PubMed Health⌕ Search

Biomedical subjects

Steve E Humphries

Publications and source records attributed to Steve E Humphries.

At least 19 recordsLinked to original sources
PubMed2025

Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed-methods study exploring participant experiences of receiving secondary findings from genomic sequencing.

PURPOSE: The 100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia. Here, we evaluate stakeholder experiences to inform clinical practice. METHODS: Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF) and interviews with participants who had no AFs (NAF). RESULTS: There were 146 surveys followed by 35 interviews with PAF participants and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious and found telling family members challenging compared with participants with a familial hypercholesterolemia PAF. Although most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing. CONCLUSION: Patient experiences of receiving AFs were primarily positive, and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.

Humans↗
PubMed2020

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274.

BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Chromosomes, Human, Pair 9↗
PubMed2006

The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes.

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.

Adult↗
PubMed2006

Candidate gene genotypes, along with conventional risk factor assessment, improve estimation of coronary heart disease risk in healthy UK men.

BACKGROUND: One of the aims of cardiovascular genetics is to test the efficacy of the use of genetic information to predict cardiovascular risk. We therefore investigated whether inclusion of a set of common variants in candidate genes along with conventional risk factor (CRF) assessment enhanced coronary heart disease (CHD)-risk algorithms. METHODS: We followed middle-aged men in the prospective Northwick Park Heart Study II (NPHSII) for 10.8 years and analyzed complete trait and genotype information available on 2057 men (183 CHD events). RESULTS: Of the 12 genes previously associated with CHD risk, in stepwise multivariate risk analysis, uncoupling protein 2 (UCP2; P = 0.0001), apolipoprotein E (APOE; P = 0.0003), lipoprotein lipase (LPL; P = 0.007), and apolipoprotein AIV (APOA4; P = 0.04) remained in the model. Their combined area under the ROC curve (A(ROC)) was 0.62 (0.58-0.66) [12.6% detection rate for a 5% false positive rate (DR(5))]. The A(ROC) for the CRFs age, triglyceride, cholesterol, systolic blood pressure, and smoking was 0.66 (0.61-0.70) (DR(5) = 14.2%). Combining CRFs and genotypes significantly improved discrimination (P = 0.001). Inclusion of previously demonstrated interactions of smoking with LPL, interleukin-6 (IL6), and platelet/endothelial cell adhesion molecule (PECAM1) genotypes increased the A(ROC) to 0.72 (0.68-0.76) for a DR(5) of 19.1% (P = 0.01 vs CRF combined with genotypes). CONCLUSIONS: For a modest panel of selected genotypes, CHD-risk estimates incorporating CRFs and genotype-risk factor interactions were more effective than risk estimates that used CRFs alone.

Algorithms↗
PubMed2006

Acute renal failure in a patient with paroxysmal cold hemoglobinuria.

Acute renal failure following auto-immune hemolysis is rare. We report a child with acute paroxysmal cold hemoglobinuria (PCH) complicated by renal failure. She was treated by peritoneal dialysis and red blood cell transfusion. After 2 weeks she had made a complete recovery with a normal blood count and renal profile, and the peritoneal dialysis catheter was removed. Extensive investigation, including an analysis of heme oxygenase-1 gene promoter region polymorphisms, failed to identify a cause for the renal failure in this patient.

Acute Kidney Injury↗
PubMed2006

Association between plasma IL-6, the IL6 -174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus.

Elevated plasma interleukin-6 (IL-6) is associated with coronary heart disease (CHD), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). We and others have described an association between the human interleukin-6 -174G>C gene variant and body mass index (BMI). Within our previous sample of subjects with T2DM, we measured plasma IL-6 and grouped subjects by the WHO-defined metabolic syndrome, in order to study the association between the -174G>C gene variant, plasma IL-6 and the metabolic syndrome (and component parts). Genotype was obtained in 571 Caucasian subjects with plasma IL-6 measures. There was a significant association between genotype and plasma IL-6 (GG vs GC vs CC: 3.23+/-0.93 pg/ml vs 3.42+/-0.95 pg/ml vs 4.16+/-1.18 pg/ml, p=0.02; for GG/GC vs CC p=0.008). No interactions were observed between genotype and the individual components of the metabolic syndrome in determining plasma IL-6. Increased plasma IL-6 was also associated with the number of components (none vs 1 vs 2 vs > or =3: 2.67+/-0.71 pg/ml vs 2.97+/-0.94 pg/ml vs 4.07+/-1.13 pg/ml, p<0.0001). Within the sample, 76% of CC compared to 56% of GG subjects had the metabolic syndrome (p=0.007). Further analysis of association between the genotype and the components of the metabolic syndrome revealed no further associations than that with BMI previously described. The association of this gene variant with the metabolic syndrome is intimately linked with obesity per se. Further prospective work is required to explore the effect of this gene variant in relation to obesity, the metabolic syndrome and 'prediabetes'.

Aged↗
PubMed2006

The association of left ventricular mass with blood pressure, cigarette smoking and alcohol consumption; data from the LARGE Heart study.

BACKGROUND: Left ventricular mass is a risk factor for cardiovascular morbidity and mortality. Although factors associated with elevated left ventricular mass have been sought and studied extensively in elderly and in diseased subjects, few studies have examined the young and healthy. The aim of this study was to examine the possible influence of lifestyle on left ventricular mass in a large group of young men. METHODS: Left ventricular mass was assessed using cardiovascular magnetic resonance in 541 healthy Caucasian male army recruits. Anthropometric, lifestyle and blood pressure data were collected. RESULTS: Mean unadjusted left ventricular mass and left ventricular mass indexed to body surface area were 163.8+/-24.9 g and 86.6+/-10.2 g m(-2) respectively. In univariate analysis, age, height, weight, alcohol consumption, systolic blood pressure, diastolic blood pressure and indices of physical activity were positively associated with unadjusted left ventricular mass (all P<0.02). By contrast, smoking was associated with lower mean left ventricular mass; never smoked 167.5+/-25.8 g vs ex-smokers 159.1+/-25.2 g vs current smokers 161.0+/-23.1 g (P=0.007). Multivariate analysis revealed weight, systolic blood pressure, smoking status and indices of physical activity to be independent predictors of left ventricular mass. CONCLUSIONS: Our data confirm an association of age, body weight, height, physical activity, diastolic and systolic blood pressure with left ventricular mass. In addition, unexpectedly, we have found smoking is associated with lower left ventricular mass in a large sample of young healthy men. Although the latter association may result from confounding effects, such an interesting observation deserves further investigation.

Adolescent↗
PubMed2006

Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review.

This review examines the association of a subset of endothelial nitric oxide synthase gene (NOS3) polymorphisms (Glu298Asp, intron 4, and -786T>C) with cardiovascular disease. The Glu298Asp polymorphism within exon 7 is the only common nonsynonymous variant. The variants have been associated with low plasma nitric oxide concentrations and reduced vascular reactivity; difficulties in measuring those phenotypes means that their functional role remains unclear. A large meta-analysis of NOS3 polymorphisms in coronary heart disease revealed per-allele odds ratios of 1.17 (95% confidence interval: 1.07, 1.28) for Glu298Asp, 1.17 (95% confidence interval: 1.07, 1.28) for -786T>C, and 1.12 (95% confidence interval: 1.01, 1.24) for intron 4. However, there was evidence that small studies with more striking results could affect the associations of the Glu298Asp and -786T>C polymorphisms with coronary heart disease. Associations of NOS3 polymorphisms with hypertension, preeclampsia, stroke, and diabetes remain uncertain. To date, no reliable gene-gene or gene-environmental interactions have been described. Use of these variants in predictive testing is unlikely to be useful, although the population attributable fraction could be substantial if the modest associations are causal. The need for large-scale genetic association studies using tagging polymorphisms is warranted to confirm or refute a role of the NOS3 gene in coronary heart disease.

Cardiovascular Diseases↗
PubMed2006

Common variants of apolipoprotein A-IV differ in their ability to inhibit low density lipoprotein oxidation.

Apolipoprotein A-IV (apoA-IV) inhibits lipid peroxidation, thus demonstrating potential anti-atherogenic properties. The aim of this study was to investigate how the inhibition of low density lipoprotein (LDL) oxidation was influenced by common apoA-IV isoforms. Recombinant wild type apoA-IV (100 microg/ml) significantly inhibited the oxidation of LDL (50 microg protein/ml) by 5 microM CuSO(4) (P<0.005), but not by 100 microM CuSO(4), suggesting that it may act by binding copper ions. ApoA-IV also inhibited the oxidation of LDL by the water-soluble free-radical generator 2,2'-azobis(amidinopropane) dihydrochloride (AAPH; 1 mM), as shown by the two-fold increase in the time for half maximal conjugated diene formation (T(1/2); P<0.05) suggesting it can also scavenge free radicals in the aqueous phase. Compared to wild type apoA-IV, apoA-IV-S347 decreased T(1/2) by 15% (P=0.036) and apoA-IV-H360 increased T(1/2) by 18% (P=0.046). All apoA-IV isoforms increased the relative electrophoretic mobility of native LDL, suggesting apoA-IV can bind to LDL and acts as a site-specific antioxidant. The reduced inhibition of LDL oxidation by apoA-IV-S347 compared to wild type apoA-IV may account for the previous association of the APOA4 S347 variant with increased CHD risk and oxidative stress.

Amidines↗
PubMed2006

Apolipoprotein A-V, triglycerides and risk of coronary artery disease: the prospective Epic-Norfolk Population Study.

In mouse models, apolipoprotein A-V (apoA-V) exhibits triglyceride (TG)-lowering effects. We investigated the apoA-V/TG relationship and the association of apoA-V with coronary artery disease (CAD) risk by determining serum apoA-V levels and genotypes in a nested case-control (n = 1,034/2,031) study. Both univariate and multivariate apoA-V levels showed no association with future CAD (P = 0.4 and 0.5, respectively). Unexpectedly, there was a significant positive correlation between serum apoA-V and TG in men and women (r = 0.36 and 0.28, respectively, P < 0.001 each) but a negative correlation between apoA-V and LPL mass (r = -0.14 and -0.12 for men and women respectively, P < 0.001 each). The frequency of the c.56C>G polymorphism did not differ between cases and controls despite significant positive association of c.56G with both apoA-V and TG levels. For -1131T>C, the minor allele was significantly associated with lower apoA-V yet higher TG levels and was overrepresented in cases (P = 0.047). The association of -1131T>C with CAD risk, however, was independent of apoA-V levels and likely acts through linkage disequilibrium with APOC3 variants. The positive correlation of apoA-V levels with TG levels, negative correlation with LPL levels, and lack of association with CAD risk highlight the need for further human studies to clarify the role of apoA-V.

Aged↗
PubMed2006

Association between plasma levels of heat shock protein 60 and cardiovascular disease in patients with diabetes mellitus.

AIMS: Evidence is accumulating to support the hypothesis that the release of heat shock protein (Hsp)60 into the circulation is associated with the development of coronary heart disease (CHD). As diabetes is a risk factor for CHD, it was of interest to determine Hsp60 blood levels in a cross-sectional cohort of diabetic patients, some of whom had cardiovascular disease, and relate levels to relevant biochemical markers. METHODS AND RESULTS: A total of 855 patients with T1DM or T2DM, recruited as part of the UCL Diabetes and Cardiovascular disease Study (UDACS), were assayed for plasma levels of Hsp60. Immunoreactive Hsp60 was detected in 54% of the samples, with 26% having plasma levels > 1 microg/mL. Levels of Hsp60 were higher in Caucasians than in other ethnic groupings, with 56.5% of Caucasian subjects, 37.5% of African-Caribbean subjects, and 47.1% of Indian subjects having detectable levels (P = 0.007), and with a higher proportion of non-smokers having detectable Hsp60 levels than smokers (54.9 vs. 43.5%, P = 0.01). Of note was the finding of an association between higher mean plasma levels of Hsp60 in subjects with clinically manifest cardiovascular disease and those with a history of myocardial infarction having an adjusted odds ratio of having detectable Hsp60 of 2.17 (CI 1.26-3.73). CONCLUSION: This is the first report of circulating Hsp60 levels in diabetic patients, which suggests that this secreted mitochondrial cell stress protein may be playing an unexpected role in the cardiovascular pathology associated with diabetes.

Antioxidants↗
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

Lipoprotein-associated phospholipase A2 A379V variant is associated with body composition changes in response to exercise training.

Lipoprotein-associated PLA2 (Lp-PLA2) hydrolyses the sn-2 position of glycerophospholipids, in particular platelet activating factor (PAF), generating significant amounts of Lyso-PAF which in turn, via a remodelling pathway, can generate arachidonic acid (AA) from alkyl-acyl-glycerophosphorylcholine. AA is a precursor for prostaglandin synthesis, which regulates adipogenesis through the peroxisome proliferator-activated receptor subfamily. AA may also modulate skeletal muscle growth. We investigated the association of the PLA2G7 A379V variant with changes in body composition in a longitudinal study of 123 male Caucasian army recruits over 10 weeks of intensive physical training. There was no effect of genotype on baseline measures. However, after exercise training, homozygosity for the 379V allele was associated with a decrease in percentage adipose tissue mass (-3.61+/-1.14%), compared to AV (-1.67+/-0.38%) and AA (-1.09+/-0.24%) genotypes (p=0.01), and a significant mean increase (3.51+/-1.17%) in percentage lean mass, compared to AV (1.64+/-0.38%) and AA (1.10+/-0.24%) recruits (p=0.02). The association of this genotype with changes in body composition after training suggests a novel role for Lp-PLA2.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts.

Understanding the mechanisms by which estrogens affect cardiovascular disease risk, including the role of variation in the gene for estrogen receptor alpha (ESR1), may be key to new treatment strategies. We investigated whether the CC genotype at ESR1 c.454-397T>C is associated with increased risk among men. Study of more than 7000 whites in 5 cohorts from 4 countries provided evidence that genotype CC, present in roughly 20% of individuals, is a risk factor for nonfatal acute myocardial infarction (odds ratio=1.44; P<0.0001), after adjustment for established cardiovascular risk factors. After exclusion of younger subjects from 2 cohorts, because of age interaction, the odds ratio increased (to 1.63).

Adult↗
PubMed2006

Variation in the lipoprotein lipase gene influences exercise-induced left ventricular growth.

The adult heart relies predominantly on fatty acids (FA) for energy generation, and defects in FA catabolism cause dramatic left ventricular (LV) growth in early age. Since lipoprotein lipase (LPL) is the key enzyme in plasma triglyceride catabolism and is highly expressed in the myocardium, we investigated an association between the functional LPL gene serine 447 stop (S447X) variant and exercise-induced LV growth. The S447X variant was genotyped in 146 British Army recruits undergoing a 10-week exercise programme. Over the training period, X447 allele carriers showed less LV growth than S447 homozygotes (SS, 5.8+/-0.7%; SX, 2.2+/-1.5%; P=0.03) and a decrease in systolic blood pressure (DeltaSBP: SS, 1.9+/-1.3 mmHg; SX, -5.7+/-2.2 mmHg; P=0.015). Although LPL genotype did not significantly predict LV growth with DeltaSBP in statistical modelling (LPL, P=0.14; DeltaSBP, P=0.06), regression analysis indicated that LPL S447X genotype effect on DeltaSBP accounted for only 20% of the effect on LV growth. In multivariate analysis, LPL, peroxisome-proliferator-activated receptor alpha and angiotensin-converting enzyme genotypes were independent predictors of cardiac growth. Thus, LPL S447X genotype influenced exercise-induced changes in LV mass and SBP. Change in blood pressure accounted for a proportion of LV growth. These data suggest that increased myocardial FA availability may reduce exercise-induced LV growth.

Adult↗
PubMed2006

Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies.

Coronary artery disease (CAD) has a polygenic basis, and identification of CAD susceptibility genes has the potential to aid the development of new treatments and enhance prediction of disease risk. Thus far, the strategy has firstly been to choose "candidate" genes coding for important "rate-limiting" proteins in the homeostatic systems involved in maintaining cardiovascular health; secondly to identify common variants in these candidate genes; thirdly to carry out genotyping and statistical analysis using genetic association studies; and finally to test the functional effects of the identified variants in vitro and in vivo. However, lack of reproducibility of genetic association studies has led to uncertainty about the nature and number of genes involved. In part this is because many of the studies conducted have not been adequately powered to detect small risk effects, or to permit adequate exploration of gene-gene or gene-environment interactions in a robust manner. Spurious positive and negative associations due to type I and type II statistical errors are likely to co-exist with real associations in the published literature. By utilising all available data to increase statistical power, meta-analysis of genetic association studies is increasingly being used to identify genotypic risk with a greater degree of precision. Though potentially powerful, this approach may be prone to publication bias. Therefore, very large genetic association studies will also be required to identify risk genes for CAD. This review lays out the framework for the candidate gene approach for CAD and illustrates this with published results from a UK prospective study of 3000 middle-aged men.

Cardiovascular Diseases↗