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J E Hixson

Publications and source records attributed to J E Hixson.

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

A genome search identifies major quantitative trait loci on human chromosomes 3 and 4 that influence cholesterol concentrations in small LDL particles.

Small, dense LDL particles are associated with increased risk of cardiovascular disease. To identify the genes that influence LDL size variation, we performed a genome-wide screen for cholesterol concentrations in 4 LDL size fractions. Samples from 470 members of randomly ascertained families were typed for 331 microsatellite markers spaced at approximately 15 cM intervals. Plasma LDLs were resolved by using nondenaturing gradient gel electrophoresis into 4 fraction sizes (LDL-1, 26.4 to 29.0 nm; LDL-2, 25.5 to 26.4 nm; LDL-3, 24.2 to 25.5 nm; and LDL-4, 21.0 to 24.2 nm) and cholesterol concentrations were estimated by staining with Sudan Black B. Linkage analyses used variance component methods that exploited all of the genotypic and phenotypic information in the large extended pedigrees. In multipoint linkage analyses with quantitative trait loci for the 4 fraction sizes, only LDL-3, a fraction containing small LDL particles, gave peak multipoint log10 odds in favor of linkage (LOD) scores that exceeded 3.0, a nominal criterion for evidence of significant linkage. The highest LOD scores for LDL-3 were found on chromosomes 3 (LOD=4.1), 4 (LOD=4.1), and 6 (LOD=2.9). In oligogenic analyses, the 2-locus LOD score (for chromosomes 3 and 4) increased significantly (P=0.0012) to 6.1, but including the third locus on chromosome 6 did not significantly improve the LOD score (P=0.064). Thus, we have localized 2 major quantitative trait loci that influence variation in cholesterol concentrations of small LDL particles. The 2 quantitative trait loci on chromosomes 3 and 4 are located in regions that contain the genes for apoD and the large subunit of the microsomal triglyceride transfer protein, respectively.

Adolescent↗
PubMed1999

Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC.

We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.

Chromosome Mapping↗
PubMed1999

A quantitative trait locus influencing BMI maps to the region of the beta-3 adrenergic receptor.

The beta-3 adrenergic receptor (ADRB3) has been implicated as a regulator of energy expenditure, and a polymorphism in codon 64 of this gene (Trp64Arg) has been associated in some studies with obesity and insulin resistance. However, many studies have failed to detect an effect of this variant, and the importance of the Trp64Arg variant in human obesity remains controversial. We performed a quantitative linkage analysis of the ADRB3 and obesity, using 12 markers (including the intragenic Trp64Arg polymorphism) spanning a 57-cM region of chromosome 8. The study population consisted of 470 individuals from 10 large multigenerational families of Mexican-American ancestry residing in San Antonio, TX. In two-point analysis, logarithm of odds (LOD) scores >1.0 were observed for six markers surrounding ADRB3 in a 33-cM region spanned by markers D8S1477 and D8S1136. The multipoint LOD score was 3.21, occurring between markers D8S1121 and ADRB3, approximately 2-3 cM from ADRB3. Adjusting for the presence of the Arg64 allele or excluding from the analysis the 11 individuals homozygous for the Arg64 allele did not reduce the evidence for linkage. A genome scan was conducted at 10 cM map density to detect other loci influencing variation in BMI. Multipoint LOD scores >1.0 were observed in four other regions, including two on chromosome 17, one on chromosome 6q, and one on chromosome 2p. These data suggest that the ADRB3 should continue to be regarded as a strong candidate gene for obesity even though evidence for an effect of the Trp64Arg polymorphism could not be established. It is also possible that a gene closely linked to ADRB3 may influence susceptibility to obesity.

Adult↗
PubMed1998

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Adult↗
PubMed1998

Two major loci control variation in beta-lipoprotein cholesterol and response to dietary fat and cholesterol in baboons.

We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in beta-lipoproteins (low density lipoprotein cholesterol [LDLC]) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels (LDLC(Base)), we analyzed two variables for diet response: LDLC(RF), which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLC(RC), which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities (h2) of the 3 traits were 0.59 for LDLC(Base), 0.14 for LDLC(RF), and 0.59 for LDLC(RC). In addition, LDLC(Base) and LDLC(RC) had a significant genetic correlation (ie, rhoG=0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLC(RC) and some genetic variation in LDLC(Base) and LDLC(RF) and confirmed the presence of a different major locus that influences LDLC(Base) alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations.

Animals↗
PubMed1998

Molecular basis of an apolipoprotein[a] null allele: a splice site mutation is associated with deletion of a single exon.

Apolipoprotein[a] (apo[a]), a unique component of atherogenic lipoprotein[a], is highly polymorphic in human and nonhuman primates. Null alleles, producing no detectable circulating Lp[a] or apo[a] isoforms, are found at high frequencies. The molecular basis of null alleles is not yet known. In baboons, approximately two-thirds of null alleles do not produce detectable hepatic transcripts (transcript negative nulls), and one-third of null alleles produce normal amounts of apo[a] transcripts (transcript positive nulls). We have cloned apo[a] cDNA from a baboon carrying a transcript positive null allele defective in secretion from primary hepatocytes. Compared with wild-type cDNA, the null allele contained an in-frame 47 amino acid deletion in the protease domain corresponding to one exon of the apo[a] gene. The null allele contains an A-->T substitution in the third nucleotide position of the intron downstream of the deleted exon which alters the donor splice site consensus sequence. Thus, this null is likely due to a mutation that prevents normal mRNA splicing, yielding a shortened protein that may be defective in intramolecular interactions required for normal processing and secretion of apo[a]. This is the first report of a molecular basis for apo[a] null alleles.

Alleles↗
PubMed1997

Recent polymorphic insertion of an Alu repeat in the baboon lipoprotein lipase (LPL) gene.

We have identified a polymorphic insertion in the lipoprotein lipase (LPL) gene in a captive baboon colony. Mapping and nucleotide (nt) sequence analysis of the polymorphism showed that it is due to the presence or absence of an Alu repetitive element in intron 7 of the baboon LPL gene. This polymorphic Alu repeat has not been reported in humans, and we did not detect the repeat in a survey of the LPL intron 7 gene region in other non-human primates. Comparison of nt at diagnostic positions in this Alu insertion with different Alu subfamily consensus sequences showed that it most closely resembles the young AluY subfamily. These data suggest that this polymorphic Alu repeat inserted independently in the baboon lineage.

Alleles↗
PubMed1997

Characterization of the genetic elements controlling lipoprotein(a) concentrations in Mexican Americans. Evidence for at least three controlling elements linked to LPA, the locus encoding apolipoprotein(a).

Analyses of 1163 samples from the San Antonio Family Heart Study revealed several elements of genetic control of lipoprotein(a) (Lp(a)) concentrations in Mexican Americans. Apolipoprotein(a) (apo(a)) isoform size variation was inversely related to Lp(a) concentrations and explained about 22% of total phenotypic variation. Segregation analyses suggested the existence of a major gene that influenced an additional 41% of total Lp(a) variation. A G-->A polymorphism in the LPA promoter was in strong disequilibrium with apo(a) isoform size, but did not contribute a significant amount of additional information about Lp(a) variation. However, about 25% of variation in Lp(a) concentrations was influenced by additive polygenic effects, which include the effects of null phenotype alleles. Altogether, these genetic components explained 89% of Lp(a) variation, similar to heritability estimates made in several other studies. Apo(a) size variation and the major gene (explaining a total of about 62% of Lp(a) variation) were linked to each other and, as expected, to the plasminogen locus. Thus, together with the well-established null phenotype allele, these different genetic factors represent at least three distinct elements of control exerted at the LPA locus, which encodes the apo(a) protein.

Adult↗
PubMed1997

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Adipose Tissue↗
PubMed1997

Linkage of essential hypertension to the angiotensinogen locus in Mexican Americans.

Essential hypertension has been linked to a highly polymorphic marker at the angiotensinogen locus, and association with a polymorphism in this locus has been found in some populations. We tested the hypothesis that these same polymorphic markers are linked to essential hypertension in Mexican Americans. The data comprised all the affected relative pairs in 46 extended families chosen at random from a low-income barrio in San Antonio. Specifically, we searched for linkage by testing for excessive marker alleles shared identical by descent (IBD) among hypertensive relative pairs. When women taking oral contraceptives or hormones were excluded, the affected relative pairs shared a significant excess of alleles IBD for the highly heterozygous GT repeat polymorphism (P=.038) and were marginally significant for the M235T variant (P=.079), which has a much lower heterozygosity (0.43 versus 0.85 for the GT repeat). We also assayed plasma levels of angiotensinogen and, using likelihood methods, found no significant association (P=.43) between plasma levels of angiotensinogen and M235T genotypes. These results support the linkage of essential hypertension to the angiotensinogen locus but do not indicate a specific role for the M235T variant.

Adult↗
PubMed1996

Human APOE protein localized in brains of transgenic mice.

Transgenic mice carrying the three common human apolipoprotein E (APOE) alleles have been developed. In this study, brains of the transgenic mice have been analyzed by in situ histohybridization, immunohistochemistry, and immunoblots to determine sites of gene expression, to identify specific brain cells associated with human apoE protein, and to determine the relative concentrations of the human apoE. Results indicate that (1) human APOE mRNA and apoE protein occur in the gray and white matter of transgenic mouse brains; (2) in the hippocampus of transgenic brains, human apoE protein reacts immunologically within the same cells as the glial fibrillary acidic protein (GFAP), a specific marker for astrocytes; and (3) concentrations of the apoE isoforms determined in three heterozygous transgenic brains range from 22 to 250 pmol/g wet weight of brain.

Alleles↗
PubMed1996

Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study.

BACKGROUND: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Adult↗
PubMed1996

Apolipoprotein B (apo B) signal peptide length polymorphisms are associated with apo B, low density lipoprotein cholesterol, and glucose levels in Mexican Americans.

We investigated the effects of apolipoprotein (apo) B signal peptide length polymorphisms on low density lipoprotein cholesterol (LDL-C), apo B, and post-challenge (2 h) glucose levels in 686 Mexican Americans from 34 families. The most common allele encoded an apo B signal peptide of 27 amino acids (ins; SP-27), the next most frequent allele encoded a 24 amino acid signal peptide (del; SP-24), and the rarest allele encoded a 29 amino acid signal peptide (ins; SP-29) that has been found only in Mexican Americans. Homozygotes for the SP-24 allele had significantly higher mean levels of apo B. LDL-C, and 2-h glucose than SP-27 homozygotes, and SP-27/SP-24 heterozygotes had intermediate levels (P = 0.01 for apo B, P < 0.001 for LDL-C, and P = 0.04 for 2-h glucose). Heterozygotes for the SP-29 allele had higher apo B and LDL-C levels compared to homozygotes for the SP-27 or SP-24 alleles. Apo B signal peptide length polymorphism accounted for 4.2%, 3.5%, and 3.0% of the residual variation in LDL-C, apo B, and 2-h glucose levels, respectively, among the Mexican American families.

Adolescent↗