Alison Palmer

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

BACKGROUND The 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. METHODS 4629 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. FINDINGS The 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. INTERPRETATION This 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.

A comparison of the early outcome of acute myocardial infarction in women and men. The Third International Study of Infarct Survival Collaborative Group.

BACKGROUND In previous studies, unadjusted comparisons of mortality and major morbidity after acute myocardial infarction have generally indicated that women have a poorer outcome than men. Much larger studies are needed, with more complete adjustment for coexisting conditions, to determine whether this difference is explained by the older age of the women studied or by the presence of other unfavorable prognostic factors, or both. METHODS As part of the Third International Study of Infarct Survival (ISIS-3), information was collected on deaths during days 0 to 35 and on major clinical events during hospitalization up to day 35 for 9600 women and 26,480 men with suspected acute myocardial infarction who were considered to have a clear indication for fibrinolytic therapy. We compared the outcome among women and men, first without adjustment, then with adjustment for age, and finally with adjustment for other recorded baseline characteristics by means of multiple logistic regression. RESULTS The unadjusted odds ratio for death among women as compared with men was 1.73 (95 percent confidence interval, 1.61 to 1.86). The women were significantly older than the men, and after adjustment for age the odds ratio was reduced markedly to 1.20 (95 percent confidence interval, 1.11 to 1.29). Adjustment for other differences in base-line clinical features further reduced the odds ratio to 1.14 (95 percent confidence interval, 1.05 to 1.23). Excesses in other major clinical events among women were generally reduced to a similar extent by adjustment. CONCLUSIONS It seems likely that there is at most only a small independent association between female sex and early mortality and morbidity after suspected acute myocardial infarction.

Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.

The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls

Aims Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A1, the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear. Methods and results Case–control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA1 than to HDL-C. The ratio apoB/apoA1 was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8–9.2)] and varied little with age. The ratio apoB/apoA1 was substantially more informative about risk (χ12 = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (χ12 = 407, 334, 204, and 105, respectively). Given apoB and apoA1, the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA1 and pre-onset HDL-C with risk in such retrospective case–control studies. Conclusion Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E ε2/ε3/ε4 genotype

Summary Results from two small studies, involving a total of only 174 cases, have suggested that the increased risk of coronary heart disease conferred by cigarette smoking is substantially affected by genotype at the apolipoprotein E ( APOE ) e2/e3/e4 polymorphism. We have established APOE genotypes in 4484 patients with acute myocardial infarction diagnosed before the age of 55 years for male and 65 years for female patients, and in 5757 controls with no history of cardiovascular disease. On average, the hazard ratio for myocardial infarction was 1·17 (95% CI 1·09–1·25; p APOE genotypes (χ 2 2 =0·69; p=0·7). When differences in risk between different genotypes are not extreme (as with this APOE polymorphism), reliable assessment of hypothesised gene-environment interactions will often require the study of many thousands of disease cases.

Association of symptoms of type 2 diabetic patients with severity of disease, obesity, and blood pressure

OBJECTIVE The symptoms of 430 type 2 diabetic patients were determined by a self-administered questionnaire before entry into the U.K. Prospective Diabetes Study. RESEARCH DESIGN AND METHODS Entry into the trial followed 2 months of dietary treatment for newly diagnosed patients with type 2 diabetes. Forty symptoms with five levels of severity were included in the questionnaire. A complaint rate was computed as the sum of symptom scores divided by the number of symptom questions answered. RESULTS The complaint rate was independently and positively related to BMI, fasting plasma glucose (FPG), and being a woman. Three symptoms—presence of dry mouth (P < 0.001), thirst (P < 0.01), and stomach pain (P = 0.02)—were related to FPG independent of sex, age, BMI, or blood pressure. Only dry mouth was related to HbA1c (P = 0.05). Complaints of shortness of breath, swollen ankles, headaches, heartburn, sweating, wheezing, nocturia, thirst, and diarrhea increased with BMI independently of other variables. A complaint of cold extremities decreased with BMI. Heartburn, weakness of limbs, and hot flushes were positively related to blood pressure, and unsteadiness was negatively related. CONCLUSIONS The symptoms reported by patients with type 2 diabetes increased with FPG and markedly with BMI. The symptoms associated with obesity have been underestimated in the past.

The exon 1-8C/G SNP in the PSMA6 gene contributes only a small amount to the burden of myocardial infarction in 6946 cases and 2720 controls from a United Kingdom population

The proteasome system is a proteolytic pathway that regulates the expression of genes involved in inflammation. Polymorphisms in the gene encoding subunit α type 6 (PSMA6) – in particular the rs1048990 exon 1–8C/G SNP – have been implicated with susceptibility to myocardial infarction (MI) in a Japanese study. We examined whether several polymorphisms in the PSMA6 gene were related to MI risk in 6946 nonfatal MI cases and 2720 unrelated controls in a UK population. The homozygous GG genotype for rs1048990 was much less frequent in this UK population than in the Japanese population (2.1 vs 8.9%), and was associated with an odds ratio (OR) for MI of 1.09 (95% confidence interval (CI): 0.98–1.21) per G allele in a co-dominant genetic model and 1.32 (95% CI: 0.90–1.93) in a recessive genetic model. Although not statistically significant, these results for this variant are still consistent with the Japanese hypothesis-generating study. Our findings, when taken together with four other studies (including the hypothesis-generating one), yielded a combined OR for MI of 1.15 (95% CI: 1.08–1.21) per G allele in a co-dominant model and 1.38 (95% CI: 1.22–1.57) for the GG genotype in a recessive model. Larger studies involving more than 10 000 disease cases would be required to further elucidate the role of this variant for susceptibility to MI. However, given the rarity of this variant in Caucasians, the attributable risk of rs1048990 for MI is unlikely to be great in western populations.

Causes of Death and Risk Factors in Young and Old Diabetic Patients Referred to a Retinopathy Clinic

The causes of death and associated risk factors are compared in young and old diabetic patients attending a retinopathy clinic. Mortality in those diagnosed under and over the age of 30 years is also examined in order to compare insulin-dependent with non-insulin-dependent patients. A defined cohort attending the Hammersmith Hospital Retinopathy Clinic was followed for an average of 11 years. Main outcome measures were standardized mortality ratios (SMRs) in different age/sex groups and relative hazard rates (RHRs) for possible risk factors related to mortality. The patients were divided into those aged under and over the age of 60 years at attendance at the clinic. The RHRs were smaller in the elderly for plasma urea [1.015 versus 1.107 (p < 0.01)]. Attenuation of risk was also suggested for systolic blood pressure (RHR of 1.005 in the elderly versus 1.015 in the younger patients) and for the effects of smoking [RHR of 1.17 (elderly patients) and 1.35 (younger patients)]. In those diagnosed under the age of 30 years, there were very high SMRs for renal disease, cerebrovascular disease (men only), ischemic heart disease, other heart disease, and respiratory disease (men only), but increased SMRs were also demonstrated in those diagnosed over the age of 30 years. The risk factors associated with poor survival were similar for those diagnosed over and under the age of 30 years: poor diabetic control, high systolic and diastolic blood pressure, and increased plasma urea. In conclusion, there was no evidence that blood sugar control or diastolic blood pressure were less important in older age groups. Plasma urea, systolic pressure, and being on insulin were less useful as predictors of mortality in the elderly, but were still important in patients diagnosed over the age of 30 years.