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Biomedical subjects

Christopher E Aston

Publications and source records attributed to Christopher E Aston.

12 recordsLinked to original sources
PubMed2006

Racial differences in correlates of misreporting of energy intake in adolescent females.

OBJECTIVE: To determine the extent of misreporting of energy intake (EI) and its anthropometric, demographic, and psychosocial correlates in a bi-racial cohort of young women. RESEARCH METHODS AND PROCEDURES: This was a cross-sectional study of 60 black and 60 white young women, 18 to 21 years old, enrolled in a longitudinal study. Total energy expenditure was assessed using doubly labeled water. Self-reported EI was obtained from 3-day food records. BMI was computed from height and weight. Fat mass was assessed by DXA. Multivariate analyses examined racial differences on the extent of misreporting and its effect on other potential correlates of misreporting. Race-specific step-wise linear regression analysis was performed to examine the effect of BMI, parental education, and drive for thinness on misreporting of EI. RESULTS: More white women tended to under-report EI than black women (22% vs. 13%, p = 0.07). In black women, under-reporting was significantly (p = 0.01) associated with drive for thinness score but was only marginally (p = 0.1) associated with BMI. Each point increase in drive for thinness score was associated with under-reporting by 40 kcal/d. In white women, under-reporting was significantly (p = 0.03) associated with higher parental education by 440 kcal/d and also only marginally (p = 0.09) with BMI. DISCUSSION: This tendency for under-reporting of EI limits the use of self-reported EI in studying energy balance in free-living subjects. Most black and almost all white women in their late teens significantly under-reported their EI, whereas under-reporting was not as evident among lean young black women.

Absorptiometry, Photon↗
PubMed2005

Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.

OBJECTIVE: To determine whether frequencies of the mutations in the 21-hydroxylase (CYP21) gene and the G972R variant of the insulin receptor substrate-1 (IRS1) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95). INTERVENTION(S): Blood and DNA sampling before hormonal therapy. MAIN OUTCOME MEASURE(S): Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants. RESULT(S): Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3). CONCLUSION(S): The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

Adrenal Glands↗
PubMed2004

Oligogenic combinations associated with breast cancer risk in women under 53 years of age.

Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene-gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5-5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.

Adolescent↗
PubMed2003

Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect.

Hereditary paraganglioma type 1 (PGL1) is characterized by slow-growing and vascularized tumors that often develop in the carotid body (CB) and is caused by mutations in the gene for succinate dehydrogenase D ( SDHD) of mitochondrial complex II. The mechanisms of tumorigenesis and the factors affecting penetrance and expressivity are unknown. Because chronic hypoxic stimulation at high altitudes causes sporadic CB paragangliomas, it has been hypothesized that the SDHD gene product may be involved in oxygen sensing. On this background, we examined genotype-phenotype-environment relationships and tested whether higher altitudes adversely affect the phenotype in PGL1. An analysis of 58 subjects from 23 families revealed that nonsense/splicing mutation carriers developed symptoms 8.5 years earlier than missense mutation carriers ( P<0.012). We also found that subjects who were diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors ( P<0.012). Pheochromocytomas developed in six subjects (approximately 10%), five of whom had nonsense mutations ( P=0.052). Subjects with pheochromocytomas also lived at higher average altitudes and were exposed to higher altitude-years than those without them ( P=0.026). To test whether altitude is also associated with the more frequent detection of germ-line founder mutations among sporadic cases in The Netherlands than in the USA ( P=0.00033), we calculated population-weighted elevations of the two countries. We found that the population-weighted elevations were approximately 260 m for the US and 2 m for the central-western Netherlands ( P~0), where three Dutch founder mutations were discovered. This finding suggests that low altitudes in The Netherlands reduce penetrance and relax the natural selection on SDHD mutations. Collectively, these data suggest that higher altitudes and nonsense/splicing mutations are associated with phenotypic severity in PGL1 and support the hypothesis that SDHD mutations impair oxygen sensing.

Adrenal Gland Neoplasms↗
PubMed2003

A practice approach for identifying previously unsuspected environmental contributors to systemic lupus erythematosus and other complex diseases.

Existing medical records and health surveys provide insights into potential environmental contributors to complex chronic diseases. Those recognizable risks (e.g., workplace exposures and behaviors including smoking) do not, however, exhaust the domain of potential environmental contributors. Qualitative ethnographic investigation can be used to generate statistically testable hypotheses about environmental contributors to complex disease that otherwise would not be recognized as such. Consequently, we can empirically specify lifestyle beliefs and behaviors usually summarized by proxy identities such as race, ethnicity, gender, class, and culture. The investigation of potential environmental contributors to complex diseases may be particularly useful in confirming or disconfirming suggestive or established linkages and for indicating the kind of gene-environment interaction that may be involved.

Environmental Exposure↗
PubMed2002

Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia.

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (alpha = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.

Anemia, Hemolytic↗
PubMed2002

SLEB3 in systemic lupus erythematosus (SLE) is strongly related to SLE families ascertained through neuropsychiatric manifestations.

Seizures and psychosis are neuropsychiatric (NP) manifestations of a large number of systemic lupus erythematosus (SLE) patients. Since NP manifestations were part of the SLE phenotype for some, but not all SLE affecteds, we hypothesized that those SLE patient families with NP manifestations might be more genetically homogeneous at loci important to NP-related SLE, and hence have increased power to detect linkage. We identified 23 families of European-American (EA) origin and 20 families of African-American (AA) origin, in which at least one SLE patient in each family was diagnosed with the presence of NP manifestations. A total of 318 microsatellite markers at an average marker density of 11 cM were genotyped. Uncertainty of the genetic model led us to perform the initial genome scan by a multipoint non-parametric allele sharing linkage method. Once the evidence of linkage was suggestive, we then performed parametric model-based linkage by maximizing the relevant parameters to define a parsimonious genetic model. We found the maximum multipoint parametric LOD score was 5.19 and the non-parametric linkage score (Zlr) was 3.12 ( P=9x10(-4)) for EA NP pedigrees at 4p16, previously identified as SLEB3. The segregation behavior of this linked locus suggests a dominant mode of inheritance with an almost 100% homogeneous genetic effect in these pedigrees. The results demonstrated a significant increase of LOD score to detect SLEB3 when the families were further ascertained through NP, compared with the analysis of all EA SLE families together.

Chromosome Mapping↗
PubMed2002

Reduced body weight and increased postimplantation fetal death in tyrosylprotein sulfotransferase-1-deficient mice.

Tyrosine sulfation is mediated by one of two Golgi isoenzymes, called tyrosylprotein sulfotransferases (TPST-1 and TPST-2). A relatively small number of proteins are known to undergo tyrosine sulfation, including certain adhesion molecules, G-protein-coupled receptors, coagulation factors, serpins, extracellular matrix proteins, and hormones. As one approach to explore the role of these enzymes in vivo and how they might interact in biological systems, we have generated TPST-1-deficient mice by targeted disruption of the Tpst1 gene. Tpst1(+/-) mice appear normal and, when interbred, yield litters of normal size with a Mendelian genetic distribution and an equal sex distribution. Tpst1(-/-) mice appear healthy but have approximately 5% lower average body weight than Tpst1(+/+) controls. In addition, we show that although fertility of Tpst1(-/-) males and females per se is normal, Tpst1(-/-) females have significantly smaller litters because of fetal death between 8.5 and 15.5 days postcoitum. These findings suggest that there are proteins involved in regulation of body weight and reproductive physiology, which require tyrosine sulfation for optimal function that are yet to be described. Our findings also strongly support the conclusion that TPST-1 and TPST-2 have distinct biological roles that may reflect differences in their macromolecular substrate specificity.

Animals↗
PubMed2002

Inter- and intrafamilial variability in premature pubarche and polycystic ovary syndrome.

OBJECTIVE: To ascertain the extent of phenotypic heterogeneity for premature pubarche and polycystic ovary syndrome between and within families. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Three families in which the propositus had presented with either premature pubic hair or adolescent hyperandrogenism. INTERVENTION(S): Detailed medical histories, hormone determinations, and genotype analyses. MAIN OUTCOME MEASURE(S): Clinical phenotype. Genotypes for CYP21, HSD3B2, G972R variant of IRS-1, N363S variant of GRL, W64R variant of ADRB3, CAG repeat in exon 1 of AR, MspAI polymorphism in CYP17, and R264C variant of CYP19. RESULT(S): Significant phenotypic and genetic heterogeneity was observed both within and between families. In one family, CYP21 and IRS-1 variants were observed to co-segregate with symptoms of androgen excess and obesity. No genetic markers were consistently noted to associate with clinical features of hyperandrogenism in the other two families. CONCLUSION(S): The difficulties in classifying female family members as clearly affected or unaffected and lack of definitive male phenotype complicate the use of linkage analysis to identify the polycystic ovary syndrome genes. Each family is best considered on an individual basis to identify genetic markers that segregate with the clinical features of androgen excess.

Age Factors↗
PubMed2002

Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche.

To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism.Association study. Academic research environment. Adolescent girls with a history of PP and healthy adolescent female control subjects. Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

Adolescent↗
PubMed2002

Racial differences in the relation between uncoupling protein genes and resting energy expenditure.

BACKGROUND: Lower resting energy expenditure (REE) in African American women may contribute to their obesity. The identification of uncoupling protein (UCP) genes has fueled a search for genes involved in energy metabolism in humans. OBJECTIVE: We examined variation in REE in relation to variation in UCP1, UCP2, and UCP3 in 141 women aged 18-21 y. DESIGN: Standard methods were used for REE measurements and genetic analysis. Body composition was determined with the use of dual-energy X-ray absorptiometry. Multivariate analysis was used to examine the effect of genotypes on REE and on fat mass in relation to other potentially confounding variables. RESULTS: REE was 295 kJ/d lower in African American women than in white women. No significant variation in REE was seen for UCP1, UCP2, and UCP3 (p-55; exon 3a; and exon 3b) variants after adjustment for other variables including smoking status. For the UCP3 exon 5 variant, REE was significantly (P = 0.019) lower in African American women with the CC genotype than in those with the TT genotype. In African American women, there was a significant trend (P = 0.012) toward lower REE and a weak but nonsignificant trend (P = 0.1) toward greater fat mass across the 3 genotypes (TT, CT, and CC). CONCLUSIONS: The significant and dose-dependent relation between lower REE and the C allele suggests that it may be a thrifty allele. The presence of this parsimonious energy metabolism in African American women, possibly linked to UCP3, may be implicated in their susceptibility to obesity. The absence of a UCP3 effect in white women is intriguing and needs to be explored to further understand possible interactions between UCP3 and other genes.

Absorptiometry, Photon↗