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C E Aston

Publications and source records attributed to C E Aston.

At least 37 records · Page 2Linked to original sources
PubMed1999

A simple allele sharing statistic for multiple locus systems.

For complex disorders where the actions of several interacting loci must be taken into account, current methods of joint linkage analysis are problematic. We have undertaken an exploration of simultaneous search statistics originally proposed by Dupuis et al. [1995]. Additionally, we have extended these methods slightly and propose here a simple simultaneous search statistic based upon the single-point allele sharing statistic calculated from GENEHUNTER (GH). The use of conditional search techniques is also explored.

Alleles↗
PubMed1999

Correlates of lipoprotein(a) levels in a biracial cohort of young girls: the NHLBI Growth and Health Study.

Elevated levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary heart disease (CHD). However, racial differences in both Lp(a) levels and their associated CHD risk are observed, with African Americans having, on average, higher Lp(a) levels than US whites but not the expected increase in CHD risk. We determined Lp(a) levels and their correlates in a large cohort (n = 2379) of black and white girls, ages 9 to 10 years, at the baseline visit of a longitudinal study of obesity development, the National Heart, Lung, and Blood Institute Growth and Health Study. Lp(a) levels were available for 1269 girls. The median Lp(a) level in black girls was over 3-fold higher than that in white girls. Associations were examined between Lp(a) levels and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, adiposity, pubertal maturation stage, body fat patterning (triceps/truncal skinfold ratio), and dietary fat (Keys' score). In black girls multiple regression analysis identified LDL-C (P <.001) and adiposity (P =. 08) as predictors of Lp(a) levels. In white girls only LDL-C (P =. 02) was associated with Lp(a). In conclusion, the level of Lp(a) was significantly higher in black girls. Our study also revealed a racial difference in correlates of Lp(a), such as LDL-C and adiposity. Whether this racial difference is due to an underlying biologic difference or is merely a reflection of a greater statistical power to detect a relationship with the level, which was 2.5-fold higher in black girls than in white girls, needs further investigation.

Analysis of Variance↗
PubMed1999

Apolipoprotein J polymorphisms and serum HDL cholesterol levels in African blacks.

Apolipoprotein J (apoJ, protein; APOJ, gene) is found in serum associated with high-density lipoprotein (HDL) subfractions, which also contain apolipoprotein A-I (apoA1) and cholesteryl ester transfer protein. ApoJ has been shown to be involved in a variety of physiological functions, including lipid transport. In earlier studies we reported the existence of a common genetic polymorphism (APOJ*1 and APOJ*2 alleles) using isoelectric focusing (IEF) and immunoblotting. In this study we determined the molecular basis of this polymorphism and together with another polymorphism at codon 328 (G-->A) evaluated its relationship with serum HDL cholesterol and apoA1 levels in 767 African blacks stratified by staff level: junior (less affluent, n = 450) and senior (more affluent, n = 317). The molecular analysis of the cathodally shifted APOJ*2 allele on IEF gels revealed an amino acid substitution of asparagine by histidine resulting from a missense mutation (A-->C) at codon 317 in exon 7. The frequency of the APOJ*2 (C) allele of codon 317 in the total sample was 0.267, whereas that of the less common allele A of codon 328 was 0.04. Despite their close proximity, no linkage disequilibrium was observed between the 2 polymorphisms. The impact of the codon 317 polymorphic variation was significant on serum HDL cholesterol (p = 0.003) and HDL3 cholesterol (p = 0.001) in junior staff. The adjusted mean values of these traits were higher in the codon 317 APOJ*2/*2 genotype than in the *1/*1 and *1/*2 genotypes. Overall, the APOJ codon 317 polymorphism explained 10.2% and 8.3% of the phenotypic variation in HDL cholesterol and HDL3 cholesterol, respectively, in junior staff. The codon 328 polymorphism showed a significant effect on HDL2 cholesterol (p = 0.039) and apoA1 (p = 0.007) only in junior women and accounted for 2.5% and 4.2% of the phenotypic variation in HDL2 cholesterol and apoA1, respectively. We also analyzed the combined effects of these genotypes at the 2 polymorphic sites. Significant effects on HDL cholesterol (p = 0.004) and HDL3 cholesterol (p = 0.008) in junior men and on HDL2 cholesterol (p = 0.003) in junior women were observed in the combined genotype data. The 2-locus genotypes explained 6.0% and 5.3% of the residual phenotypic variation of HDL cholesterol and HDL3 cholesterol in junior men and 10.4% of HDL2 cholesterol in junior women. These data indicate that the effect of the APOJ polymorphism on HDL cholesterol levels is modulated by socioeconomic status, as measured by staff level. Given the association of HDL and its subfractions with cardiovascular disease, these polymorphisms may lead to a better understanding of interracial differences in the risk of cardiovascular disease.

Adult↗
PubMed1998

Racial differences in the distribution of a low density lipoprotein receptor-related protein (LRP) polymorphism and its association with serum lipoprotein, lipid and apolipoprotein levels.

The low density lipoprotein (LDL) receptor-related protein (LRP) is a cell receptor that has close structural homology to the LDL and very low density lipoprotein receptors and thus is believed to play an important role in lipid metabolism. This study was carried out to evaluate the distribution of a known tetranucleotide repeat polymorphism in the LRP gene and its association with serum lipoprotein-lipid and apolipoprotein levels in four large samples comprising Hispanics (n=373) and non-Hispanic Whites (n=522) from the U.S. and Nigerian Blacks from Sokoto (n=390) and Benin (n=800). A total of four alleles, designated 83, 87, 91 and 95 bp, were observed. The 83 bp allele was observed at 0.4-1.1% in the two U.S. populations but was completely absent in African Blacks. Sokoto Blacks had significantly different frequencies of the 87 and 91 bp alleles compared to Hispanics (P=0.008) and non-Hispanic Whites (P=0.024). The frequency of the 91 bp allele was also significantly higher in Benin Blacks compared to Hispanics (P=0.026) and non-Hispanic Whites (P=0.054). The analysis of the relationship between the LRP polymorphism and serum lipid traits yielded some significant race and gender specific significant association for lipoprotein(a) in non-Hispanic White males (P=0.02); HDL2-cholesterol in Hispanic females (P=0.03) and apolipoprotein B in Benin males (P=0.04). We also observed an interaction between the LRP polymorphism and menopausal status for Lp(a) in Hispanic females (P=0.014). However, considering multiple comparisons were performed, these associations could be due to chance. Our data indicate that although the LRP tetranucleotide polymorphism exhibits inter-racial differences in its distribution, it does not appear to have a significant role in affecting serum lipid traits.

Age Factors↗
PubMed1998

DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease.

A common polymorphism at codon 192 in the human paraoxonase (PON) 1 gene has been shown to be associated with increased risk for coronary heart disease (CHD) in Caucasian populations. However, these findings have not been reported consistently in all Caucasian and non-Caucasian populations, suggesting that this is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Recently, two other PON-like genes, designated "PON2" and "PON3," have been identified, and they are linked with the known PON1 gene on chromosome 7. Identification of additional polymorphisms in the PON-gene cluster may help to locate the functional polymorphism. In this report, we describe the existence of a common polymorphism at codon 311 (Cys-->Ser; PON2*S) in the PON2 gene, as well as its association with CHD alone and in combination with the PON1 codon 192 polymorphism in Asian Indians. The frequency of the PON2*S allele was significantly higher in cases than in controls (.71 vs. .61; P=.016). The age- and sex-adjusted odds ratio (OR) was 2.5 (95% confidence interval &sqbl0;95% CI&sqbr0;=1.8-3.1; P=.0090) for the PON2*S allele carriers. Further stratification of the PON2*S association, on the basis of the presence or absence of the PON1*B allele, showed that the CHD risk associated with the PON2*S allele was confined to PON1*B-allele carriers. Likewise, the PON1*B-allele risk was present only among PON2*S carriers. Age- and sex-adjusted ORs for the PON2*S and PON1*B were 3.6 (95% CI=2.6-4.6; P=.011) and 2.9 (95% CI=2.4-3.5; P=.0002) among the PON1*B and PON2*S carriers, respectively. Our data indicate that both polymorphisms synergistically contribute to the CHD risk in this sample and that this genetic risk is independent of the conventional plasma lipid profile.

Adult↗
PubMed1998

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.

Chromosomes, Human, Pair 12↗
PubMed1998

Apolipoprotein A kringle 4 polymorphism and serum lipoprotein (a) concentrations in African blacks.

Several epidemiological studies have established that elevated serum lipoprotein (a) [Lp(a)] levels are independent risk factors for coronary heart disease, stroke, and restenosis of coronary lesions in white and Asian populations. Serum Lp(a) levels vary over a 1000-fold range among individuals and are under strict genetic control. Serum Lp(a) levels are significantly higher in populations with African ancestry than in populations of European ancestry. The APOA gene exhibits hypervariable length polymorphism resulting from a variable number of expressed kringle 4 repeats. An inverse relationship exists between the size of kringle 4 repeats and serum Lp(a) levels. However, most studies have been conducted in whites, and the data are scanty in African populations. To explore this relationship among Africans, we determined serum Lp(a) levels and APOA Kringle 4 size polymorphisms in 781 unrelated Africans (490 men, 291 women) from Benin City, Nigeria. Mean and median serum Lp(a) values were 25.6 +/- 0.6 mg/dl and 20.9 mg/dl, respectively. Although there was no difference in mean Lp(a) values between men and women, median Lp(a) values were higher in women than in men (p = 0.02). Using SDS-agarose gel electrophoresis, we detected 38 APOA isoforms, the highest number recorded to data. There were 10 consecutive medium-size alleles whose frequencies ranged between 4.2% and 10.9%, and together they accounted for 72.8% of the alleles observed in this population. Spearman's correlation coefficients showed an inverse relationship between the size of the APOA isoform and Lp(a) levels using either single-banded (r = 0.46; p < 0.0001) or double-banded (r = 0.42; p < 0.0001) phenotypes. Using random effects analysis of variance on the entire sample, the APOA size polymorphism explained about 15% of the phenotypic variation in Lp(a) levels. These data suggest that despite significant correlation between the APOA kringle 4 size polymorphism and Lp(a) levels, other sequence variations either in the APOA gene or closely linked genes may account for relatively higher Lp(a) levels found in Africans.

Analysis of Variance↗
PubMed1997

Plasma apolipoprotein A-I, apolipoprotein B, and lipoprotein(a) concentrations in normoglycemic Hispanics and non-Hispanic whites from the San Luis Valley, Colorado.

Lower levels of plasma apolipoprotein (apo) A-I and higher levels of apoB, lipoprotein(a) (Lp(a)), and the ratio of apoB to apoA-I are considered to be independent risk factors for coronary heart disease. To examine race differences in the distributions of plasma levels of apoA-I, apoB, and Lp(a), the authors have determined quantitative levels of these traits in 252 nondiabetic Hispanics and 459 nondiabetic non-Hispanic whites (NHWs) from the San Luis Valley, Colorado. Hispanic men and women, respectively, had significantly higher plasma apoB levels (p < 0.003; p < 0.01) and the ratio of apoB to apoA-I (p < 0.003; p < 0.0003) than their NHW counterparts. Plasma Lp(a) concentrations were also significantly higher in Hispanic men (p < 0.003) and apoA-I levels were significantly lower in Hispanic women (p < 0.0003) than NHW men and women, respectively. Overall, the threshold points of apoA-I (< 120 mg/dl), apoB (> 120 mg/dl), and Lp(a) (> 25 mg/dl) were higher in Hispanics than in NHWs for apoA-I (22.8 vs. 15.7%), apoB (16.9 vs. 9.9%), and Lp(a) (18.6 vs. 12.4%). These data suggest that the quantitative risk profile for coronary heart disease with respect to these three quantitative traits is not favorable for Hispanics compared with that for NHWs in the San Luis Valley, Colorado.

Adult↗
PubMed1997

A dietary and behavioral intervention designed to lower coronary heart disease. Risk factors are unaffected by variation at the APOE gene locus.

Variation at the apolipoprotein E (APOE) gene locus has demonstrated a consistent impact on lipoprotein levels. APOE typing was performed for 488 healthy, caucasian, premenopausal women participating in the Women's Healthy Lifestyle Project (WHLP) aimed at reducing total fat, saturated fat and cholesterol intake and promoting physical activity. Women in both the intervention and control groups were included in the trial. The purpose of the present study was to determine whether the magnitude of the changes in total cholesterol (Tc), low density lipoprotein cholesterol (LDLc) and high density lipoprotein cholesterol (HDLc) due to the dietary intervention were dependent on the variation in APOE. Weight, body mass index (BMI), and lipoprotein levels were measured at baseline and at a 6 month follow-up. ANOVA was used to determine whether the change in Tc and LDLc was dependent on dietary intervention and variation at APOE levels. The levels of Tc and LDLc were higher in women with the APOE*4 genotype. There were no statistically significant effects of APOE genotype and changes in Tc and LDLc (P > 0.1). Adjusted Tc and LDLc changes were comparable in the 3 APOE subgroups (Tc = -14.3, -12.9 and -11.7 mg/dl; LDLc = -12.1, -10.7 and -10.7 mg/dl, respectively as above). In conclusion, the genetic (APOE) background of premenopausal women in this study did not have a significant effect on their response to dietary intervention.

Apolipoproteins E↗
PubMed1997

Gender-specific nonrandom association between the alpha 1-antichymotrypsin and apolipoprotein E polymorphisms in the general population and its implication for the risk of Alzheimer's disease.

A common polymorphism in the alpha 1-antichymotrypsin (ACT) gene has been found co modify the APOE*4-associated risk of Alzheimer's disease due to an apparent interaction between the two loci. This study was undertaken to determine the gender- and age-related distributions of these two polymorphisms in two large population-based samples of Caucasians (n = 803) and Nigerian Blacks (n = 730). Significantly higher frequencies of the ACT*A (78.6% vs. 48.4%; P < 0.001) and APOE*4 (25.6% vs. 15.6%; P < 0.001) alleles were observed in Nigerian Blacks than in Caucasians. In Caucasian women but not in men, the frequency of the APOE*4 allele was significantly lower in the ACT/AA genotype as compared to the ACT/AT and ACT/TT genotypes, while a reverse trend was seen for the APOE*3 allele frequency among the ACT genotypes. The distribution of the ACT*A allele between the APOE*4 carriers and non-APOE*4 carriers was also different in Caucasian women but not in men. A similar gender-specific nonrandom association between the two polymorphisms was observed in Black women but this was not as strong as observed in Caucasian women. When the two samples were stratified by age group, an association or trend of association was observed in all age groups in women only. These data indicate the existence of a nonrandom association between the APOE and ACT loci in women which may have an important implication for the higher prevalence of Alzheimer's disease in women.

Adult↗
PubMed1997

Genetic analysis of families with nonsmoking lung cancer probands.

As part of a genetic epidemiologic study of lung cancer among nonsmokers, we investigated the role of genetic predisposition in familial aggregation. Cases were identified from the Metropolitan Detroit Cancer Surveillance System. Information on lung cancer occurrence, smoking habits (active or passive), and chronic respiratory diseases in first-degree relatives was obtained for 257 nonsmoking lung cancer probands (71 males, 186 females) diagnosed at ages 40-84 years. Among the 2,021 first-degree relatives, 24 (2.6%) males and 10 (1.1%) females were reported as having lung cancer. The occurrence of lung cancer among smoking and nonsmoking relatives was 4.5% and 1.1% in males and 2.8% and 0.4% in females, respectively. To evaluate the role of a putative Mendelian gene (one locus, two alleles) in the presence of other risk factors, we performed complex segregation analyses on the data using two different regressive model approaches [Segregation Analysis of a Discrete Trait Under a Class A Regressive Logistic Model, V4.0 (REGD) and Segregation Analysis of a Truncated Trait, V2.0, Model 1(REGTL)] as implemented in the Statistical Analysis for Genetic Epidemiology (SAGE) program. Using either approach, an environmental model best explained the observed lung cancer aggregation in families ascertained through nonsmoking probands. Based on our final model, only 0.04% of this population had a very high risk and 4.2% had a moderate risk of lung cancer. The rest of the population had virtually no risk of lung cancer during their lifetime unless they have multiple risk factors. Among the high-risk individuals without any risk factor under study, the estimated risks at ages 40, 60, and 80 years in males were 16.7%, 83.6%, and 95.4%, and in females were 14.0%, 72.2%, and 88.0%, respectively. Among at-moderate-risk smokers the estimated risks at the same age and gender groups were essentially the same as in the high-risk nonsmokers. Our results suggest that the pattern of lung cancer occurrence in families of nonsmoking lung cancer patients differs from that in families of smoking lung cancer patients. Despite the profound effect of smoking on the risk of lung cancer, other environmental and/or genetic risk factors need to be identified.

Adult↗
PubMed1997

Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.

BACKGROUND & AIMS: We recently identified a single R117H mutation in the cationic trypsinogen gene in several kindreds with an inherited form of acute and chronic pancreatitis (HP1), providing strong evidence that trypsin plays a central role in premature zymogen activation and pancreatitis. However, not all families studied have this mutation. The aim of this study was to determine the disease-causing mutation in kindreds with hereditary pancreatitis that lack the previously identified mutation. METHODS: Clinical features of the HP1 kindreds were compared with those of the new kindreds (HP2), and genetic linkage analysis, screening for mutations through DNA sequencing, and screening an unaffected population were performed. RESULTS: The onset of symptoms was delayed and hospitalizations were fewer in HP2 compared with HP1 (P < 0.05). Linkage of the disease gene to chromosome 7q35 was established (logarithm of the odds, 3.73). Mutational screening identified a single A to T mutation resulting in an asparagine to isoleucine transition mutation at position 21 (N21I) in cationic trypsinogen. The mutation was absent in 94 unrelated individuals, representing 188 unique chromosomes. CONCLUSIONS: The identification of a second mutation in the cationic trypsinogen gene (HP2) suggests a dominant role of trypsin in premature protease activation-mediated forms of acute pancreatitis. The pathogenesis of hereditary pancreatitis also suggests that chronic pancreatitis may result from recurrent acute pancreatitis.

Acute Disease↗
PubMed1997

Genetic polymorphism of paraoxonase and the risk of coronary heart disease.

Recent studies have implicated paraoxonase, an HDL-associated enzyme, in providing protection against LDL oxidation, thus affecting the risk of coronary heart disease (CHD) in the general population. In this study, we evaluated the distribution of a biallelic PON polymorphism at codon 192 (A and B alleles) and its relationship with plasma lipids and CHD in two racial groups comprising Asian Indians and Chinese from Singapore. The frequency of the B allele was significantly higher in Chinese control subjects than in Indian control subjects (0.58 versus 0.33; P < .0001). With the exception of a marginal effect on apolipoprotein A-I levels in Indians, no other significant association was observed between the PON polymorphism and quantitative lipid traits in either racial group. However, there was a race-specific association of the B allele with CHD in Indians but not in Chinese. The Indian CHD patients had a significantly higher frequency of the B allele than control subjects (.43 versus .33; P = .014). The age- and sex-adjusted odds ratio for developing CHD with the B allele (BB+AB genotypes) was 2.01 (95% CI, 1.17 to 3.45; P = .011) compared with the A allele (AA genotype). When the Indian patients were stratified into subgroups, the association remained significant in nondiabetic patients (odds ratio, 2.29; P = .008), and it became stronger in patients with myocardial infarction (odds ratio, 2.94; P = .004) than in patients without myocardial infarction (odds ratio, 1.11; P = .76). These data indicate that a common polymorphism in the PON gene is an independent risk factor for CHD in populations with white ancestry.

Adult↗
PubMed1997

Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.

Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 168000) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subject to genomic imprinting. Genetic linkage analysis in two large, unrelated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 North American PGL families and confirmed maternal imprinting (inactivation). In three of six families, linkage analysis provided evidence of linkage to the PGL1 locus at 11q23. Recombinants narrowed the critical region to an approximately 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of symptoms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onset of symptoms in 39 of 57 father-child pairs (chi2 = 7.74, P < .006). However, a more conservative comparison of the number of pairs in which a child had > or = 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no significant difference (chi2 = 1.42, P > .2). Whether these data represent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs.

Adolescent↗
PubMed1997

Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG)

OBJECTIVES: Because there are no markers for hereditary pancreatitis (HP), diagnosis has relied on clinical features and inferences. Identification of the HP disease gene locus on chromosome 7q35 provides the first genetic marker for HP, allowing an accurate comparison of the clinical diagnosis of HP with the presence of a high-risk HP haplotype. Our objectives were to compare the clinical diagnosis of HP with inheritance of the HP gene and to characterize the common clinical features. METHODS: A detailed questionnaire was administered to 102 study participants of a large HP kindred. Blood samples were taken for DNA extraction and high-risk haplotype determination. Clinical findings were compared with the presence of a high-risk haplotype. RESULTS: A family tree of more than 500 members and eight generations was constructed, and clinical features of the 102 participants were determined. HP occurred before the age of 5 yr in 58% of subjects, who presented with common symptoms of abdominal pain, nausea/vomiting, and frequent attacks. Thirty-five probands, of whom 80% had clinical symptoms, carried the high-risk haplotype, confirming previous estimates of 80% penetrance. Thirty-two of the study participants had been clinically diagnosed with HP, whereas 70 were clinically unaffected. With regard to the presence of the high-risk haplotype, 87.5% of the clinically diagnosed patients were affected by HP (true positive), whereas 12.5% did not carry the high-risk haplotype (false positive). Seven obligate carriers were identified through DNA analysis; three had previously been unrecognized because of lack of affected offspring. CONCLUSIONS: The diagnosis of hereditary pancreatitis on clinical grounds alone may be inaccurate in less severe cases, as is the exclusion of carrier status through family tree analysis. Therefore, a definitive diagnosis of hereditary pancreatitis in equivocal cases or exclusion of a carrier state should include analysis of genetic markers.

Chromosomes, Human, Pair 7↗