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Sarah Parish,
Richard Peto,
Alison Palmer,
Robert Clarke,
Sarah Lewington,
Alison Offer,
Gary Whitlock, Sarah Clark,
Linda Youngman,
Peter Sleight,
Rory Collins
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[hide abstract]
ABSTRACT: 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 A(1), 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.
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 apoA(1) than to HDL-C. The ratio apoB/apoA(1) 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/apoA(1) was substantially more informative about risk (chi(1)(2) = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (chi(1)(2) = 407, 334, 204, and 105, respectively). Given apoB and apoA(1), 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 apoA(1) and pre-onset HDL-C with risk in such retrospective case-control studies.
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.
European Heart Journal 06/2009; 30(17):2137-46. · 10.48 Impact Factor
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Robert Clarke,
Jonathan R Emberson,
Sarah Parish,
Alison Palmer,
Martin Shipley,
Pamela Linksted,
Paul Sherliker, Sarah Clark,
Jane Armitage,
Astrid Fletcher,
Rory Collins
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ABSTRACT: The relevance of blood lipid levels as risk factors for ischemic heart disease (IHD) in older people is uncertain; hence, cholesterol-lowering therapy is not routinely prescribed in older populations.
We assessed IHD mortality associations with plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein A(1) measured in older men. Ischemic heart disease was assessed in a 7-year follow-up of a cohort of 5344 men (mean age, 76.9 years), including 74.3% without cardiovascular disease (CVD) or statin use and 25.6% with CVD or statin use. Hazard ratios (HRs) for 447 deaths from IHD were estimated for a 2-SD difference in usual plasma lipid levels.
Ischemic heart disease mortality was not significantly associated with total cholesterol levels in all men (HR, 1.05), but a significant positive association in men without CVD and a slight nonsignificant inverse association in men with CVD were observed (HR, 1.47 vs 0.84). The patterns were similar for low-density lipoprotein cholesterol levels (HR, 1.50 vs 0.98) and for apolipoprotein B levels (HR, 1.68 vs 0.93). Ischemic heart disease risks were inversely associated with high-density lipoprotein cholesterol levels and with apolipoprotein A(1) levels in men with and without CVD. Ischemic heart disease risks were strongly associated with total/high-density [corrected] lipoprotein cholesterol levels (HR, 1.57) and apolipoprotein B/apolipoprotien [corrected] A(1) levels (HR, 1.54), and remained strongly related at all ages.
Blood lipid levels other than total cholesterol levels were associated with IHD in older men. Differences in lipid levels that are achievable by statin use were associated with about a one-third lower risk of IHD, irrespective of age.
Archives of Internal Medicine 08/2007; 167(13):1373-8. · 11.46 Impact Factor
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ABSTRACT: Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position -148 in the beta-fibrinogen gene promoter (beta - 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question.
Genotyping and measurement of blood fibrinogen concentration were carried out in 4,685 cases of confirmed MI and 3,460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12,220 coronary disease cases and 18,716 controls was conducted.
Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case-control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14-1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A(1) ratio, this risk ratio fell to 1.03 (95% CI 1.00-1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96-1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95-1.04) per allele in the meta-analysis.
Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk.
International Journal of Epidemiology 08/2006; 35(4):935-43. · 6.41 Impact Factor
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Robert Clarke,
Peng Xu,
Derrick Bennett,
Sarah Lewington,
Krina Zondervan,
Sarah Parish,
Alison Palmer, Sarah Clark,
Lon Cardon,
Richard Peto,
Mark Lathrop,
Rory Collins
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ABSTRACT: Lymphotoxin-alpha (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-alpha (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.
PLoS Genetics 08/2006; 2(7):e107. · 8.69 Impact Factor
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International Journal of Epidemiology 05/2006; 35(2):243-9. · 6.41 Impact Factor
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Bernard Keavney,
Alison Palmer,
Sarah Parish, Sarah Clark,
Linda Youngman,
John Danesh,
Colin McKenzie,
Marc Delépine,
Mark Lathrop,
Richard Peto,
Rory Collins
[show abstract]
[hide abstract]
ABSTRACT: Blood lipid concentrations are causally related to the risk of coronary heart disease (CHD). Various associations between CHD risk and genes that moderately affect plasma lipid levels have been described, but previous studies have typically involved too few 'cases' to assess these associations reliably.
The present study involves 4685 cases of myocardial infarction (MI) and 3460 unrelated controls without diagnosed cardiovascular disease. Six polymorphisms of four 'lipid-related' genes were genotyped.
For the apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphism, the average increase in the plasma ratio of apolipoprotein B to apolipoprotein A(1) (apoB/apoA(1) ratio) among controls was 0.082 (s.e. 0.007) per stepwise change from epsilon3/epsilon2 to epsilon3/epsilon3 to epsilon3/epsilon4 genotype (trend P < 0.0001). The case-control comparison yielded a risk ratio for MI of 1.16 (95% CI: 1.06, 1.27; P = 0.001) per stepwise change in these genotypes. But, this risk ratio was not as extreme as would have been expected from the corresponding differences in plasma apoB/apoA(1) ratio between genotypes. Hence, following adjustment for the measured level of the plasma apoB/apoA(1) ratio, the direction of the risk ratio per stepwise change reversed to 0.83 (95% CI: 0.74, 0.92; P < 0.001). Similarly, for the apolipoprotein B Asn4311Ser and Thr71Ile polymorphisms, genotypes associated with more adverse plasma apolipoprotein concentrations were associated with significantly lower risk of MI after adjustment for the apoB/apoA(1) ratio. The B2 allele of the cholesteryl ester transfer protein TaqIb polymorphism was associated with a significantly lower plasma apoB/apoA(1) ratio, but with no significant difference in the risk of MI. Finally, the lipoprotein lipase Asn291Ser and T4509C (PvuII) polymorphisms did not produce clear effects on either the plasma apoB/apoA(1) ratio or the risk of MI.
It remains unresolved why some of these genetic factors that produce lifelong effects on plasma lipid concentrations have significantly less than the correspondingly expected effects on CHD rates in adult life.
International Journal of Epidemiology 10/2004; 33(5):1002-13. · 6.41 Impact Factor
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ABSTRACT: Biochemical measurement of fat-soluble vitamins would allow direct assessment in epidemiological studies of their association with disease. However, the perceived instability of these compounds and typically high cost of collection and analysis may make their measurement impractical, particularly in large-scale studies. Using a high performance liquid chromatography assay developed in-house, we have investigated the separate effects of temperature and light on the stability of vitamins in whole blood over several days.
Multiple blood samples from 10 volunteers were stored at 20 degrees C or 4 degrees C and in dark or light conditions. Immediately after collection and 1, 2, 3, 4, and 7 days later, samples stored under each condition were centrifuged, and the plasma was aliquoted and stored at -80 degrees C. Subsequently, all aliquots from each individual were analysed in one analytical run.
In whole blood stored under any of the four conditions for up to 7 days, concentrations of alpha-carotene, beta-carotene, lutein, lycopene, retinol, and alpha-tocopherol changed by less than 8%, and cryptoxanthin and gamma-tocopherol by less than 11%. Although significant temperature effects were observed for alpha-carotene, and alpha- and gamma-tocopherol, and a significant effect of light was observed for alpha-carotene, cryptoxanthin, and lycopene, these analytes changed by less than 1% per day under all conditions.
Concentrations of these fat-soluble vitamins change by only a few per cent in whole blood during storage at room temperature for several days. Hence, delayed separation of blood samples (which may be required for practical reasons in large-scale epidemiological studies) does not preclude reliable measurement of fat-soluble vitamins.
International Journal of Epidemiology 07/2004; 33(3):518-25. · 6.41 Impact Factor
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Clinical Chemistry 04/2003; 49(3):518-20. · 7.91 Impact Factor
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ABSTRACT: Large blood-based epidemiological studies require simple, cost-effective sample collection methods. Immediate sample separation or rapid transport of chilled blood samples to a central laboratory may be impractical or prohibitively expensive. To assess the feasibility and reliability of transporting blood samples over several days at ambient temperature (e.g. by mail), we evaluated the stability of various plasma analytes in samples stored at room temperature or chilled.
Multiple vacutainers of blood, containing EDTA and aprotinin as preservative, were drawn from 12 volunteers and stored at 21 degrees C or 4 degrees C. Immediately after collection and 1, 2, 3, 4, and 7 days later, vacutainers stored at each temperature were centrifuged, and the plasma was aliquoted and stored at -80 degrees C. Subsequently, all aliquots from each individual were analysed in one analytical run for a range of chemistries.
In whole blood stored at room temperature for up to 7 days, concentrations of albumin, apolipoproteins A1 and B (apoA1 and apoB), cholesterol, high density lipoprotein (HDL), total protein, and triglycerides changed by less than 4%, and low density lipoprotein (LDL) by less than 7%. Whilst alanine transaminase (ALT), creatine kinase (CK), creatinine, and gamma-glutamyl transferase (GGT) concentrations changed substantially at room temperature, there was less than 4% change during chilled storage up to 7 days. By contrast, aspartate transaminase (AST) concentrations increased markedly under both conditions.
A wide range of important analytes, including lipids, change by only a few per cent in whole blood during storage at room temperature for several days. Mailed transport of whole blood samples may, therefore, be a simple and cost-effective option for large-scale epidemiological studies.
International Journal of Epidemiology 03/2003; 32(1):125-30. · 6.41 Impact Factor
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Bernard Keavney,
Sarah Parish,
Alison Palmer, Sarah Clark,
Linda Youngman,
John Danesh,
Colin McKenzie,
Marc Delépine,
Mark Lathrop,
Richard Peto,
Rory Collins
[show abstract]
[hide abstract]
ABSTRACT: 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) epsilon2/epsilon3/epsilon4 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<0.00001) per stepwise change from epsilon3/2 to epsilon3/3 to epsilon3/4 genotype. Among individuals in this study with known cigarette smoking status, the hazard ratio for myocardial infarction in smokers versus non-smokers was 4.6 (4.2-5.1). There was, however, no significant difference between the smoker/non-smoker hazard ratios for those with different APOE genotypes (chi2(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.
The Lancet 02/2003; 361(9355):396-8. · 38.28 Impact Factor
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Clinical Chemistry 10/2002; 48(9):1627-9. · 7.91 Impact Factor
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ABSTRACT: 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 measure- ments. 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 (x1 2 ¼ 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL choles- terol, and total cholesterol (x1 2 ¼ 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 associ- ated 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.
