleotide polymorphisms (SNPs) throughout the human genome is expected to facilitate large-scale studies to identify genes associated with drug efficacy and side effects, or susceptibility to common diseases. We have already described collections of SNPs present among various genes encoding drug-metabolizing enzymes. Here we report SNPs for such enzymes at additional loci, including 8 alcohol dehydrogenases, 12 glutathione S-transferases, and 18 belonging to the NADH-ubiquinone oxidoreductase family. Among DNA samples from 48 Japanese volunteers, we identified a total of 434 SNPs at these 38 loci: 27 within coding elements, 52 in 5' flanking regions, five in 5' untranslated regions, 293 in introns, 20 in 3' untranslated regions, and 37 in 3' flanking regions. The ratio of transitions to transversions was approximately 2.1 to 1. Among the 27 coding SNPs, 13 were nonsynonymous changes that resulted in amino acid substitutions. Our collection of SNPs derived from this study should prove useful for investigations designed to detect associations between genetic variations and common diseases or responsiveness to drug therapy.

Alcohol Dehydrogenase↗
PubMed2003

Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes.

Individual risk and the population incidence of disease result from the interaction of genetic susceptibility and exposure. DNA repair is an example of a cellular process where genetic variation in families with extreme predisposition is documented to be associated with high disease likelihood, including syndromes of premature aging and cancer. Although the identification and characterization of new genes or variants in cancer families continues to be important, the focus of this paper is the current status of efforts to define the impact of polymorphic amino acid substitutions in DNA repair genes on individual and population cancer risk. There is increasing evidence that mild reductions in DNA repair capacity, assumed to be the consequence of common genetic variation, affect cancer predisposition. The extensive variation being found in the coding regions of DNA repair genes and the large number of genes in each of the major repair pathways results in complex genotypes with potential to impact cancer risk in the general population. The implications of this complexity for molecular epidemiology studies, as well as concepts that may make these challenges more manageable, are discussed. The concepts include both experimental and computational approaches that could be employed to develop predictors of disease susceptibility based on DNA repair genotype, focusing initially on studies to assess functional impact on individual proteins and pathways and then on molecular epidemiology studies to assess exposure-dependent health risk. In closing, we raise some of the non-technical challenges to the utilization of the full richness of the genetic variation to reduce disease occurrence and ultimately improve health care.

Amino Acid Substitution↗
PubMed2002

A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma.

Multiple endocrine neoplasia type 2 (MEN 2) comprises a heterogeneous group of neoplasic disorders that most commonly have a single missense substitution of the RET protooncogene (RET) involving exons 10 and 11. It was previously reported a MEN 2A kindred in which the father presented with a rare phenotype consisting of bilateral ACTH-producing pheochromocytoma and medullary thyroid carcinoma. We recently performed mutational analysis of the father and his 4 children using a denaturing gradient gel electrophoresis approach and PCR-amplified genomic DNA, followed by direct sequencing or restriction fragment length polymorphism testing. All 4 children showed a RET sequence variation. The common exon 11 Cys(634)Arg RET mutation was present in 2 of the 4 children who had undergone thyroidectomy for C cell disease. The remaining 2 children, who did not harbor the Cys(634)Arg mutation and are negative for C cell and adrenal disease, carry a previously unreported Val(648)Ile missense change in RET exon 11. This novel substitution was not found in the unaffected mother or in 200 control alleles. Both RET variants were present in the father affected with MEN 2A and the unusual ACTH-producing pheochromocytoma. We speculate that the double RET mutation may have modified and contributed to the rare MEN 2A phenotype in the father.

Adrenal Gland Neoplasms↗
PubMed2003

The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.

Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.

Black or African American↗
PubMed1985

Anatomy of the choledochopancreatic duct junction in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare disease for which the etiology is unknown. Because abnormalities of the choledochopancreatic duct junction (CDPDJ) have been implicated in the pathogenesis of other rare biliary problems such as choledochal cysts and biliary atresia, we reviewed the cholangiographic anatomy of the CDPDJ in our patients with PSC. From 1955 through July 1983, 46 patients with PSC were seen at the University of California at Los Angeles Medical Center. In 20 of these 46 patients anatomy of the CDPDJ could be evaluated by review of endoscopic retrograde cholangiopancreatography (11 patients) or by reflux into the pancreatic duct during transhepatic, operative, or postoperative tube cholangiography (nine patients). Roentgenograms were evaluated for the length of common channel of the biliary and pancreatic ducts and the degree of reflux into and anatomic abnormalities of the pancreatic duct. All bile ducts were abnormal, and pancreatic duct reflux occurred in 14 of 42 patients (33%) who underwent transhepatic or tube cholangiography. An abnormally long (greater than 15 mm) common channel was present in two of 20 patients (10%), pancreatic duct reflux of more than 100 mm occurred in six of 14 patients (43%), and pancreatic duct abnormalities were seen in nine of 18 patients (50%). These data suggest that in patients with PSC abnormal pancreatic duct reflux and anatomy are common but variations in the anatomy of the CDPDJ are rare. However, altered function of the CDPDJ may contribute to excessive reflux into and anatomic changes of the pancreatic ducts and the moderate incidence of pancreatitis observed in patients with PSC.

Adult↗
PubMed2005

Metal concentrations in the radula of the common limpet, Patella vulgata L., from 10 sites in the UK.

Metal (Al, As, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, Pb, Zn) levels in the feeding organ or radula of the common limpet Patella vulgata L. were surveyed in 10 populations over a approximately 150-km stretch of coastline in north-east England. The most northern population was at Beadnell in Northumberland and the most southern was at Port Mulgrave in North Yorkshire; sites included unspoilt bays and areas heavily affected by industrial contamination such as the River Tees estuary. We hypothesized that the radula might be used as an indicator of environmental contamination. There were significant differences between the sites in the ratio of radula length to shell length. Limpets from Whitburn had the smallest radula fraction (mean = 1.665), while those from Port Mulgrave the largest (mean = 1.998). Such variation is common in the literature and we detected no correlate and propose no cause. Iron was clearly the dominant metal in the radulae, with an overall of mean of 1.46% of radular weight, though this is rather low in comparison to values in the literature. Iron is naturally secreted into the developing radula as a putative hardening agent. The next most abundant metals, in descending order, were Na (at approximately 2000-8000 microg g(-1)), K, Mg, Ca (approximately 1000-1500 microg g(-1)), Zn, Cu, Al, Pb (approximately 7-75 microg g(-1)), Mn, As, Cd (approximately 0-1 microg g(-1)). All but Al and Cd showed significant differences between the sites, but not in any consistent or convincing geographic manner. Nevertheless, the variations in metal levels between sites (e.g. Fe > 72%, Cu and Zn > 10-fold) suggest an environmental cause, but we are unable to offer any responsible factor, for example, there appeared little effect of the River Tees estuary. Cadmium is at a relatively low level in the radula in comparison to published data on pedal mucus and the flesh, but Pb is relatively high in pedal mucus and the radula and this might suggest that the radula is a detoxification route for Pb. Although the relationship between radula metal content and environmental metal content is unknown, the radula is constantly replaced and so may yet have the potential to be of use as a bioindicator, integrating metal exposure over much shorter periods than whole body burdens.

Animals↗
PubMed2002

Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.

The plasma concentrations of cholesterol precursor sterols and plant sterols vary over a 5- to 10-fold range among normolipidemic individuals, and provide indices of the relative rates of cholesterol synthesis and fractional absorption. In the present study, we examined the relative contributions of genetic and environmental factors to variation in the plasma concentrations and sterol-cholesterol ratios of five noncholesterol sterols, including the 5alpha-saturated derivative of cholesterol (cholestanol), two precursors in the cholesterol biosynthesis pathway (desmosterol and lathosterol), and two phytosterols (campesterol and sitosterol). Plasma sterol concentrations were highly stable in 30 individuals measured over a 48 week period. Regression of offspring sterol levels on the parental values indicated that plasma levels of all five noncholesterol sterols were highly heritable. Analysis of monozygotic and dizygotic twin pairs also indicated strong heritability of all five sterols. Two common sequence variations (D19H and T400K) in ABCG8, an ABC half-transporter defective in sitosterolemia, were associated with lower concentrations of plant sterols in parents, and in their offspring.Taken together, these findings indicate that variation in the plasma concentrations of noncholesterol sterols is highly heritable, and that polymorphism in ABCG8 contributes to genetic variation in the plasma concentrations of plant sterols.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Directly transmitted unbalanced chromosome abnormalities and euchromatic variants.

In total, 200 families were reviewed with directly transmitted, cytogenetically visible unbalanced chromosome abnormalities (UBCAs) or euchromatic variants (EVs). Both the 130 UBCA and 70 EV families were divided into three groups depending on the presence or absence of an abnormal phenotype in parents and offspring. No detectable phenotypic effect was evident in 23/130 (18%) UBCA families ascertained mostly through prenatal diagnosis (group 1). In 30/130 (23%) families, the affected proband had the same UBCA as other phenotypically normal family members (group 2). In the remaining 77/130 (59%) families, UBCAs had consistently mild consequences (group 3). In the 70 families with established EVs of 8p23.1, 9p12, 9q12, 15q11.2, and 16p11.2, no phenotypic effect was apparent in 38/70 (54%). The same EV was found in affected probands and phenotypically normal family members in 30/70 families (43%) (group 2), and an EV co-segregated with mild phenotypic anomalies in only 2/70 (3%) families (group 3). Recent evidence indicates that EVs involve copy number variation of common paralogous gene and pseudogene sequences that are polymorphic in the normal population and only become visible at the cytogenetic level when copy number is high. The average size of the deletions and duplications in all three groups of UBCAs was close to 10 Mb, and these UBCAs and EVs form the "Chromosome Anomaly Collection" at http://www.ngrl.org.uk/Wessex/collection. The continuum of severity associated with UBCAs and the variability of the genome at the sub-cytogenetic level make further close collaboration between medical and laboratory staff essential to distinguish clinically silent variation from pathogenic rearrangement.

Chromosome Aberrations↗
PubMed1989

Orthopedic assessment of young children: developmental variations.

Parents often seek orthopedic evaluation of their young children because of apparent abnormalities. However, many of these are simply developmental variations that are part of normal growth and development. Pes planus, or flat foot, is one of the earliest and most common concerns. Torsional variations are also often seen; the presenting complaint may be intoeing (metatarsus adductus, tibial torsion and increased femoral anteversion) or out-toeing (pes calcaneovalgus and external rotation contractures of the hips). Angular variations (genu varum and genu valgum) are also seen frequently in young children. In assessing each finding, consideration must be given to the age at which the finding may be considered within normal limits, methods of examination and documentation, the expected course, findings that may signify abnormality, and appropriate follow-up and referral. An understanding of these common developmental variations in the orthopedic assessment of young children will enable the health care provider to respond to parents' concerns with accurate information and counseling.

Child↗
PubMed1996

Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge.

We examined the role of common genetic variation in determining the consistency and magnitude of change in plasma total cholesterol (TC) levels in response to two separate changes from a high-saturated (SFA) to a low-saturated/high-polyunsaturated-fat (PUFA) diet, in a group of free-living healthy men and women. Consistent responders were defined as those whose mean difference in the change in TC was within one SD of the mean for all participants, and the remainder were defined as variable responders. DNA was obtained from 55 individuals and genotype determined at the apolipoprotein (apo) B locus (signal peptide, SP), apoCIII (C1100-T) and lipoprotein lipase (LPL) gene loci (HindIII). In the 38 consistent responders, the apoBSP24 allele was significantly more common than in the 17 individuals with a variable response (0.29 vs. 0.12; p < 0.05). No other polymorphism showed a significant frequency difference between groups. In the group as a whole, the correlation between the change in TC level in response to the first and second dietary change was 0.28 (p = 0.05), but those with one or more apoB SP24 alleles and those with the apoCIII genotype CC had a significantly higher correlation than those with other genotypes (0.46 (p = 0.05) vs. 0.12 (NS) and 0.31 (p = 0.05) vs. 0.02 (NS), respectively). In the group as a whole, mean response left TC 10% higher on the SFA than on the PUFA diet, and neither apoB nor apoCIII genotypes affected the magnitude of this response. However, individuals with the LPL HindIII genotype H+ H+ had a significantly smaller change in mean TC in response to diet than those with one or more H- allele (9.3% vs. 14.4%; p = 0.03). Thus variation at the apoB and apoCIII loci affects the consistency of response to change in dietary fat content, while variation at the LPL gene locus affects magnitude of response.

Apolipoproteins B↗
PubMed2003

M129V variation in the prion protein may influence cognitive performance.

Correlations between general intelligence (g) and brain volume are about 0.40, and the correlation between g and white matter volume has been reported to be largely due to genetic factors. Establishing that the correlation between brain volumes and cognitive abilities is mediated by shared genetic factors is only the first step in unveiling the relation between them. We have recently shown that methionine at codon 129 in the prion protein is associated with white matter reduction in a group of healthy volunteers and schizophrenic patients. The present study examines the influence of the same genetic variation on psychometric cognitive performance measurements in 335 community-based healthy volunteers. The polymorphism was associated with Full Scale IQ (genotype: F=4.38, df=2/317, P=0.013; allele: F=8.04, df=1/658, P=0.005), as measured by HAWIE-R (German version of the Wechsler Adult Intelligence Scale, Revised). Genotype accounted for 2.7% of the total variability in Full Scale IQ (partial eta2=0.027). An exploratory analysis revealed association with several HAWIE-R subscales; the association with the Digit Symbol subtest remained significant after correction for multiple testing. In summary, we deliver evidence for an association of a common genetic variation in the prion protein gene with cognitive performance. However, independent replications are needed before firm conclusions can be drawn.

Adult↗
PubMed2006

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males.

Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioural traits in normal individuals has been examined. DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioural traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 ("straightforwardness") facet with common allelic variants at the promoter VNTR. Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioural traits in normal males may be very specific. In contrast, several traits of the C ("conscientiousness") axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioural attribute of "straightforwardness", while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to "conscientiousness". This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioural traits.

Black or African American↗
PubMed2001

Receptor polymorphisms and diseases.

The aim of our review is to summarize common genetic variations of some receptors associated with clinical consequences, which were not outlined in the previous special issue of this journal. Because of the multiple pathomechanisms of diseases, a set of genetic variation can play a role in the development of pathological conditions. From the data available three articles would merit a greater interest. In systemic lupus erythematosus the associations related to some polymorphisms of Fc-, tumor necrosis factor (TNF) alpha- and interferon receptor may explore new autoimmunological and inflammatorical pathomechanisms. In the endocrinology, the androgen receptor repeat polymorphism will exert significant aspects in the development of prostate cancer. The pleoitropic responsibility of vitamin D3 receptor polymorphism in the pathogenesis of immunological disorders (primary biliary cirrhosis, inflammatory bowel disease, type 1 diabetes mellitus) and of malignancies (malignant melanoma, breast cancer) shed light on the importance of common nuclear receptors. Nevertheless, in the future studies a more consistent approach minimizing requirement bias in the selection of patients will approve our understanding the role of genetic influence on the pathogenesis of diseases.

Antigens, CD↗
PubMed2003

Pharmacogenomics of hypertension.

PURPOSE OF REVIEW: The emerging field of pharmacogenomics has the potential to fundamentally change the management of essential hypertension, a common, perhaps polygenic syndrome characterized by substantial inter-individual variability in drug responsiveness. As understanding of sequence diversity in the human genome progresses, the prospect grows for tailoring the prescription of antihypertensive drugs to complement common genetic variations among individual patients, allowing optimization of blood pressure control and improved avoidance of drug side effects. Some principles of pharmacogenomics are presented here, along with a review of the most recent literature on genetic determinants of antihypertensive drug responses, with a preview of likely developments to come. RECENT FINDINGS: Polymorphisms at candidate pharmacodynamic loci (such as angiotensinogen, angiotensin converting enzyme, and the angiotensin II receptor) have already been shown to predict responses to such specific treatments as angiotensin converting enzyme inhibition and angiotensin II blockade. The National Institutes of Health have established a multi-institutional pharmacogenetics network and knowledge base, whose goals include understanding how common polymorphisms influence therapeutic responses to a variety of drugs, including antihypertensive agents. SUMMARY: The study of genetic determinants of drug responses, particularly at the pharmacodynamic (drug target/receptor and post-receptor) level, is likely to allow us to more precisely tailor therapy to the individual patient, as well as to promote the creation of novel therapies.

Animals↗
PubMed2003

Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study.

We describe an approach for picking haplotype-tagging single nucleotide polymorphisms (htSNPs) that is presently being taken in two large nested case-control studies within a multiethnic cohort (MEC), which are engaged in a search for associations between risk of prostate and breast cancer and common genetic variations in candidate genes. Based on a preliminary sample of 70 control subjects chosen at random from each of the 5 ethnic groups in the MEC we estimate haplotype frequencies using a variant of the Excoffier-Slatkin E-M algorithm after genotyping a high density of SNPs selected every 3-5 kb in and surrounding a candidate gene. In order to evaluate the performance of a candidate set of htSNPS (which will be genotyped in the much larger case-control sample) we treat the haplotype frequencies estimate above as known, and carry out a formal calculation of the uncertainty of the number of copies of common haplotypes carried by an individual, summarizing this calculation as a coefficient of determination, R2h. A candidate set of htSNPS of a given size is chosen so as to maximize the minimum value of R2h over the common haplotypes, h.

Aromatase↗