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C E Aston

Publications and source records attributed to C E Aston.

13 recordsLinked to original sources
PubMed1995

The relationship of APOE polymorphism and cholesterol levels in normoglycemic and diabetic subjects in a biethnic population from the San Luis Valley, Colorado.

We have determined apolipoprotein E (apoE = protein, APOE = gene) polymorphism and its relationship with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels in normoglycemic Hispanics (n = 446) and non-Hispanic whites (NHWs) (n = 659) as well as in diabetic Hispanics (n = 235) and NHWs (n = 116) from the San Luis Valley, Colorado. Effects were estimated separately for each group, and within each group men and women were analyzed separately; women were further categorized into pre- and post-menopausal status. The distribution of the APOE genotype pattern was comparable between the NHW normoglycemics and diabetics but it was significantly different among Hispanic normoglycemics and diabetics (P < 0.005). In the normoglycemic sample the APOE allele frequencies were significantly different between the two ethnic groups: the APOE*2 (0.09 vs. 0.05; P < 0.01) and APOE*4 (0.15 vs. 0.09; P < 0.002) allele frequencies were higher while the APOE*3 (0.76 vs. 0.86; P < 0.0001) allele frequency was lower in NHWs than in Hispanics. Significant variability among the three common APOE genotypes (3-2, 3-3, and 4-3) was observed for TC and LDL-C in normoglycemic Hispanic women (P = 0.09 and P = 0.03) but not in Hispanic men. In normoglycemic NHWs, however, significant mean differences among APOE genotypes were observed for TC and LDL-C in both women (P < 0.0001 and P < 0.0001) and men (P = 0.009 and P = 0.01). In Hispanic females, the APOE polymorphism accounted for 5.6% and 7.6% of the phenotypic variance for TC and LDL-C, respectively. In NHW females, the APOE polymorphism explained 10.2% of the phenotypic variance for TC and LDL-C, and in NHW males these values were 6.2% and 7.5%, respectively. There was no evidence of physiologic interaction between the APOE polymorphism and menopause status in affecting TC and LDL-C in NHW women (P = 0.65 and P = 0.55) but a suggestion of interaction was observed in Hispanic women for TC and LDL-C (P = 0.11 and 0.07). After the Hispanic women were stratified into pre- and postmenopausal groups, the effect of the APOE polymorphism on TC and LDL-C was significant only in the premenopausal group. Among diabetics, no significant effect of the APOE polymorphism was seen on cholesterol levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Genetic epidemiology of rheumatoid arthritis.

We conducted family studies and segregation analyses of rheumatoid arthritis (RA) that were based on consecutive patients with RA ascertained without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. These analyses demonstrated that both proband gender and age at onset are important risk factors but that proband gender appears to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling identified proband gender, familiality (multiplex or simplex), and an interaction term between these two variables as being adequate to define the distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males having a young age at onset may be the most informative in identifying the putative recessive gene and its modifiers.

Adult↗
PubMed1992

Molecular basis of a unique African variant (A-IV 5) of human apolipoprotein A-IV and its significance in lipid metabolism.

Human apolipoprotein A-IV (apoA-IV) exhibits a genetically determined structural polymorphism amenable to analysis by isoelectric focusing and immunoblotting techniques. We have determined the allele frequency and molecular basis of a unique ApoA-IV*5 allele which is widely distributed among blacks but is absent in other populations. The frequency of the ApoA-IV*5 allele in blacks (N = 308) was estimated to be 3.2%. In comparison to the common ApoA-IV*1 allele, analysis of coding and non-coding sequences of the ApoA-IV*5 allele revealed an in-frame insertion of 12 nucleotides near the carboxyl terminal region of the mature protein. The insertion involves an exact duplication of the second of the four repeats and codes for 4 amino acids glutamic acid (GAA), glutamine (CAG), glutamine (CAG), and glutamine (CAG) and is responsible for the charge shift of the the apoA-IV 5 isoform slightly toward the anode as compared to the wild type apoA-IV 1 isoform on the isoelectric focusing gel. This in-frame insertion occurs in a region which is highly conserved among rat, mouse, and humans. In addition to the 12 nucleotide insertion, the four individuals sequenced for the ApoA-IV*5 allele also revealed a same-sense mutation by replacing G to T at the third position of codon 316. Our preliminary data suggest that this unique black allele marker may be of potentially significance in studies of human lipid metabolism and in microevolution.

Adolescent↗
PubMed1992

Apolipoprotein A-IV genetic polymorphism and its impact on quantitative traits in normoglycemic and non-insulin-dependent diabetic Hispanics from the San Luis Valley, Colorado.

Apolipoprotein A-IV exhibits a common two-allele polymorphism in several human populations studied to date. Using isoelectric focusing and immunoblotting, we have analyzed plasmas from 188 non-insulin-dependent diabetic and 238 normoglycemic Hispanic individuals from the San Luis Valley, Colorado, to determine APOA4 genotype frequencies and to estimate the impact of the genotypes on quantitative traits. The frequencies of the two common alleles, APOA4*1 and APOA4*2, were 0.929 and 0.069, respectively, in normal subjects and 0.901 and 0.096, respectively, in diabetics. The third rare allele, APOA4*3, was detected sporadically in both groups. We studied the impact of APOA4 polymorphism on the levels of total plasma cholesterol, HDL cholesterol and its subfractions (HDL3 and HDL2), LDL cholesterol, triglycerides, glucose, and insulin. We observed no significant effect of the APOA4 polymorphism on any trait in diabetics. However, we did note a significant sex-specific effect in normoglycemic females on the level of total HDL cholesterol (p = 0.001) and its subfractions HDL2 (p = 0.043) and HDL3 (p = 0.001). The effect of the APOA4*2 allele in normal Hispanic females was to lower the total HDL, HDL2, and HDL3 cholesterol by 8.75 mg/dl, 2.37 mg/dl, and 5.36 mg/dl, respectively, compared to the common APOA4*1 allele.

Adult↗
PubMed1991

Investigating genomic imprinting and susceptibility to insulin-dependent diabetes mellitus: an epidemiologic approach.

Children of fathers with insulin-dependent diabetes mellitus (IDDM) are at greater risk of developing the disease than are children of IDDM mothers, reasons for which are currently unknown. To explore the possibility that genomic imprinting contributes to this phenomenon, 1,774 families with at least one IDDM child diagnosed before the age of 17 years and between 1950 and 1981 from the Children's Hospital at Pittsburgh IDDM Registry were evaluated. Approximately 1% of the mothers and 2.9% of the fathers were reported to have IDDM diagnosed before the age of 36 years (P less than 0.001). Excluding IDDM probands, the IDDM recurrence risk to siblings in families with an IDDM father was greater than that in families with an IDDM mother or in those with neither parent affected. Lifetable analyses revealed that among all children of diabetic fathers (probands included), there was a greater prevalence of IDDM, through age 30 years, for sons compared to daughters (59.5% vs. 34.1%, P = 0.02). However, there was no significant sex difference in the prevalence of IDDM among children of affected mothers (41.1% vs. 45.5%, P greater than 0.05). These data are not consistent with the genomic imprinting hypothesis and suggest that other genetic and/or environmental factors contribute to the increased risk for children of IDDM fathers.

Adolescent↗
PubMed1991

Apolipoprotein A-IV polymorphism, and its role in determining variation in lipoprotein-lipid, glucose and insulin levels in normal and non-insulin-dependent diabetic individuals.

Apolipoprotein A-IV (apo A-IV) is a major component of several lipoprotein particles and may, therefore, play an important role in lipid metabolism. Genetic polymorphism of apo A-IV has been reported in humans and several other animal species. The presence of two common alleles, apo A-IV * 1 and apo A-IV * 2 has been documented in several human populations. In this investigation, we have determined apo A-IV polymorphism by isoelectric focusing-immunoblotting in 82 non-insulin-dependent diabetic and 204 control non-Hispanic Whites from the San Luis Valley, Colorado. We have also estimated the impact of apo A-IV polymorphism on eight quantitative traits: total cholesterol, HDL-cholesterol, HDL3 and HDL2-cholesterol, LDL-cholesterol, triglycerides, fasting glucose and fasting insulin. No statistically significant difference was seen in apo A-IV allele frequencies between the control and diabetics, and these frequencies were comparable with those reported for U.S. White and European populations. Among controls, the impact of the apo A-IV polymorphism was significant on LDL-cholesterol (P = 0.04) in females and on fasting insulin levels (P = 0.06) in males. In diabetics, the effect was significant on insulin (P = 0.03) levels in males only. Furthermore, our data suggest that when making comparison of lipid profiles between the controls and diabetics the presence or absence of common apo A-IV phenotypes should be taken into account as these appear to effect these comparisons.

Adult↗
PubMed1990

Familial iron overload with possible autosomal dominant inheritance.

A 96 member Melanesian kindred with 31 cases of iron overload is reported. Liver biopsies from 19 of these patients showed features similar to those of genetic haemochromatosis in Caucasians, but in contrast to the previous reported HLA-linked autosomal recessive pattern of inheritance for haemochromatosis, this family shows a pattern that is most consistent with autosomal dominant inheritance. This is suggested by involvement of three and possibly four consecutive generations, with a high frequency of transmission from parents to children and equal gender distribution. Linkage and segregation analysis supported dominant inheritance, with no demonstrable HLA linkage.

Female↗
PubMed1990

Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics.

To determine the nature of the genetic component controlling liability to alcoholism, complex segregation analysis was performed on 35 multigenerational families each ascertained through a pair of male alcoholics. The results suggest that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. Mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus. Absence of this major effect, leaving only multifactorial effects, was also rejected. Some sources for the non-Mendelian character of the major effect are suggested, such as a combination of two or more Mendelian loci, the presence of phenocopies, sex-dependent differences in the underlying liability model, or heterogeneity in the alcoholism phenotype. Evidence for and against each is discussed.

Age Factors↗
PubMed1988

Genetic mapping of the 21-hydroxylase locus: estimation of small recombination frequencies.

The locus for 21-hydroxylase (CA21HB) has been mapped to the interval between the HLA-B and HLA-DR loci on chromosome 6. Several methods of estimating genetic distance were used to determine whether CA21HB is closer to HLA-B or HLA-DR based on data collected on 157 families ascertained through a proband with the classical form of 21-hydroxylase deficiency (CA12Hd). The results were inconclusive but serve to highlight the limitations of present methods of estimating genetic distance when recombination frequencies are of the order of .005.

Chromosome Mapping↗
PubMed1988

A segregation and linkage study of classical and nonclassical 21-hydroxylase deficiency.

The segregation of classical and nonclassical 21-hydroxylase deficiency (21-OHD) and its linkage to HLA-B was investigated in 220 families. First, the surprisingly high frequency of the nonclassical 21-OHD gene estimated elsewhere was confirmed using a different methodology which avoided particular assumptions concerning the classification of an individual's genotype. In the present study the gene frequency was found to be .103 +/- .020 in an ethnically pooled sample and was as high as .223 +/- .062 among Ashkenazi Jews. Second, the segregation analysis of families ascertained through a nonclassical 21-OHD proband and those ascertained through a classical 21-OHD proband showed essentially identical results. A partial recessive model with no recombination between 21-OHD and HLA-B fitted the data better than did a complete recessive model with approximately 0.5% recombination between 21-OHD and HLA-B. The support for the partial over the complete recessive model depended on the assumed ascertainment probability, an unknown parameter in these data. Four families provided most of the evidence against the complete recessive model. All these included an unaffected sib who shared both HLA-B specificities in common with the affected proband. Possible explanations for the condition in these families include recombination, gene conversion, mutation in one of the parental gametes, or technical errors.

Adrenal Hyperplasia, Congenital↗
PubMed1986

Log-linear model analysis of allelic associations.

An approach is outlined for the analysis of nonrandom allelic associations in multilocus systems in a diploid population. The concept of composite link functions in generalised linear model analysis is used to handle the problem of incomplete identification of constituent gametes often encountered in genotypic data for two or more marker loci.

Alleles↗