Population study

Abstract: Coronary heart disease (CHD), the commonest cause of death worldwide, is highly heritable, but the DNA sequence variations associated with elevated cardiovascular risk are largely unknown. The investigators planned a genome-wide associational study based on 100,000 single nucleotide polymorphisms and involving 3 sequential case-control comparisons made at a nominal significance threshold of P < 0.025. The study population included more than 23,000 participants from 4 Caucasian populations. Cases had severe, premature CHD starting before age 60 years and leading to coronary artery revascularization. Controls were healthy Caucasian men over age 65 and women over age 70 who lacked symptoms and a history of CHD. Individuals with diabetes or hypercholesterolemia were excluded. A 58-kilobase interval on chromosome 9p21 was consistently associated with CHD. The interval is near the CDKN2A and CDKN2B genes. It contains no annotated genes and is not associated with established CHD risk factors such as diabetes, plasma lipoproteins, or hypertension. Between 20% and 25% of Caucasians are homozygous for the risk allele, and they have an approximately 30%-40% increased risk of CHD. Mechanisms for the association between the risk allele and CHD remain incompletely understood. The allele might promote the development of atherosclerotic plaque, augment thrombogenesis, or increase the tendency of plaques to rupture. The association persisted after controlling for numerous possible confounding factors including age, gender, plasma lipid levels, blood pressure, diabetes, and plasma levels of C-reactive protein. The researchers believe that the effect of the risk allele on chromosome 9 on CHD is not mediated by established risk factors for cardiovascular disease. The present findings support the use of the whole-genome association approach for studying conditions as complex as CHD.

Abstract: Context High levels of lipoprotein(a) are associated with increased risk of myocardial infarction (MI). Objective To assess whether genetic data are consistent with this association being causal. Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a prospective general population study with 16 years of follow-up (1991-2007, n = 8637, 599 MI events); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (2003-2006, n = 29 388, 994 MI events); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (1991-2004, n = 2461, 1231 MI events). Main Outcome Measures Plasma lipoprotein(a) levels, lipoprotein(a) kringle IV type 2 (KIV-2) size polymorphism genotype, and MIs recorded from 1976 through July 2007 for all participants. Results In the CCHS, multivariable-adjusted hazard ratios (HRs) for MI for elevated lipoprotein(a) levels were 1.2 (95% confidence interval [CI], 0.9-1.6; events/10 000 person-years, 59) for levels between the 22nd and 66th percentile, 1.6 (95% CI, 1.1-2.2; events/10 000 person-years, 75) for the 67th to 89th percentile, 1.9 (95% CI, 1.2-3.0; events/10 000 person-years, 84) for the 90th to 95th percentile, and 2.6 (95% CI, 1.6-4.1; events/10 000 person-years, 108) for levels greater than the 95th percentile, respectively, vs levels less than the 22nd percentile (events/10 000 person-years, 55) (trend P Conclusion These data are consistent with a causal association between elevated lipoprotein(a) levels and increased risk of MI.

Abstract: We read the article by McCarter et al. (1) with interest. Technically, all nonanalytical variation, irrespective of its source, is biological variation. Thus, mean blood glucose (MBG)-associated changes are included in biological variation. It must also be stressed that all population regression equations have confidence limits that need to be taken into account when comparing values from individuals to the population study mean. However, such …