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R T Acton

Publications and source records attributed to R T Acton.

At least 37 records · Page 2Linked to original sources
PubMed1996

Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks.

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11 beta-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used chi 2 analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (chi 2 = 6.98, df = 1, P < or = .008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer's disease family.

Alzheimer's disease (AD) is a progressive, degenerative neurological disorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialized societies. The etiology of AD is unknown, but clinical, pathological, epidemiological, and molecular investigations suggest it is etiologically heterogeneous. Mutations in the amyloid protein are rare and segregate with the disease in a few early-onset familial AD (FAD) families. Similarities between AD and the unconventional viral (UCV) diseases, and between the amyloid and prion proteins, implicate the human prion protein gene (PRNP) as another candidate gene. Single strand conformation polymorphism (SSCP) analysis was used to screen for mutations at this locus in 82 AD patients from 54 families (30 FAD), vs. 39 age-matched controls. A 24-bp deletion around codon 68 that codes for one of five Gly-Pro rich octarepeats was identified in two affected sibs and one offspring of one late-onset FAD family. Two other affected sibs, three unaffected sibs, and three offspring from this family, in addition to one sporadic AD patient and three age-matched controls, were heterozygous for another octarepeat deletion located around codon 82. Two of the four affected sibs had features of PD, including one who was autopsy-verified AD and PD. Although these deletions were found infrequently in other AD patients and controls, they appear to be a rare polymorphism that is segregating in this FAD family. It does not appear that mutations at the PRNP locus are frequently associated with AD in this population.

Alzheimer Disease↗
PubMed1994

Variability of the pancreatic islet beta cell/liver (GLUT 2) glucose transporter gene in NIDDM patients.

The purpose of these experiments was to test the hypothesis that impaired glucose-stimulated insulin secretion in NIDDM is due to mutations in the islet beta cell/liver glucose transporter (GLUT 2) gene. Using oligonucleotide primers flanking each of the 11 exons, the structural portion of the gene was studied by PCR-SSCP analysis. DNA from African-American females (n = 48), who had gestational diabetes but developed overt NIDDM after delivery, was studied. Each SSCP variant was sequenced directly from genomic DNA. Two amino acid substitutions from the previously reported sequence were found, one in exon 3 and the other in exon 4B. Four additional silent mutations in the coding region, and six intron mutations outside the splice junction consensus sequences, were also identified. The mutation GTC x ATC in exon 4B substituted Val197 to Ile197. This amino acid substitution was found in only one NIDDM patient in a single allele, and was not found in 52 control subjects. This residue exists in the fifth membrane spanning domain, and Val at this position is conserved in mouse and rat GLUT 2, and human GLUT 1 to GLUT 4. The other codon change in exon 3, ACT x ATT, substituted Thr110 to Ile110 in the second membrane spanning domain. To determine the frequency of this non-conservative amino acid substitution, a PCR-LCR assay was developed. This assay was simple and highly specific for detection of this single nucleotide substitution. The allelic frequency of the ATT (Ile110) in NIDDM patients (39.6%, n = 48) and that in controls (47.1%, n = 52) did not differ (p = 0.32, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning.

Mutations of the glucokinase gene result in early-onset familial Type 2 (non-insulin-dependent) diabetes mellitus, and several members of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period. Two simple sequence repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes, after adjustment for multiple comparisons. To detect single base changes, all 11 exons and proximal islet and liver promoter regions were examined by polymerase chain reaction plus single-stranded conformational polymorphism analysis in 45 gestational diabetes only patients who had not yet developed Type 2 diabetes. Nine coding region variants were identified: Ala11 (GCC) to Thr11 (ACC) in islet exon 1, and 8 variants either in untranslated regions or in the third base of a codon. Four variant sites were found in introns, but none in splicing consensus sequences. Analysis of the promoter regions revealed two common variants, G-->A at islet -30 (24%), and G-->A at liver -258 (42%). The frequencies of the promoter variants, determined by allele specific polymerase chain reaction analysis, but did not differ among the three groups. Thus, no significant coding sequence glucokinase mutations were found in 90 alleles from 45 patients with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

HLA in ankylosing spondylitis: is HLA-B27 the only MHC gene involved in disease pathogenesis?

Linkage analysis of HLA haplotypes, HLA-B27 subtypes, and a 9.2-kb PvuII B7 restriction fragment length polymorphism (RFLP) (shown previously to be associated with peripheral arthritis in ankylosing spondylitis [AS]) in 115 relatives from 12 multiplex spondyloarthropathy (SNSA) and 2 B27-positive control families showed AS to be linked to HLA-B27 haplotypes. The RFLP segregated with HLA-A3- and HLA-A9-bearing haplotypes (lod score, 10.98; odds in favor of linkage, 9.2 x 10(10):1), although its linkage to AS or other SNSA per se was not seen. The association of HLA-A3/A9 with the RFLP was also seen in 52 AS patients and 92 controls, although no HLA-A, -B, -C, or -DR allele (other than HLA-B27) was significantly increased in frequency. The HLA-B27 subtype seen on all but one of the haplotypes studied was B*2705, the sole exception being HLA-B*2702. Although not ruling out a second HLA-A-linked gene influencing the clinical expression of AS, these data fail to support the role of a second MHC-associated gene in the pathogenesis of AS per se.

Alleles↗
PubMed1994

Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease.

High plasma homocyst(e)ine (Hcy) concentrations may be a determinant of coronary artery disease (CAD). Folate and vitamin B-12 are required for the primary metabolic pathway to reduce Hcy concentrations. The interrelationships of Hcy and these two vitamin cofactors were investigated in a case-control study of 101 white males aged 30-50 y with angiographically demonstrated CAD, and 108 white male, similarly aged, control subjects living in the same community as the patients. The odds ratio (OR) of CAD per quartile increase of plasma Hcy concentration based on control values was 1.6 (95% CI: 1.3, 2.1). After age, HDL and LDL cholesterol, body mass index, smoking, hypertension, and diabetes were controlled for, Hcy remained an independent risk factor (OR: 1.4; 95% CI: 1.0, 2.0). The OR change per quartile increase of folate concentration was 0.8 (95% CI: 0.6, 1.0). This difference was reduced (OR: 0.9; 95% CI: 0.7, 1.2) after Hcy adjustment. No difference in the geometric mean of vitamin B-12 concentration was found between patients and control subjects, both 5.8 nmol/L. However, after Hcy and the other CAD risk factors were controlled for, the OR per quartile increase in vitamin B-12 concentration was 1.5 (95% CI: 1.0, 1.8). Reduction in plasma Hcy by interventions to increase plasma folate concentration may decrease CAD risk.

Adult↗
PubMed1994

Genes within the major histocompatibility complex predict NIDDM in African-American women in Alabama.

OBJECTIVE: To test the hypothesis that genes within the major histocompatibility complex (MHC) are associated with gestational diabetes mellitus (GDM) and, subsequently, non-insulin-dependent diabetes mellitus (NIDDM) in African-American women. RESEARCH DESIGN AND METHODS: African-American women who presented with GDM were compared with pregnant African-American control subjects. Following pregnancy, GDM patients were assessed at various intervals of time (median = 6 years) to determine whether they had developed diabetes. RESULTS: GDM patients who required insulin during pregnancy possessed a significantly higher frequency of A33, DR2, DR9, and BF-S phenotypes than control subjects. GDM patients who subsequently developed NIDDM had a significantly higher frequency of B41, DR2, and BF-S and a lower frequency of DR1 and DR6 phenotypes than control subjects. Even after controlling for age and body mass index, B41 and DR2 were independent predictors of developing insulin-requiring GDM and NIDDM in GDM subjects. CONCLUSIONS: These results suggest that either one or more genes within the MHC are involved in the etiology of NIDDM.

Alabama↗
PubMed1993

Concordance of 21-hydroxylase gene ratio, human leukocyte antigen haplotyping and adrenal testing results in a family with late-onset adrenal hyperplasia.

Late-onset adrenal hyperplasia (LOAH) due to 21-hydroxylase (21-OH) deficiency is one of the most common autosomal recessive disorders. There appear to be two 21-OH genes, CYP21A (a pseudogene) and CYP21B (the functional gene), which lie in close proximity to the human leukocyte antigen (HLA) encoding region on the short arm of chromosome 6. While the CYP21A/CYP21B ratio is normally 1:1, ratio abnormalities are frequent in LOAH, suggesting gene deletion, duplication or conversion. The objective of this study was to determine whether an abnormal CYP21A/CYP21B ratio could predict carriers of LOAH, as determined by endocrine and HLA results. The probands appear to be compound heterozygotes carrying a 21-OH gene for LOAH and a deletion of the homologous gene. However, concordance between an abnormal 21-OH gene ratio and the inheritance of the LOAH gene does not appear to be complete, as demonstrated by this family study. Further studies of the feasibility of screening carriers for 21-OH deficiencies with the CYP21A/CYP21B ratio or other molecular probes must be performed.

Adolescent↗
PubMed1991

Gestational diabetes mellitus among African-American women.

Gestational diabetes mellitus (GDM) is associated with increased risk of poor outcomes for the pregnancy. It is a strong risk factor for subsequent diabetes. The epidemiology of GDM in African-American women is not well known. It has not been demonstrated that their risk factors are similar in character and weight to those among White women. There is considerable multicollinearity among GDM risk factors such as age, parity, obesity, hypertension, and family history of diabetes, and this needs to be sorted out. This review is based on the results of a nested case-control study to evaluate the frequency of, and the relationships of the known risk factors with, the onset of GDM among African-American women. All cases of GDM within a cohort of women seen at any of the county health department clinics in Jefferson County, Alabama from 1981 to 1987 were identified. The cohort represents approximately 63% of all African-American pregnancies in the county during the period. With few exceptions (5.1% based on fasting plasma glucose greater than or equal to 120 mg/dl), potential GDM cases (7.1%) were selected on the basis of a 2 h post 100 g carbohydrate meal screening plasma glucose measure at their second prenatal visit and again at 28-32 weeks greater than or equal to 115 mg/dl and diagnosed on the basis of the results of an oral glucose tolerance test (OGTT) using the criteria of O'Sullivan and Mahan. Women with any prior history of diabetes (even in pregnancy), 1.6%, were excluded. The frequency of the new diagnosis of GDM among African-American women in this pregnancy in the cohort was 2.5% of pregnancies and 3.4% of women, which is similar to the values reported in the other studies. Controls were selected from women with negative screening tests who delivered after a GDM subject. The results reported in this paper reflect 358 cases (86% of all eligible GDM cases identified) and 273 controls. Cases were significantly older (28.3 vs. 21.7 years), of higher gravidity (2.7 vs. 1.9), more obese (76.7 vs. 61.7 kg), gained weight more rapidly (0.34 vs. 0.28 kg/week), had more hypertension in this pregnancy (28.2 vs. 2.6%), and there was a higher proportion with a family history of diabetes (41.3 vs. 16.5%) (p less than 0.001 for all comparisons). Because there were significant correlations among the risk factors in both cases and controls, multivariable logistic regression analyses were performed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

X-linked codominant genes control all types of non-major histocompatibility complex-restricted cytotoxicity.

In most individuals, natural killer (NK) activity is abolished after lymphocyte irradiation with 3,000 cGy, while lymphocytes from a minority of males retain 100% NK activity and lymphocytes from some females retain 50% NK activity after this dose. Radiation sensitivity of NK activity is controlled by X-linked codominant genes. The frequency of the allele that imparts resistance is 7%. We studied a unique family in which both parents have the resistant allele such that the father is completely resistant and the mother is partially resistant. The three offspring of this couple were one sensitive male, one partially resistant female, and one completely resistant female. The radiation sensitivity of nonspecific cytotoxic functions mediated by various types of effector cells from all five family members were evaluated in order to determine whether other cytotoxic functions were controlled by the same set of genes. The cytotoxic functions investigated were: NK and lymphokine-activated killing, anomalous killing and lectin-dependent cellular cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. Our data indicate that the radiation sensitivity of all types of nonspecific cytotoxic cells is under the same genetic control.

Adult↗
PubMed1991

A novel DRB1 allele in DR2-positive American blacks.

Class II D region antigens of the major histocompatibility complex are naturally occurring dimeric proteins found on the surface of lymphoid cells. In most haplotypes at least two of the polymorphic beta chains are associated with a nonpolymorphic alpha chain. The allelic variation of these proteins lies in the first domain of the expressed protein. At present, there are four known DRB genes. DRB1 encodes for the classical DR 1, 3, 4, 5, etc., specificities. DRB3 and DRB4 encode the four supertypic specificities of DRw52 and the single phenotype of DRw53, respectively. Two DRB genes are expressed in human leukocyte antigen DR2-positive individuals. While DRB1 is the more polymorphic gene in most haplotypes, in DR2 haplotypes it appears that DRB5 encodes the polymorphic DR beta chain and the DRB1 encodes a nonpolymorphic beta chain. We attempted to further define the diversity of this region by direct dideoxynucleotide sequencing of polymerase-chain-reaction-amplified genomic DNA. We identified a novel DRB1 allele in DR2-positive individuals that was only observed in the American blacks sampled. This allele may code for a black specific class II antigen.

Alleles↗
PubMed1991

Autoantibodies in black women with class A1 or class GB diabetes mellitus.

No marker except repeated fasting glucose determinations has proven useful to ascertain prospectively which women with gestational diabetes mellitus will remain euglycemic by diet modification or will require insulin therapy. We screened 183 black women with gestational diabetes mellitus to determine if the presence of islet cell, mitochondrial, nuclear, DNA, parietal cell, smooth muscle, thyroid microsomal, thyroid thyroglobulin autoantibodies, or rheumatoid factor predicted the need for insulin therapy to maintain euglycemia in women with gestational diabetes mellitus. One hundred forty-two women maintained normal fasting plasma glucose levels with dietary modifications and 41 required institution of split-dose insulin therapy. We found no significant differences in the prevalence of these autoantibodies in black women with Class GB versus Class A1 diabetes mellitus. We conclude that screening for autoantibodies in women with gestational diabetes mellitus is not useful in determining which patients will subsequently require insulin therapy during their pregnancies.

Antibodies, Antinuclear↗
PubMed1991

Histocompatibility antigen subtypes in black women with class A1 or class GB diabetes mellitus.

Insulin-dependent diabetes mellitus is associated with an increased frequency of certain histocompatibility antigens located on chromosome six, the most common types being B-8, B-15, DR-3, DR-4, and DR-7. We therefore theorized that screening for these subtypes may allow the identification of those women with gestational diabetes who will remain euglycemic on dietary modification (class A1) compared with those who will require insulin to achieve euglycemia (class GB). From 1982 to 1987, 228 black women with gestational diabetes were screened for the above histocompatibility antigens. As theorized, certain histocompatibility antigen subtypes were more common in women with class GB gestational diabetes mellitus; DR-2 (41.8% versus 23.7% p = 0.015), B-15 (p = 0.07), and DR-3 (p = 0.08). However, because of the low sensitivity (42%), specificity (75%), and positive predictive value (36%), this test is impractical in the clinical management of women with gestational diabetes mellitus.

Black People↗
PubMed1991

Abnormalities of 21-hydroxylase gene ratio and adrenal steroidogenesis in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to acute adrenal stimulation.

One to 2% of hyperandrogenic women demonstrate a 17-hydroxyprogesterone (17-HP) level greater than 36.3 nmol/L (1200 ng/dL) after acute ACTH-(1-24) adrenal stimulation, consistent with 21-hydroxylase (21-OH) deficient late-onset adrenal hyperplasia (LOAH). The following study was undertaken to endocrinologically and genetically define hyperandrogenic patients with an exaggerated 17-HP response to ACTH stimulation, and which do not represent LOAH. Of 265 consecutive patients suffering from hirsutism and/or hyperandrogenic oligomenorrhea, 23 (8.7%) demonstrated a 17-HP level 30 min post stimulation greater than 9.6 nmol/L or 316 ng/dL (the upper 95th percentile in 41 eumenorrheic nonhirsute healthy control women). Seven patients or five separate families (1.8% of total) demonstrated poststimulation 17-HP levels consistent with LOAH. Of the remaining 16 patients, the net increment in 17-HP (delta 17-HP0-30) was within normal limits in seven (2.6%) and these women were assumed to have a normal 17-HP adrenocortical response superimposed on an elevated basal level of nonadrenal (e.g. ovarian) origin. In the remaining nine hyperandrogenic patients (3.4%) various abnormalities of adrenal response were noted in all but one patient, consistent with adrenal hyper-responsiveness. One patient demonstrated an 11-deoxycortisol poststimulation level greater than 3-fold the upper 95th percentile of normal, consistent with 11-hydroxylase LOAH and was excluded from further study. Six of these women were available for further genetic characterization, all Caucasian and unrelated. Three were heterozygotes for HLA-B14, three for B40, and one for B35 antigen, HLA-types associated with the inheritance of 21-OH deficiencies. Although, normally there are two 21-OH genes (a pseudogene and a functional gene) present in a 1:1 ratio, we have previously reported a high frequency of 21-OH gene ratio abnormalities in LOAH. All but one of our patients demonstrated an abnormal 21-OH gene ratio. In conclusion, 3.4% of our hyperandrogenic population demonstrated an exaggerated 17-HP increment after ACTH stimulation, not consistent with LOAH or increased extraadrenal 17-HP production. The increased prevalence of HLA alleles known to be linked to inherited defects of 21-OH function and the increased frequency in 21-OH gene ratio abnormalities suggest that a majority of these individuals may be carriers for these genetic disorders. However, the adrenocortical abnormalities noted were more consistent with a generalized hyperreactivity of the adrenal to ACTH stimulation, than a specific enzyme deficiency, implying that carrier status for 21-OH deficiency may be incidental to the hyperandrogenism.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus.

HLA-DR, DQ, DP and C4 null alleles were determined by restriction fragment length polymorphism (RFLP) analysis in 60 Caucasian patients with systemic lupus erythematosus (SLE) and 66 controls. DR3 (DRw17) and DQw2.1 were increased in frequency in the patients with SLE associated with the presence of C4A null genes. HLA-DP alleles determined by RFLP analysis of genomic DNA as well as of PCR amplified DNA were not associated with SLE or any clinical or autoantibody subset thereof. No DR, DQ, or C4 null gene association was found with renal or neuropsychiatric involvement or nDNA antibodies (or levels thereof). These data suggest that the primary predisposition to SLE lies with HLA-DR or C4 null alleles, and not with HLA-DP.

Alleles↗