Genetic Testing for Early Detection of Individuals at Risk of Coronary Heart Disease and Monitoring Response to Therapy: Challenges and Promises

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient’s lifetime, can help guide therapy selection, and may be of utility in family counseling

Large-Scale Candidate Gene Analysis of HDL Particle Features

Background: HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings: We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10(-6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). Conclusions: We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C

Survival bias and drug interaction can attenuate cross-sectional case-control comparisons of genes with health outcomes. An example of the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism and coronary heart disease

<p>Abstract</p> <p>Background</p> <p>Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the <it>KIF6 </it>Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the <it>KIF6 </it>Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using <it>KIF6 </it>Trp719Arg as an example.</p> <p>Results</p> <p>Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among <it>KIF6 </it>Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between <it>KIF6 </it>genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.</p> <p>In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the <it>KIF6 </it>719Arg variant, should also attenuate the <it>KIF6 </it>719Arg odds ratio in case-control studies.</p> <p>Conclusions</p> <p>These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for <it>KIF6 </it>Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of <it>KIF6 </it>719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.</p

21. Cardiovascular disease risk attributed to blood fish oil (omega-3 fatty acid) levels differ significantly in Saudi Men and Women

Cardiovascular disease is a major health problem in the Saudi population. Fish consumption and blood fish oil levels have been linked to CHD risk in European, American, and Japanese populations. A knowledge gap exists regarding blood omega-3 fatty acid levels in the Saudi population. The omega-3 index (% of fatty acids composed of EPA + DHA) <3.5% has been linked to increased CVD risk in European and American investigations. A EPA/AA ratio <0.75 has been linked to increased CVD risk in a Japanese population. The aim of this investigation is to determine population distribution and gender ranges in a Saudi population. Methods: This population study involved 2672 consecutive blood samples (1544 men and 1128 women) from residence of Saudi Arabia that were de-identified and analyzed for eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachadonic acid (AA) using mass spectroscopy. Data was analyzed for analysis of variance following adjustment for age differences between genders. Results: For the entire population mean ±SD, age = 44.8 ± 14.2 years, omega-3 index = 3.91 ± 1.45%, EPA = 0.27 ± 0.22%, DHA = 3.67 ± 1.37% and AA=0.36 ± 0.13%. Mean and standard deviation age was higher in Females (45.6 ± 15 years) versus Males (44.1 ± 14 years) p = 0.005. Age adjusted differences in Females versus Males were EPA (0.23 ± 0.23% vs. 0.26 ± 0.20%, p = 0.0001), DHA (3.54 ± 1.36 vs. 3.73 ± 1.37, p = 0.0001), Omega-3 index (3.76 + 1.44 vs. 3.99 + 1.47), p = 0.0001, AA (0.36 + 0.13 vs. 0.36 + 0.13, p = NS), and EPA/AA (0.70 ± 0.64 vs. 0.79 ± 0.66, p = 0.0002). 46.4% of females and 39.1% of males had a blood omega-3 index <3.5% (p < 0.0002), and 73.7% of females and 66.3% of males (p < 0.0001) had an EPA/AA <0.75 suggesting increased CVD risk which was evident significantly more in women compared to men. Conclusion: A large proportion of the Saudi population may be at increased CVD risk due to low blood levels of omega-3 fatty acids and low EPA/AA blood level ratio. Females may be at higher risk than males. Future research will investigate the relationship of blood omega-3 blood levels and CHD incidence in the Saudi population