Bernard Keavney

Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls

BACKGROUNDnThe original report of a possible association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardial infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the association was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but all were small, and much larger studies were needed.nnnMETHODSn4629 myocardial infarction cases and 5934 controls were compared. Cases were UK men aged 30-54 years and women aged 30-64 years recruited on presentation to hospital with confirmed myocardial infarction. Controls were aged 30-64 years with no history of cardiovascular disease, but were siblings or children of myocardial infarction survivors, or spouses of such relatives. All risk-ratio calculations allow for this relatedness of some of the controls. An updated meta-analysis of previous studies was also conducted.nnnFINDINGSnThe ACE DD genotype was found in 1359 (29.4%) of the myocardial infarction cases and in 1637 (27.6%) of the controls (risk ratio 1.10 [95% CI 1.00-1.21]). The association between myocardial infarction and the DD genotype did not seem to be stronger in the subgroup defined as low risk by previously used criteria (234 [28%] of 836 cases and 911 [28%] of 3253 controls: risk ratio 1.04 [95% CI 0.87-1.24]), or in any other subgroup. Nor was the ACE I/D genotype predictive of subsequent survival.nnnINTERPRETATIONnThis study involved many more cases than any previously reported study of this question, but did not confirm the existence of any substantial association. In an updated meta-analysis of these results with those of previously published studies, the risk ratio for myocardial infarction with the DD genotype seems to lie in the range 1.0 to about 1.1. Although an increase in risk of up to about 10-15% cannot be ruled out, substantially more extreme risks can be. Moreover, there are not especially strong associations in the subgroups previously selected for emphasis. These findings illustrate the need for some studies of candidate genes to involve much larger populations than is customary, without undue emphasis on retrospectively defined subgroups.

Four paraoxonase gene polymorphisms in 11 212 cases of coronary heart disease and 12 786 controls: meta-analysis of 43 studies

BACKGROUNDnAlthough there have been suggestions that serum paraoxonase is important in protecting against coronary heart disease (CHD), a large number of studies of genetic determinants of serum paraoxonase have reported apparently conflicting results about their association with CHD.nnnMETHODSnWe conducted a meta-analysis of 43 studies of the Q192R, L55M, and T(-107)C polymorphisms in the paraoxonase PON1 gene and the S311C polymorphism in the PON2 gene (all of which are in moderately strong linkage disequilibrium with one another), involving a total of 11212 CHD cases and 12786 controls. We explored potential sources of heterogeneity.nnnFINDINGSnIn a combined analysis of all studies, the per-allele relative risk of R192 for CHD was 1.12 (95% CI 1.07-1.16), but in the five largest studies it was only 1.05 (0.98-1.13). Combined analyses of studies of the M55, (-107)T, and C311 variants showed no significant overall associations with CHD, yielding per-allele relative risks of 1.00 (0.95-1.06), 1.02 (0.92-1.14), and 1.04 (0.93-1.17), respectively.nnnINTERPRETATIONnIn contrast to previous suggestions, this meta-analysis shows no significant association of CHD with the L55M or T(-107)C polymorphism in PON1 or with the S311C polymorphism in PON2. The weak overall association between the Q192R polymorphism and CHD is of uncertain relevance, particularly since there was no significant association among the larger studies which should be less prone to selective publication. These findings reinforce the need for much larger and more rigorous investigations of the genetic determinants of complex diseases than is now customary, as well as for regularly updated systematic appraisals of such studies to help improve interpretation and prioritise hypotheses.

Evaluation of the Angiotensinogen Locus in Human Essential Hypertension A European Study

Different family and case-control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM.

SummaryThe deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be “low-risk” by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p=0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p=0.002), or low triglyceride (odds ratio 3.14, p=0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p<0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.

Measurement of blood pressure using the auscultatory and oscillometric methods in the same cuff deflation: validation and field trial of the A&D TM2421 monitor.

We have evaluated under laboratory validation conditions and in an extensive field trial the behaviour of an ambulatory monitoring device that is capable of recording both by the Korotkoff-sound and oscillometric methods in a single cuff deflation (TM2421: A&D Co, Tokyo, Japan). The effects of subject age and blood pressure (BP) level on the accuracy and field reliability of the two methods implemented in the device have been determined. In the validation phase, automatic BP measurements were compared with readings by two trained observers in 96 subjects, and the results compared with the AAMI criteria for automatic BP monitors. In the field trial phase, the performances of Korotkoff-sound and oscillometric methods over a 24-h period of ambulatory BP monitoring were compared in 515 subjects, with analysis of the agreement between the two methods in patients where both provided satisfactory recordings. In the validation phase, the Korotkoff-sound method gave satisfactory results for both systolic and diastolic BP, but the oscillometric technique narrowly failed to meet the AAMI criteria for the measurement of either systolic or diastolic BP. In the field trial, the K-sound method failed to record BP accurately in 12% of subjects whereas the oscillometric method was successful in all of these. Where both methods provided technically adequate records, agreement between mean values for each method was close. In 18% of patients, the availability of the oscillometric measurement as a ‘back-up’ method for the K-sound method significantly improved the number of available measurements in the monitoring period, which should result in improved accuracy and reproducibility of the ambulatory mean values.

Screening for the GRA mutation in Jamaica.

Glucocorticoid-remediable aldosteronism (GRA) is a form of hypertension which is transmitted as an autosomal dominant. The syndrome is characterised by hyperaldosteronism, hypokalaemia and low plasma renin activity. These abnormalities can be corrected with low-dose glucocorticoid therapy. Non-reciprocal recombination between the 11b-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes creates a chimaeric gene which has 5′ regulatory elements of CYP11B1 spliced to CYP11B2 sequences. GRA is caused by the high-level expression of this mutant form of CYP11B2 under the influence of adrenocorticotrophin instead of angiotensin II. GRA is thought to be uncommon in Caucasians. However, patients with GRA have variable clinical features (for instance, hypokalaemia may be less common than previously thought) so the true prevalence of the disease is unknown. Furthermore, the prevalence of GRA may vary

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