Biomedical subjects

Dairena Gaffney

Publications and source records attributed to Dairena Gaffney.

11 recordsLinked to original sources

PubMed2006

Insight into the nature of the CRP-coronary event association using Mendelian randomization.

BACKGROUND: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded. METHODS: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies). RESULTS: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs. CONCLUSIONS: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.

C-Reactive Protein↗

PubMed2006

Serum calcium, urine calcium and polymorphisms of the calcium sensing receptor gene.

BACKGROUND: Recent studies have suggested a correlation between the A986S polymorphism of the calcium sensing receptor (CASR), and serum total and ionized calcium. This study aimed to assess the prevalence of three CASR polymorphisms in a West of Scotland population and relate genotype to serum and urine calcium levels. METHODS: Fasting blood and urine samples were obtained from 121 healthy male and female volunteers aged 20-60 years. Volunteers were genotyped for the A986S, Q1011E and R990G polymorphisms using allele-specific amplification and amplification-created restriction site techniques. Total calcium, ionized calcium and urine calcium excretion were measured using automated clinical chemistry analysers. RESULTS: Genotype frequencies for the A986S polymorphism were: AA, 74.4%; AS, 24.8%; SS, 0.8%. There was a small but statistically significant (P < 0.01) increase in ionized calcium concentration in AS individuals compared with the wild type (1.22 versus 1.20 mmol/L). No statistical difference was detected in serum total calcium or parameters of urine calcium excretion. Genotype frequencies for the remaining polymorphisms were: RR, 82.6%; RG, 16.5%; GG, 0.8% and QQ, 93.4%; QE, 6.6%; EE, 0%. Biochemical parameters in these individuals were not statistically different from the wild type. CONCLUSION: The increase in serum ionized calcium in the AS group was small and, therefore, unlikely to be of clinical significance.

Adult↗

PubMed2005

Influence of apolipoprotein E genotype on progression of diabetic nephropathy.

AIMS: Diabetic nephropathy progresses at a variable rate part of which may be explained by genetic polymorphisms. ApoE polymorphisms are associated with progression of atherosclerosis and because of the similarities between atherosclerosis and glomerulosclerosis, we chose to examine apoE and its role in progression of diabetic nephropathy. METHODS: The apoE genotypes of 90 patients with type 2 diabetes and nephropathy who were recruited into a 2-year prospective randomised controlled study comparing intensive medical management with routine clinical care were analysed. The primary endpoint was the rate of progression of renal disease in the second year. RESULTS: The apoE genotype frequencies were 49 with E3/3, 20 with E2/3, 17 with E3/4 and 4 with of E2/4. There were no significant differences in age, degree of renal failure, BP, albuminuria or glycaemic control between any genotype. The rate of progression of renal failure of patients with the E3/4 genotype was 0.80 ml/min/month compared to 0.30 ml/min/month for E2/3 and 0.18 ml/min/month for those with E3/3. Patients with E3/4 genotype had significantly faster rates of progression in the second year when compared with the other 3 genotypes (0.80 vs. 0.25 ml/min/month, p = 0.012). There was no difference in mortality according to apoE genotype. CONCLUSION: Patients who possess the apoE3/4 genotype had significantly faster rates of progression of renal failure.

Aged↗

PubMed2004

Apolipoprotein E and cholesteryl ester transfer protein polymorphisms in normal and preeclamptic pregnancies.

OBJECTIVES: To evaluate the association of apolipoprotein (apo) E polymorphism and a cholesteryl ester transfer protein (CETP) polymorphism (CETP/TaqIB) with preeclampsia and with lipid/lipoprotein profile in pregnancy. MATERIALS AND METHODS: A group of 144 normal pregnant women (67 in the third trimester) were compared with 51 cases of preeclampsia in the third trimester of gestation. Apo E and CETP genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Serum lipids, lipoproteins and apolipoproteins were evaluated using commercially available kits. LDL size was assessed by gradient gel electrophoresis. RESULTS: No differences were found in the distribution of subjects with respect to genotypes, in the apo E and CETP polymorphisms, between control and pathologic groups. In the third trimester of gestation (both control and case groups considered), apo E polymorphism, but not CETP polymorphism, was associated with different lipid and lipoprotein levels. Patients carrying the E2 allele (E2+) presented with significantly lower values of LDL cholesterol (LDLc) compared with carriers of E4 (E4+) and E3/3 individuals. E2+ also presented with the highest triglyceride (TG) level, although this was not statistically significant. On the other hand, HDL cholesterol (HDLc) and apo A-I levels were significantly reduced in E4+, compared with E3/3. Furthermore, E4+ presented with the highest total cholesterol and LDL and therefore LDLc/HDLc and apo B/apo A-I ratios were significantly higher in this group compared with the other two. CONCLUSIONS: Neither of our candidate genes showed association with preeclampsia. However, apo E genotype was associated with changes in lipid and lipoprotein profiles in pregnant women.

Adult↗

PubMed2004

Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review.

Mutations in the calcium-sensing receptor gene (CaSR) may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcaemia (FBHH), neonatal severe hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemia with hypercalciuria (ADHH). FBHH may have a population prevalence as high as one in 16 000, and ADHH one in 70 000. NSHPT is very rare. The FBHH condition is usually asymptomatic. Parathyroidectomy does not result in normal serum calcium, and no active treatment is indicated. To differentiate FBHH from primary hyperparathyroidism (PHPT), a guideline which includes measurement of serum calcium, intact parathyroid hormone (PTH), magnesium and fasting urinary calcium excretion is proposed. Screening of family members for hypercalcaemia, and occasionally a search for mutations in the CaSR gene, may be required. The NSHPT condition may manifest with hypercalcaemia, (usually) very elevated serum PTH concentration, subperiosteal erosions and fractures. Milder cases may be managed medically, but respiratory failure, extreme hypercalcaemia and failure to thrive are indications for early parathyroidectomy. The ADHH condition may result in asymptomatic hypocalcaemia, but some affected family members have minor symptoms, and a minority experience seizures in infancy which can recur into adulthood. A significant proportion of cases previously reported as idiopathic hypoparathyroidism (IHP) may in fact be due to mutations in the CaSR gene. In a moderately hypocalcaemic patient with no other clearly discernible cause, an elevated urine calcium:creatinine ratio is suggestive of ADHH, as is the presence of a first-degree relative with hypocalcaemia. If treatment with vitamin D analogues is undertaken, serum and urine calcium should be monitored, advice which applies equally to ADHH and IHP.

Calcium Metabolism Disorders↗

PubMed2004

Whose TPMT activity is it anyway?

Determination of thiopurine S-methyltransferase (TPMT) activity prior to starting azathioprine therapy is used to identify individuals with low or deficient TPMT activities who are at risk of severe complications and even death This case describes a patient treated with azathioprine without prior knowledge of TPMT status. Pancytopaenia developed over several months and at this point TPMT activity was determined and found to be low at 16 nmol 6-methyl thioguanine (6-MTG)/g Hb/h, which is within the reference interval associated with heterozygosity for TPMT mutant alleles. On repeating the TPMT measurement 3 months later, the TPMT activity was 2 nmol 6-MTG/g Hb/h, consistent with deficient TPMT activity (homozygosity for TPMT mutant alleles), suggesting the patient is at high risk of myelosuppression if treated with thiopurine drugs. Retrospectively, it was found that the patient had received transfusions of red blood cell and platelets 6 days before TPMT activity was first measured. This case underlines the importance of determining TPMT activity status prior to azathioprine treatment, rather than taking a dose incrementation approach. It also highlights the caution that must be taken in interpreting TPMT activity in patients who have recently been transfused.

Chromatography, High Pressure Liquid↗

PubMed2003

A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study.

AIM: The association of cholesteryl ester transfer protein (CETP) gene polymorphisms with risk of a cardiovascular event and whether any association was explained by an influence on high-density lipoprotein (HDL) levels or low-density lipoprotein (LDL) size was tested in the West of Scotland Coronary Prevention Study (WOSCOPS). Gene-smoking and gene-treatment interactions were investigated. METHODS AND RESULTS: Cases (n=498) and controls (n=1108) were typed for TaqIB, C(-631)A, C(-629)A, I405V and D442G CETP polymorphisms. Homozygotes for the TaqIB2 allele (B2B2) had a 30% reduced risk of a cardiovascular event (odds ratio [OR] 0.70, CI(95)0.51-0.96, P=0.03) compared to B1B1 homozygotes. Inclusion of HDL or LDL diameter in multivariate analysis only marginally attenuated the relationships. Non-smokers, but not smokers, showed a dose-dependent association of risk with TaqIB genotype. Treatment benefit was not significantly different in B1B1 (OR 0.71, pravastatin vs placebo), B1B2 (OR 0.68) and B2B2 (OR 0.61) individuals. The other CETP polymorphisms studied had no significant association with cardiovascular risk. Haplotype analysis did not add to the information given by the individual polymorphisms. CONCLUSION: The association between CETP TaqIB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by effects on HDL levels or LDL size, and the benefit of pravastatin treatment was not influenced by this polymorphism.

Aged↗

PubMed2002

Influence of an asparagine to lysine mutation at amino acid 3516 of apolipoprotein B on low-density lipoprotein receptor binding.

BACKGROUND: Three mutations in the apolipoprotein B (apoB) gene have previously been established as important causes of impaired receptor binding of LDL and, hence, Familial Defective Apolipoprotein B 100 (FDB). Previously, undescribed mutations were sought. METHODS: Using denaturing gradient gel electrophoresis for mutation detection, DNA from 1852 new patients was examined. RESULTS: A previously undiscovered mutation was found in codon 3516, located between known FDB mutations at codons 3500 and 3531. The new mutation introduces a positively charged amino acid-lysine-while other FDB mutations remove a positively charged residue, arginine. The phenotype was intriguing, LDL derived from N3516K heterozygotes allowed only poor growth of an LDL cholesterol-dependent cell line. ApoB-100-specific antibody MB47 bound to LDL from N3516K heterozygotes with increased affinity indicating a probable conformational change caused by the substitution. In contrast to these results, a competitive displacement assay in fibroblasts showed normal (or better) binding affinity to LDL receptors and using dynamic laser scattering no preferential accumulation of 3516K LDL particles in plasma was found. CONCLUSION: Discovery of the mutation and characterisation of N3516K LDL reveals another naturally occurring apoB mutation that influences conformation of LDL apoB and its interaction with the LDL receptor.

Adult↗

PubMed2002

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia.

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.

Abetalipoproteinemia↗

PubMed2002

Changes in LDL size and HDL concentration in normal and preeclamptic pregnancies.

The aim of this study was to evaluate changes in lipids, apolipoproteins and lipoproteins in Portuguese pregnant women and their potential involvement in the pathophysiology of preeclampsia. A cross-sectional study was performed by collecting blood samples in the first (n=64), second (n=48) and third (n=67) trimesters and puerperium (n=32) of normal pregnancies. Samples from preeclamptic women were obtained in the third trimester (n=51) and in puerperium (n=26). As normal pregnancy progressed and triglyceride (TG) levels rose there was a decrease in low density lipoprotein (LDL) size, as measured by peak and mean particle diameter (MPD), with an increased proportion of atherogenic small dense LDL. Preeclamptic women exhibited, in the third trimester and puerperium, higher mean serum TG concentration and lower high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) levels compared with healthy pregnant women. In the third trimester, LDL-mean particle diameter (LDL-MPD) and LDL cholesterol-apolipoprotein B (LDLc-apo B) ratio were also significantly reduced in the pathologic group. We conclude that human gestation is associated with an 'atherogenic' lipid profile that is further enhanced in preeclampsia and that this profile may be a potential contributor to endothelial cell dysfunction.

Adult↗

PubMed2002

Application of polymerase chain reaction with oligoligation assay to determine genotype in individuals presenting with congenital adrenal hyperplasia.

BACKGROUND: Current methods for the molecular diagnosis of the 21-hydroxylase deficiency variant of congenital adrenal hyperplasia use cumbersome combinations of Southern blotting and polymerase chain reaction (PCR). The aim of the present study was to develop a practical genetic test for the unambiguous diagnosis of this condition, and to use this procedure to determine the range of mutations in Scottish patients. In addition, we wished to obtain further information to that currently available in the literature regarding the correlation of genotype with phenotype in any identified carriers. METHODS: We studied five Scottish probands and their family members. To try to obviate the need for Southern blotting, we investigated a technique that uses the oligoligation chain reaction after gene-specific PCR. RESULTS: We found a spectrum of mutations in the ten unrelated mutant alleles studied. These consisted of at least three different 30-kb deletions, two intron 2 splice-site mutations and single occurrences of the 1172N, V281L and R356W substitutions. CONCLUSIONS: The genotype-phenotype correlations agreed with those previously described. In addition, our results suggest that there is no predominant Scottish genotype.

Adrenal Hyperplasia, Congenital↗