Paraoxonase 1 promoter and coding region polymorphisms in Parkinson's disease.
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Adult↗
Biomedical subjects
G P Jarvik
Publications and source records attributed to G P Jarvik.
Genetic association studies: genes in search of diseases.
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Brain Diseases↗
Germline mutations in the p73 gene do not predispose to familial prostate-brain cancer.
BACKGROUND: Analysis of high-risk prostate cancer (PC) families with at least one confirmed case of primary brain cancer (BC) has identified a region of genetic linkage on chromosome 1p36 termed CAPB. The p36 region of chromosome one has been reported to have frequent loss of heterozygosity (LOH) in brain and central nervous system (CNS) tumors and epidemiological studies have shown an increased relative risk of BC and tumors of the CNS in PC families. In 1997 a reported tumor suppressor with high homology to p53, termed p73, was mapped to the p36 region of chromosome one. Here, we examine the p73 gene as a potential candidate for CAPB. METHODS: Ninety-four members from the 12 prostate-brain cancer families in which linkage was originally found were examined. The complete coding region and intron-exon boundaries of the p73 gene were analyzed for germline mutations by Single Stranded Conformational Polymorphism analysis (SSCP) and direct DNA sequencing. RESULTS: Silent nucleotide substitutions only were detected within the coding regions of the gene in affected individuals. Nucleotide changes were detected in introns 1, 6, 8, 9, and 10, but all were located >or=16 base pairs from the splice site, and are thus unlikely to be deleterious mutations. CONCLUSIONS: Germline mutations in the p73 gene are unlikely to be critical for inherited susceptibility to PC in this specified subset of families.
Aged↗
Effects of 5' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression.
Human HDL-associated paraoxonase (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces oxidation of LDLs and HDLs. These properties of PON1 account for its ability to protect against pesticide poisonings and atherosclerosis. PON1 also hydrolyzes a number of lactone and cyclic-carbonate drugs. Among individuals in a population, PON1 levels vary widely. We previously identified three polymorphisms in the PON1 regulatory region that affect expression levels in cultured human hepatocytes. In this study, we determined the genotypes of three regulatory-region polymorphisms for 376 white individuals and examined their effect on plasma-PON1 levels, determined by rates of phenylacetate hydrolysis. The -108 polymorphism had a significant effect on PON1-activity level, whereas the -162 polymorphism had a lesser effect. The -909 polymorphism, which is in linkage disequilibrium with the other sites, appears to have little or no independent effect on PON1-activity level in vivo. Other studies have found that the L55M polymorphism in the PON1-coding region is associated with differences in both PON1-mRNA and PON1-activity levels. The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-region polymorphism. The codon 55 polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108 and Q192R polymorphisms were made. The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1-expression levels, which was much greater than that attributable to the other PON1 polymorphisms. We also identified four sequence differences in the 3' UTR of the PON1 mRNA.
3' Untranslated Regions↗
Polymorphisms in the human paraoxonase (PON1) promoter.
Paraoxonase (PON1) is a protein component of high-density lipoprotein (HDL) particles that protects against oxidative damage to both low-density lipoprotein and HDL and detoxifies organophosphorus pesticides and nerve agents. A wide range of expression levels of PON1 among individuals has been observed. We examined the promoter region of PON1 for genetic factors that might affect PON1 activity levels. We conducted a deletion analysis of the PON1 promoter region in transient transfection assays and found that cell-type specific promoter elements for liver and kidney are present in the first 200bp upstream of the coding sequence. Sequence analysis of DNA from a BAC clone and a YAC clone identified five polymorphisms in the first 1000 bases upstream of the coding region at positions -108, -126, -162, -832 and -909. Additionally, the promoter sequences of two individuals expressing high levels of PON1 and two individuals expressing low levels of PON1 were analysed. The two polymorphisms at -126 and -832 had no apparent effect on expression level in the reporter gene assay. The polymorphisms at position -909, -162 (a potential NF-I transcription factor binding site) and -108 (a potential SP1 binding site) each have approximately a two-fold effect on expression level. The expression level effects of the three polymorphisms appear not to be strictly additive and may depend on context effects.
Aryldialkylphosphatase↗
Genetic linkage analysis of prostate cancer families to Xq27-28.
OBJECTIVES: A recent linkage analysis of 360 families at high risk for prostate cancer identified the q27-28 region on chromosome X as the potential location of a gene involved in prostate cancer susceptibility. Here we report on linkage analysis at this putative HPCX locus in an independent set of 186 prostate cancer families participating in the Prostate Cancer Genetic Research Study (PROGRESS). METHODS: DNA samples from these families were genotyped at 8 polymorphic markers spanning 14.3 cM of the HPCX region. RESULTS: Two-point parametric analysis of the total data set resulted in positive lod scores at only two markers, DXS984 and DXS1193, with scores of 0.628 at a recombination fraction (theta) of 0.36 and 0.012 at theta = 0.48, respectively. The stratification of pedigrees according to the assumed mode of transmission increased the evidence of linkage at DXS984 in 81 families with no evidence of male-to-male transmission (lod = 1.062 at theta = 0.28). CONCLUSIONS: Although this analysis did not show statistically significant evidence for the linkage of prostate cancer susceptibility to Xq27-28, the results are consistent with a small percentage of families being linked to this region. The analysis further highlights difficulties in replicating linkage results in an etiologically heterogeneous, complexly inherited disease.
Age Factors↗
Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci.
PURPOSE: Hereditary prostate cancer is an etiologically heterogeneous disease with six susceptibility loci mapped to date. We aimed to describe a collection of high-risk prostate cancer families and assess linkage to multiple markers at four loci: HPC1 (1q24-25), PCaP (1q42.2-43), HPCX (Xq27-28), and CAPB (1p36). EXPERIMENTAL DESIGN: Medical record data on 505 affected men in 149 multiply-affected prostate cancer families were reviewed, and correlations of clinical traits within each family were calculated. Logarithm of odds (LOD) score and nonparametric (NPL) linkage analyses were performed; white families were stratified by age of diagnosis, grade and stage of disease, and evidence of linkage to the other loci to increase genetic homogeneity. RESULTS: Age at diagnosis was the most correlated clinical trait within families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm HPC1 linkage for families that had a prevalence of high-grade or advanced-stage prostate cancer and which were not likely to be linked to PCaP, HPCX, or CAPB. Because the NPL scores improved when families more likely to be linked to the other loci were excluded, HPC1 may act independently of the other loci. The relationship of HPC1 and aggressive disease was strongest in families with median age at diagnosis > or =65 years (NPL, 3.48; P = 0.0008). CONCLUSIONS: The current results suggest that HPC1 linkage may be most common among families with more severe prostate cancer. Stratification by clinical characteristics may be a useful tool in prostate cancer linkage analyses and may increase our understanding of hereditary prostate cancer.
Adult↗
Affective disorders and Alzheimer disease: a missing-link hypothesis.
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Aged↗
Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10.
We studied a large kindred with nonsyndromic autosomal dominant thrombocytopenia to define the phenotype and used genomic linkage analysis to determine the locus of the abnormal gene. Affected family members are characterized by lifelong moderate thrombocytopenia (mean = 42.7 x 10(9)/L) with moderate propensity toward easy bruising and minor bleeding. Megakaryocytes are present in bone marrow with reduced frequency, and there are no apparent abnormalities of myeloid or erythroid cells. This type of inherited thrombocytopenia has no evident association with hematopoietic malignancy or progression to aplastic anemia. In the past, members of this family have failed therapeutic trials of immunosuppression and splenectomy. In our investigation, we found that affected individuals had normal platelet size compared with unaffected family members and modestly increased thrombopoietin levels. Hematopoietic colony assays from bone marrow and peripheral blood demonstrated that megakaryocyte precursors (CFU-Mk) were dramatically increased in both number and size in affected individuals. Bone marrow cells grown in liquid culture with thrombopoietin failed to develop polyploid cells greater than 8N. Also, electron microscopy demonstrated that megakaryocytes from an affected individual had markedly delayed nuclear and cytoplasmic differentiation. Genome-wide linkage analysis established a single locus for the disease gene on the short arm of chromosome 10 with a maximum 2-point lod score of 5.68 (at theta = 0). By recruiting additional family members, the genomic region was narrowed to 17 centimorgans. We conclude that a gene in this locus plays an important role in megakaryocyte endomitosis and terminal maturation.
Bone Marrow Cells↗
A genomic scan of families with prostate cancer identifies multiple regions of interest.
A 10-cM genomewide scan of 94 families with hereditary prostate cancer, including 432 affected men, was used to identify regions of putative prostate cancer-susceptibility loci. There was an average of 3.6 affected, genotyped men per family, and an overall mean age at diagnosis of 65.4 years. A total of 50 families were classified as early onset (mean age at diagnosis <66 years), and 44 families were classified as later onset (mean age at diagnosis > or =66 years). When the entire data set is considered, regions of interest (LOD score > or =1.5) were identified on chromosomes 10, 12, and 14, with a dominant model of inheritance. Under a recessive model LOD scores > or =1.5 were found on chromosomes 1, 8, 10, and 16. Stratification by age at diagnosis highlighted a putative susceptibility locus on chromosome 11, among the later-onset families, with a LOD score of 3. 02 (recombination fraction 0) at marker ATA34E08. Overall, this genomic scan suggests that there are multiple prostate cancer loci responsible for the hereditary form of this common and complex disease and that stratification by a variety of factors will be required for identification of all relevant genes.
Adult↗
Linkage analysis of 150 high-risk prostate cancer families at 1q24-25.
Confirmation of linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of cancer susceptibility genes. We report here on an analysis of 150 high-risk prostate cancer families (2,176 individuals) for potential linkage to the HPC1 prostate cancer susceptibility locus at 1q24-25. This dataset includes 640 affected men with an average age at prostate cancer diagnosis of 66. 8 years (range, 39-94), representing the largest collection of high-risk families analyzed for linkage in this region to date. Linkage to multiple 1q24-25 markers was strongly rejected for the sample as a whole (lod scores at theta = 0 ranged from -30.83 to -18. 42). Assuming heterogeneity, the estimated proportion of families linked (alpha) at HPC1 in the entire dataset was 2.6%, using multipoint analysis. Because locus heterogeneity may lead to false rejection of linkage, data were stratified based on homogeneous subsets. When restricted to 21 Caucasian families with five or more affected family members and mean age at diagnosis < = 65 years, the lod scores at theta = 0 remained less than -4.0. These results indicate that the overall portion of hereditary prostate cancer families whose disease is due to inherited variation in HPC1 may be less than originally estimated.
Adult↗
Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy.
The E4 allele of apolipoprotein E (apoE4) has previously been associated with symptomatic gallstone disease. The aim of this study was to determine if apoE4 is associated with the development of gallbladder sludge and/or stones during pregnancy. We conducted a nested case-control study based on an ongoing cohort study of gallbladder disease in pregnancy. Women in this study receive gallbladder ultrasounds in each trimester of pregnancy. Cases (n = 52) were defined as women with incident gallbladder sludge or stones diagnosed at the third trimester ultrasound. Controls (n = 104) were defined as women without gallbladder sludge or stones on any of 3 study ultrasounds. ApoE genotyping was performed from stored white blood cell pellets. Data were analyzed by stratified analysis and multivariate logistic regression. Cases and controls were similar in baseline characteristics. Forty-two women had sludge, 6 had gallstones, and 4 had both sludge and stones. After adjusting for risk factors such as age, parity, and body mass index, the odds ratio (OR) for the association between heterozygosity or homozygosity for the apoE4 allele and incident gallbladder sludge or stones was 0.91 (95% confidence interval [CI], 0.41-2.02). Further adjustment for family medical history and serum lipid levels did not substantially change these results (OR, 0.73; 95% CI, 0.29-1.82). In conclusion, apoE4 appears to have little or no overall association with the development of new gallbladder sludge or stones in pregnancy. However, an effect could not be ruled out in certain subgroups, such as blacks or women who are homozygous for apoE4.
Apolipoprotein E4↗
Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype.
Paraoxonase (PON1) is tightly associated with high-density lipoprotein particles and is believed to contribute to the prevention of atherosclerosis by metabolizing oxidized lipids. PON1 also hydrolyses the bioactive oxon forms of organophosphorus pesticides such as parathion, diazinon and chlorpyrifos. Two common polymorphisms have been identified in the coding sequence of human PON1: L55M and R192Q. Several previous studies have found that the presence of the PON1R192 allele raises the risk of cardiovascular disease while others found no correlation. The studies, however, have focused on the genotype of PON1 and not the expression level of the protein. We found that the PON1 expression level in plasma, as determined by the rates of paraoxon and diazoxon hydrolysis, varies widely among individuals and within a genotype. Previous studies found that individuals having Met at PON155 have lower levels of both PON1 mRNA and activity. In this study, we determined the plasma activity levels of PON1 and examined the relationships between PON155 genotype and PON1 level. As with PON1192, we found considerable overlap in activity among the PON155 genotypes. Of the 317 individuals whose PON1 status was determined in this study, 48.9% were PON1Q192 homozygotes. Analysis of the PON1QQ192 population showed that while the average PON1 activity (diazoxon hydrolysis) was 12266 U/L for PON1LL55 and 7777 U/L for PON1MM55, a given PONMM55 individual could have more than twice the activity of a PON1LL55 individual. PON1 status, which includes PON1 level as well as PON1192 genotype, may be a better predictor for cardiovascular disease or organophosphate susceptibility than PON1 genotype alone.
Aged↗
Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype.
The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P=0.005; DZOase, P=0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P<0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a "level crossing" approach that includes intervening phenotypes in the study of complexly inherited disease.
Aged↗
The PON1 gene and detoxication.
It has been assumed since its discovery that serum paraoxonase (PON1) plays a major role in the detoxication of specific organophosphorus compounds. It was also assumed that individuals with low PON1 activity would be more susceptible to paraoxon/parathion poisoning than individuals with higher PON1 activity. Evidence supporting this hypothesis was provided by injection of rabbit PON1 into rodents. Injected PON1 protected against paraoxon toxicity in rats and chlorpyrifos oxon toxicity in mice. The recent availability of PON1 knockout mice has provided an in vivo system with which one can more closely examine the role of PON1 in detoxication. PON1 knockout mice demonstrated dramatically increased sensitivity to chlorpyrifos oxon and diazoxon and moderately increased sensitivity to the respective parent compounds. The PON1 knockout mutation also resulted in the elimination of liver PON1 activity, accounting for the dramatic increase in sensitivity to chlorpyrifos oxon and diazoxon. Totally unexpected was our finding that the PON1 knockout mice were not more sensitive to paraoxon. This was particularly surprising in light of the earlier enzyme injection experiments. Differences in the relative catalytic efficiencies of rabbit vs. mouse PON1 for the specific oxon forms explain these observations. Mouse PON1 has good catalytic efficiency for the hydrolysis of diazoxon and chlorpyrifos oxon, but a poor efficiency for paraoxon hydrolysis relative to rabbit PON1. The human PON1Q192 isoform has a catalytic efficiency similar to that of mice, whereas the human PON1R192 isoform has a much better catalytic efficiency, predicting that individuals expressing high levels of the PONIR192 isoform may have increased resistance to paraoxon toxicity.
Animals↗
Impact of family structure on the power of linkage tests using sib-pair methods.
This analysis sought to determine the impact of specific ascertainment criteria based upon nuclear family affectation structures. Specifically, we evaluated the predicted and observed proportion of alleles shared identical by descent conditional on the number of affected and unaffected siblings in a pedigree, and compared sib-pair method linkage results under two ascertainment schemes, random vs. selected ascertainment, for this simulated complex genetic disease. These results suggest that samples differing in the composition of affected and unaffected siblings in the family will differ in their power to detect linkage. An effect of sampling scheme on power to map using affected-sib-pair methods should be considered when a reported linkage is not found in another study population.
Family↗
Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency.
Small low-density lipoprotein (LDL) particles are a genetically influenced coronary disease risk factor. Lipoprotein lipase (LpL) is a rate-limiting enzyme in the formation of LDL particles. The current study examined genetic linkage of LDL particle size to the LpL gene in five families with structural mutations in the LpL gene. LDL particle size was smaller among the heterozygous subjects, compared with controls. Among heterozygous subjects, 44% were classified as affected by LDL subclass phenotype B, compared with 8% of normal family members. Plasma triglyceride levels were significantly higher, and high-density lipoprotein cholesterol (HDL-C) levels were lower, in heterozygous subjects, compared with normal subjects, after age and sex adjustment. A highly significant LOD score of 6.24 at straight theta=0 was obtained for linkage of LDL particle size to the LpL gene, after adjustment of LDL particle size for within-genotype variance resulting from triglyceride and HDL-C. Failure to adjust for this variance led to only a modest positive LOD score of 1.54 at straight theta=0. Classifying small LDL particles as a qualitative trait (LDL subclass phenotype B) provided only suggestive evidence for linkage to the LpL gene (LOD=1. 65 at straight theta=0). Thus, use of the quantitative trait adjusted for within-genotype variance, resulting from physiologic covariates, was crucial for detection of significant evidence of linkage in this study. These results indicate that heterozygous LpL deficiency may be one cause of small LDL particles and may provide a potential mechanism for the increase in coronary disease seen in heterozygous LpL deficiency. This study also demonstrates a successful strategy of genotypic specific adjustment of complex traits in mapping a quantitative trait locus.
Adolescent↗
Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36.
Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region.
Aged↗