Overestimation of genetic risks owing to small sample sizes in cardiovascular studies

Tm, Morgan; Coffey, CS; Krumholz, Harlan M.

doi:10.1034/j.1399-0004.2003.00088.x

Cited by 37 publications

(23 citation statements)

References 102 publications

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“…First, we did not obtain any evidence for a relationship between the PlA1/A2 polymorphism and glucose metabolism. Second, the PlA1/A2 polymorphism was not associated with CHD or with a history of myocardial infarction, a finding which is completely consistent with previous findings [2].…”

Section: Discussionsupporting

confidence: 81%

“…This recruitment strategy is clearly different from that used in our study, which exclusively enrolled patients scheduled for angiography. An important reason for the false-positive findings by Tschoepe and co-workers [3] may be that the PlA2 allele occurred at a frequency of 14.6% only in their non-diabetic control subjects, a value substantially lower than the prevalence of 28.5% found in the current study and the prevalence of 26.2% found in a recent meta-analysis of 8829 individuals without previous myocardial infarction [2].…”

Section: Discussioncontrasting

confidence: 55%

“…The PlA1/A2 polymorphism of the glycoprotein IIIa (GPIIIa) subunit results from a T to C transition of the GPIIIa gene, replacing leucine by proline at amino acid residue 33 of GPIIIa [1]. This polymorphism has been implicated in vascular disease (review see [2]). A recent case-control study of 215 subjects reported a more than two-fold higher prevalence of PlA2 in patients with type 2 diabetes than in individuals with normal glucose metabolism [3].…”

Section: Introductionmentioning

confidence: 99%

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The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with the risk of type 2 diabetes. The Ludwigshafen Risk and Cardiovascular Health Study

et al. 2004

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Aims/hypothesis. The PlA1/A2 polymorphism of platelet glycoprotein IIIa (GPIIIa) has been implicated in the pathogenesis of type 2 diabetes. We studied this polymorphism in a homogenous, extensively phenotyped cohort using the candidate gene approach. Methods. The PlA1/A2 polymorphism was determined in 1051 patients with type 2 diabetes and in 2247 individuals without type 2 diabetes. Results. In patients with type 2 diabetes, genotype frequencies were as follows: PlA1/A1 71.4%, PlA1/A2 26.0%, and PlA2/A2 2.7%. In individuals without type 2 diabetes, genotype frequencies were 71.6%, 25.7% and 2.8%, respectively. The PlA2 allele was not associated with fasting and postprandial glucose, glycated haemoglobin, insulin, proinsulin, C-peptide and calculated indices of insulin resistance or pancreatic beta cell function. The PlA2 allele was also not significantly associated with angiographic CHD (adjusted odds ratio [OR] 1.13; 95% CI, 0.93-1.39) or with a history of previous myocardial infarction (adjusted OR 1.09; 95% CI, 0.87-1.37). Conclusions/interpretation. The GPIIIa PlA1/A2 polymorphism is not associated with type 2 diabetes, glucose metabolism, angiographic CHD or myocardial infarction.

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Section: Discussionsupporting

confidence: 81%

Section: Discussioncontrasting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with the risk of type 2 diabetes. The Ludwigshafen Risk and Cardiovascular Health Study

et al. 2004

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“…Although the majority of the studies provided both, in three studies (Wittrup et al 1999;Boekholdt et al 2001;Morgan et al 2003) the frequency of the genotypes was calculated from the data, while in Wittrup et al (1999) the risk estimates were re-calculated compared to the protective genotype. In the case of Boekholdt et al (2005) the authors provided the additional information and analysis (personal communication).…”

Section: Meta-analysis Usedmentioning

confidence: 99%

The use of Meta‐Analysis Risk Estimates for Candidate Genes in Combination to Predict Coronary Heart Disease Risk

Drenos

Whittaker

Humphries

2007

Annals of Human Genetics

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SummaryAlthough the risk for coronary heart disease (CHD) associated with single SNPs is modest it has been suggested that, in combination, several common risk-associated alleles could lead to a substantially better heart disease risk prediction. We have modelled this using 10 SNPs in ten candidate genes (APOB, NOS3, APOE, ACE, SERPINE1, MTHFR, ITGA2B, PON 1, LPL, and CETP) and their predicted summary risk estimates from meta-analysis. Based on published allele frequencies, ∼ 29% of the general population would be expected to carry less than three risk alleles, approximately 55% would carry 3 or 4 risk alleles, 4% would have 6 and 1% 7 or more risk alleles. Compared to the mean of those with 3 or 4 risk associated genotypes, those with 6 and 7-or-more alleles have a significantly higher risk odds ratio (OR) of CHD (mean OR (95% Confidence Intervals), 1.70 (1.14 to 2.55); and 4.51 (2.89 to 7.04) respectively), while compared to those in the lowest decile of risk, those in the highest decile have a CHD odds ratio in the range of 3.05 (2.24 to 4.14). Taking into account age and the risk alleles carried, the mean 10 year probability for developing CHD for a 55 year old man was calculated to be 15% (8.6% to 24.8%), with nearly 1 in 5 having more than 20% risk. Whether this particular group of 10 SNPs will improve the accuracy of CHD predictions over the combination of classical risk factors in clinical use requires further experimental evidence.

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“…Cambien et al were the first to report such an observation. 6 Results from subsequent studies, however, have proved less consistent, and metaanalysis of published data suggest the impact of ACE genotype on myocardial infarction (MI) risk to be modest (relative risk associated with DD genotype of approximately 1.2 7,8 ).…”

mentioning

confidence: 99%

Angiotensin-Converting Enzyme Genotype Interacts With Systolic Blood Pressure to Determine Coronary Heart Disease Risk in Healthy Middle-Aged Men

et al. 2007

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Abstract-The impact of the ACE I/D polymorphism on coronary heart disease (CHD) risk is modest at most, however it may act as a modifier gene. ACE genotype was determined in 2711 healthy middle-aged men (mean age 56 years) followed for 15 years. No genotype-CHD risk association was found, but when analyzed by quartiles of systolic blood pressure (SBP), compared with II homozygotes, carriage of each additional D allele was protective at lower SBP, but in the highest quartile (SBP Ͼ150 mm Hg) conferred almost 1. A s a key component of the human endocrine renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) converts angiotensin I to pressor angiotensin II (Ang II), and degrades vasodilator kinins. However, local tissue RAS exist in diverse tissues including the human arterial vascular wall, 1 where they modulate growth and inflammatory responses. 2,3 As such, tissue ACE represents a good candidate as a mediator of coronary heart disease (CHD).The absence (deletion, D allele) rather than the presence (insertion, I allele) of a 287-bp fragment in intron 16 of the human ACE gene is associated with elevated ACE activity both in the circulation 4 and in tissues. 5 As such, one might anticipate the ACE D-allele to be associated with excess CHD risk. Cambien et al were the first to report such an observation. 6 Results from subsequent studies, however, have proved less consistent, and metaanalysis of published data suggest the impact of ACE genotype on myocardial infarction (MI) risk to be modest (relative risk associated with DD genotype of approximately 1.2 7,8 ).Such inconsistency and weakness of effect may, however, reflect the interaction of ACE genotype with environmental factors in determining risk. Indeed, accruing evidence suggests that the ACE gene may modulate the development of complex phenotypes through interaction with stimuli such as smoking, where the D-allele seems associated with higher cardiovascular disease mortality. 9 An interaction with blood pressure may also exist, the D-allele being associated with a higher risk of heart failure among hypertensives. 10 We therefore hypothesized that ACE genotype might interact with SBP to determine CHD risk. We tested this hypothesis in the Second Northwick Park Heart Study (NPHSII), which offers 15-year prospective follow-up study of middle-aged men healthy at enrollment. We have previously observed that a common functional variant in the gene for lipoprotein lipase (LPL)-the S447X polymorphism-shows interaction with SBP on CHD risk. 11 For this variant, increasing blood pressure had a greater effect on risk in X447 allele carriers than in S447 homozygotes. In view of this similar pattern of gene-blood pressure interaction, the combined effects of the ACE I/D and LPL S447X and SBP on CHD risk were also determined. MethodsSubjects comprising those recruited from the prospective Second Northwick Park Heart Study (NPHSII), described in detail elsewhere. 12 In brief, 3012 unrelated healthy white middle-aged male subjects were recruited from 9 United K...

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Overestimation of genetic risks owing to small sample sizes in cardiovascular studies

Cited by 37 publications

References 102 publications

The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with the risk of type 2 diabetes. The Ludwigshafen Risk and Cardiovascular Health Study

The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with the risk of type 2 diabetes. The Ludwigshafen Risk and Cardiovascular Health Study

The use of Meta‐Analysis Risk Estimates for Candidate Genes in Combination to Predict Coronary Heart Disease Risk

Angiotensin-Converting Enzyme Genotype Interacts With Systolic Blood Pressure to Determine Coronary Heart Disease Risk in Healthy Middle-Aged Men

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