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PubMed2002

Detection of regulatory variation in mouse genes.

Functional polymorphism in genes can be classified as coding variation, altering the amino-acid sequence of the encoded protein, or regulatory variation, affecting the level or pattern of expression of the gene. Coding variation can be recognized directly from DNA sequence, and consequently its frequency and characteristics have been extensively described. By contrast, virtually nothing is known about the extent to which gene regulation varies in populations. Yet it is likely that regulatory variants are important in modulating gene function: alterations in gene regulation have been proposed to influence disease susceptibility and to have been the primary substrate for the evolution of species. Here, we report a systematic study to assess the extent of cis-acting regulatory variation in 69 genes across four inbred mouse strains. We find that at least four of these genes show allelic differences in expression level of 1.5-fold or greater, and that some of these differences are tissue specific. The results show that the impact of regulatory variants can be detected at a significant frequency in a genomic survey and suggest that such variation may have important consequences for organismal phenotype and evolution. The results indicate that larger-scale surveys in both mouse and human could identify a substantial number of genes with common regulatory variation.

Alleles↗
PubMed2005

Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women.

OBJECTIVE: Postmenopausal estradiol (E(2)) levels vary widely between individuals and this variation is an important determinant of diseases such as osteoporosis. It has been suggested that the estrogen receptor alpha (ESR1) gene may influence peripheral E(2) levels, but the role of common sequence variations in the ESR1 gene is unclear. METHODS: In 631 postmenopausal women and 528 men from the Rotterdam Study, a population-based, prospective cohort study of individuals aged 55 years and over, ESR1 PvuII-XbaI haplotypes were determined and correlated with plasma E2 levels. RESULTS: In women, haplotype 1 (T-A) was significantly associated with an allele-dose-dependent decrease in E(2). After adjusting for age, body mass index, years since menopause and testosterone levels, plasma E(2) levels decreased by 1.90 pmol/l per allele copy of this haplotype (P < 0.05). Extreme genotypes, representing 23 and 27% of the population, varied by 3.93 pmol/l. No association with plasma testosterone was observed. In a subset of 446 women, no association of genotype with plasma concentrations of dehydroepiandrosterone sulfate, androstenedione or estrone was seen. In men, none of the sex hormone levels was associated with the ESR1 PvuII-XbaI haplotypes. CONCLUSION: We have demonstrated a role for genetic variations in the ESR1 gene in determining post-menopausal E(2) levels in women.

Aged↗
PubMed2004

Identifying functional genetic variants in DNA repair pathway using protein conservation analysis.

The role of DNA repair in initiation, promotion, and progression of malignancy suggests that variations in DNA repair genes confer altered cancer risk. Accordingly, DNA repair gene variants have been studied extensively in the context of cancer predisposition. Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome. A fraction of SNPs are located within the genes, which are likely to alter the gene expression and function. SNPs that change the encoded amino acid sequence of the proteins (non-synonymous; nsSNPs) are potentially genetic disease determinant variations. However, as not all amino acid substitutions are supposed to lead to a change in protein function, it will be necessary to have a priori prediction and determination of the functional consequences of amino acid substitutions per se, and then together with other genetic and environmental factors to study their possible association with a trait. Here we report the analysis of nsSNPs in 88 DNA repair genes and their functional evaluation based on the conservation of amino acids among the protein family members. Our analysis demonstrated that >30% of variants of DNA repair proteins are highly likely to affect the function of the proteins drastically. In this study, we have shown that three nsSNPs, which were predicted to have functional consequences (XRCC1-R399Q, XRCC3-T241M, XRCC1-R280H), were already found to be associated with cancer risk. The strategy developed and applied in this study has the potential to identify functional protein variants of DNA repair pathway that may be associated with cancer predisposition.

DNA Repair↗
PubMed2006

Persistent left superior vena cava with absent right superior vena cava: morphological CT features and clinical implications.

Here we report a rare case of the persisting left superior vena cava with simultaneous absence of the right superior vena cava. This central venous variation has been identified during a routine chest CT scan as follow-up after colonic cancer in an asymptomatic patient with no previous history of heart diseases. Morphological features of this variation are illustrated on axial CT images and 3D image reconstructions. This anomaly occurs in 0.1% of the general population. In presence with the right superior vena cava it is the most common anatomical variation in the central venous system with a reported occurrence of 0.2-8%. Such condition can be associated with additional congenital cardiovascular malformations and heart diseases or rhythm abnormalities. Diagnosis can be difficult and is often achieved incidentally since hemodynamics in these patients can be normal and clinical symptoms are mostly absent. Important clinical implications include difficulties in central venous access or cardiac pacemaker placement as well as management consequences in cardiothoracic surgery. In conclusion clinicians should be aware of this anomaly and their clinical relevance to avoid possible complications.

Aged↗
PubMedDate not supplied

Multifactorial inheritance of common white markings in the Arabian horse.

The results of a previous study were compatible with the hypothesis that common white facial markings in the Arabian horse have a multifactorial mode of inheritance. I expanded that study to (1) include the legs and therefore obtain insight into the heritability of common white markings in all peripheral regions (face and legs) of the Arabian horse and (2) investigate the influence of sex and the genotypes that produce the bay and chestnut phenotypes on the variation in common white markings. Both studies were based on computerized data obtained from the Arabian Horse Registry of America, Inc. Each leg of a horse was scored from 0 to 5 depending on the amount of whiteness present, and the four leg scores were added to obtain the total leg score for each horse. The facial region was divided into five areas, and each horse was given a score from 0 to 5 according to the number of areas with whiteness. Sire families were analyzed in which each sire family consisted of a sire, his foals, and the dams of those foals. There was a correlation between white facial scores and white leg scores, suggesting that both types of white markings are influenced by the same genetic mechanism. Sire-foal and dam-foal regression analyses were compatible with the hypothesis that common white leg markings also show multifactorial inheritance. Although the results support the model that additively acting genes (polygenes) influence the presence and extent of common white markings, the results also show that males are slightly more marked than are females and that chestnut horses are more heavily marked than are bay horses.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2006

NR4A2 genetic variation in sporadic Parkinson's disease: a genewide approach.

The NR4A2 gene, which may cause autosomal dominant Parkinson's disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotype-tagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population.

Case-Control Studies↗
PubMed1996

Allelic variation in the gene encoding the cholesteryl ester transfer protein is associated with variation in the plasma concentrations of cholesteryl ester transfer protein.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins. Mutations that abolish CETP function are associated with very high levels of HDL cholesterol, but the effect of more common allelic variation at this locus is less clear. In this study, we have measured plasma CETP concentration and plasma HDL cholesterol concentrations in 694 individuals from 106 nuclear families. Robust sibling-pair methods indicated linkage between the CETP locus and inter-individual variation in plasma CETP concentrations. Allelic variation at the CETP locus accounted for 20% of the variation in plasma CETP concentration. No relation between allelic variation at the CETP locus and plasma HDL cholesterol levels was detected. These data indicate that polymorphism in the CETP gene confers variation in plasma CETP concentration. However, this degree of variation in CETP function is not systematically associated with variation in plasma HDL-C concentrations.

Alleles↗
PubMed1999

Homocysteine: cholesterol of the 90s?

Homocysteine is a sulfur-containing amino acid generated through the demethylation of methionine. It is largely catabolized by trans-sulfuration to cysteine but it may also be remethylated to methionine. Dubbed 'the cholesterol of the 90s' by the lay press, homocysteine is thought to be thrombophilic and to damage the vascular endothelium. Total plasma homocysteine (tHcy) is now established as a clinical risk factor for coronary artery disease, as well as other arterial and venous occlusive disease in adult populations. Regulation of homocysteine is dependent on nutrient intake, especially folate, vitamins B6 and B12. It is also controlled by common genetic variations (polymorphisms) in how vitamins are utilized as cofactors in the reactions controlling homocysteine metabolism. Moreover, concentrations are age- and sex-dependent and are altered by renal function, hormonal status, drug intake and a variety of other common clinical factors. Considerable care must be taken in assaying tHcy. Plasma should be separated shortly after collection, to avoid artifactual increases due to synthesis by blood cells in vitro. Reference methods have not been validated and criteria for establishing reference ranges should take into account the variable prevalence of physiological hyperhomocysteinemia. Determination of tHcy should probably be limited to centres with relevant expertise and ability to maintain the high degree of precision required for reliable interpretation. Molecular testing for the genetic polymorphisms is still in the research phase but the ease and reliability of molecular diagnosis will speed its introduction into clinical laboratory practice--particularly in relation to diagnosis of thrombophilic disorders. Clinical research initiatives are being driven by the benefit that should be achieved by correction with vitamin supplements, particularly folate and B vitamins, but it must be recognized that prospective controlled studies to validate clinical benefit are only now being initiated. At the moment, it is safe to say that hyperhomocysteinemia is one of the few prevalent biochemical risk factors for thromboembolic disease that might be corrected by vitamin supplements. Such a possibility lies behind the growing momentum to recommend increased supplements of folate and B vitamins to at-risk population and patient groups today.

Adult↗
PubMed2005

Polymorphisms of the CLCN7 gene are associated with BMD in women.

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

Adult↗
PubMedDate not supplied

CAN'T MISS: conquer any number task by making important statistics simple. Part 7. Statistical process control: x-s control charts.

Statistical process control (SPC) can be thought of as the frequent monitoring of processes using inferential statistics. The feature that distinguishes SPC from the typical use of inferential statistics for analyzing populations is that in the former frequent samples are taken over time, whereas in inferential statistics a single sample is generaLLy taken before and after some intervention or treatment. An x-s control chart is used to monitor a continuous variable that reflects the output of a process. The x-s control chart is a graph that includes serial sample means (x) as the variables of interest, a centerline that represents the grand mean of the samples (x), and upper control limit (UCL) and lower control limit (LCL) that represent three standard errors (SEx) above and below the centerline. An x-s control chart is used to estimate with 99.7% confidence that the population mean of a continuous output variable was within the interval defined by the UCL and LCL during a period of baseline monitoring. It is further assumed that if the process remains stable, future population means wiLL remain between the control Limits for additional process outputs. Control charts allow the evaluation of both common- and special-cause variation. AnaLysis of the common-cause variation aLLows an assessment of the current process performance. Special-cause variation is identified when there is a sample mean that is beyond the UCL or LCL.

Confidence Intervals↗
PubMed2001

Catalog of 320 single nucleotide polymorphisms (SNPs) in 20 quinone oxidoreductase and sulfotransferase genes.

Single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes, transporters, receptors, and other drug targets have been widely implicated as contributors to differences among individuals as regards the efficacy and toxicity of many medications, as well as the susceptibility to complex diseases. By combining the polymerase chain reaction (PCR) technique with direct sequencing, we screened genomic DNAs from 48 Japanese volunteers for SNPs in genes encoding three quinone oxidoreductases (NQO1, NQO2, and PIG3) and 17 sulfotransferases (SULT1A1, SULT1A2, SULT1A3, SULT1C1, SULT1C2, SULT2A1, SULT2B1, ST1B2, TPST1, TPST2, SULTX3, STE, CST, HNK-1 ST, CHST2, CHST4, and CHST5). In all, we identified 320 SNPs from these 20 loci: 22 within coding elements, 21 in 5' flanking regions, 10 in 5' untranslated regions, 223 in introns, 19 in 3' untranslated regions, and 25 in 3' flanking regions. The ratio of transitions to transversions was approximately 2.3 to 1. Of the 22 coding SNPs, 6 were nonsynonymous substitutions that resulted in amino-acid substitutions. The high-density SNP maps we constructed from this data for each of the quinone oxidoreductases and sulfotransferases examined here should provide useful information for investigations designed to detect association(s) between genetic variations and common diseases or responsiveness to drug therapy.

Base Sequence↗
PubMed2000

Effect of Ava II and NcoI polymorphisms at the low density lipoprotein receptor gene on plasma lipid levels in a group of Thai subjects.

The contribution of common genetic variations at the LDL receptor gene in determining interindividual differences in plasma lipid levels in the general population has been observed in several studies. In this study, we employed the PCR-RFLP method to investigate such an effect of the common Ava II (exon 13) and Nco I (exon 18) polymorphisms at the low density lipoprotein (LDL) receptor gene locus in 54 normolipidemic Thai subjects. The mean LDL-C level was slightly higher in the Ava II (+/+) genotype than the other Ava II genotypes. This difference was significant at the 5 per cent level although there were only three homozygotes with Ava II (+/+) genotype. The average effect of Ava II (+) allele was to increase LDL-C level by 6.75 mg/dl. A gene-dosage effect was not observed for this polymorphism. In addition, the subjects with Ava II (+/+) genotype also tended to have high serum total cholesterol and triglyceride and low HDL-C levels. Nco I polymorphism revealed no statistically significant effect on lipid levels in these subjects. However, the subjects with (+) allele tended to have high levels of LDL-C, serum total cholesterol and triglyceride.

Alleles↗
PubMed2005

Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study.

BACKGROUND: RNASEL is thought to be a susceptibility gene for hereditary prostate cancer and encodes the endoribonuclease RNase L, which has a role in apoptosis and is a candidate tumour-suppressor protein. A common sequence variation in RNASEL, Arg462Gln, has been associated with hereditary and sporadic prostate cancer, and the Gln variant has about three-fold reduced RNase activity in vitro. In view of the association between the age of onset of hereditary non-polyposis colorectal cancer and functionally different variants of P53, which play a key part in the apoptotic pathway, we aimed to assess whether the Arg462Gln variation of RNASEL affects the age of onset of hereditary non-polyposis colorectal cancer. METHODS: We screened 251 patients with hereditary non-polyposis colorectal cancer who were unrelated, had pathogenic germline mutations in MSH2 (n=141) or MLH1 (n=110), and had colorectal carcinoma as the first tumour, for variation at codon 462 of RNASEL and compared them with 439 healthy controls. FINDINGS: The median age of onset was 40 years (range 17-75) for patients with an Arg/Arg genotype at codon 462, 37 years (13-69) for patients with an Arg/Gln genotype, and 34 years (20-49) for those with a Gln/Gln genotype (p=0.0198). Only the RNASEL genotype had a significant effect on age of onset (p=0.0062) in an additive mode of inheritance. Pair-wise comparisons between genotype groups showed that the two homozygous groups (ie, Arg/Arg vs Gln/Gln) differed significantly in age of disease onset (mean age difference 4.8 years [SD 1.7], p=0.0044). INTERPRETATION: A sequence variation in the prostate-cancer-susceptibility gene RNASEL has a role in a different, unassociated malignant disease. Genotypes at RNASEL codon 462 are associated with age of onset of hereditary non-polyposis colorectal cancer in a dose-dependent way, and might have a role in preventive strategies for this disease.

Adolescent↗
PubMed2006

A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).

INTRODUCTION: Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). METHODS: The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls). RESULTS: We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. CONCLUSION: Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.

Aged↗
PubMed2005

Origin, divergence, and phylogeny of epichloe endophytes of native Argentine grasses.

The epichloë endophytes are systemic, constitutive, and often vertically transmitted fungal symbionts of grass species in subfamily Poöideae. Prior studies indicate that several asexual epichloë endophytes (Neotyphodium species) have evolved directly from sexual (Epichloë) species, whereas others evolved by hybridization between two or more endophyte species. In this paper, we investigate the phylogenies of 27 Neotyphodium spp. isolates from 10 native grass species (in 4 tribes) in 22 populations throughout Argentina. Relationships among these fungi and a worldwide collection of epichloë endophytes were estimated by phylogenetic analysis of sequences from variable portions (mainly introns) of genes for beta-tubulin (tub2) and translation elongation factor 1-alpha (tef1). Most of the Argentine endophyte isolates were interspecific hybrids of Epichloë festucae and E. typhina. Only one isolate was a hybrid of a different ancestry, and three isolates were apparently non-hybrid endophytes. These results indicate that interspecific hybridization, which promotes genetic variation, was common during the evolution of the endophytes of Argentine grasses.

Base Sequence↗
PubMed1999

Using a mixed effects model to estimate geographic variation in cancer rates.

Commonly used methods for depicting geographic variation in cancer rates are based on rankings. They identify where the rates are high and low but do not indicate the magnitude of the rates nor their variability. Yet such measures of variability may be useful in suggesting which types of cancer warrant further analytic studies of localized risk factors. We consider a mixed effects model in which the logarithm of the mean Poisson rate is additive in fixed stratum effects (e.g., age effects) and in logarithms of random relative risk effects associated with geographic areas. These random effects are assumed to follow a gamma distribution with unit mean and variance 1/alpha, similar to Clayton and Kaldor (1987, Biometrics 43, 671-681). We present maximum likelihood and method-of-moments estimates with standard errors for inference on alpha -1/2, the relative risk standard deviation (RRSD). The moment estimates rely on only the first two moments of the Poisson and gamma distributions but have larger standard errors than the maximum likelihood estimates. We compare these estimates with other measures of variability. Several examples suggest that the RRSD estimates have advantages compared to other measures of variability.

Biometry↗
PubMed2006

Population variation and differences in serum leptin independent of adiposity: a comparison of Ache Amerindian men of Paraguay and lean American male distance runners.

BACKGROUND: Serum leptin variation is commonly associated with fat percentage (%), body mass index (BMI), and activity. In this investigation, we report population differences in mean leptin levels in healthy men as well as associations with fat % and BMI that are independent of these factors and reflect likely variation resulting from chronic environmental conditions. METHODS: Serum leptin levels, fat %, and BMI were compared between lean American distance runners and healthy Ache Native Americans of Paraguay. Mean levels were compared as were the regressions between fat %, BMI, and leptin. Comparisons were performed between male American distance runners (n = 13, mean age 32.2 +/- 9.2 SD) and highly active male New World indigenous population (Ache of Paraguay, n = 20, mean age 32.8 +/- 9.2) in order to determine whether significant population variation in leptin is evident in physically active populations living under different ecological circumstances independent of adiposity and BMI. RESULTS: While the Ache were hypothesized to exhibit higher leptin due to significantly greater adiposity (fat %, Ache 17.9 +/- 1.8 SD; runners 9.7 +/- 3.2, p < 0.0001), leptin levels were nonetheless significantly higher in American runners (Ache 1.13 ng/ml +/- 0.38 SD; runners 2.19 +/- 1.15; p < 0.007). Significant differences in the association between leptin and fat % was also evident between Ache and runner men. Although fat % was significantly related with leptin in runners (r = 0.90, p < 0.0001) fat % was negatively related in Ache men (r = -0.50, p < 0.03). CONCLUSION: These results illustrate that chronic ecological conditions in addition to activity are likely factors that contribute to population variation in leptin levels and physiology. Population variation independent of adiposity should be considered to be an important source of variation, especially in light of ethnic and population differences in the incidence and etiology of obesity, diabetes, and other metabolic conditions.

Journal Article↗