Estimating the Impact of Adding C-Reactive Protein as a Criterion for Lipid Lowering Treatment in the United States

BACKGROUND: There is growing interest in using C-reactive protein (CRP) levels to help select patients for lipid lowering therapy—although this practice is not yet supported by evidence of benefit in a randomized trial. OBJECTIVE: To estimate the number of Americans potentially affected if a CRP criteria were adopted as an additional indication for lipid lowering therapy. To provide context, we also determined how well current lipid lowering guidelines are being implemented. METHODS: We analyzed nationally representative data to determine how many Americans age 35 and older meet current National Cholesterol Education Program (NCEP) treatment criteria (a combination of risk factors and their Framingham risk score). We then determined how many of the remaining individuals would meet criteria for treatment using 2 different CRP-based strategies: (1) narrow: treat individuals at intermediate risk (i.e., 2 or more risk factors and an estimated 10–20% risk of coronary artery disease over the next 10 years) with CRP > 3 mg/L and (2) broad: treat all individuals with CRP > 3 mg/L. DATA SOURCE: Analyses are based on the 2,778 individuals participating in the 1999–2002 National Health and Nutrition Examination Survey with complete data on cardiac risk factors, fasting lipid levels, CRP, and use of lipid lowering agents. MAIN MEASURES: The estimated number and proportion of American adults meeting NCEP criteria who take lipid-lowering drugs, and the additional number who would be eligible based on CRP testing. RESULTS: About 53 of the 153 million Americans aged 35 and older meet current NCEP criteria (that do not involve CRP) for lipid-lowering treatment. Sixty-five percent, however, are not currently being treated, even among those at highest risk (i.e., patients with established heart disease or its risk equivalent)—62% are untreated. Adopting the narrow and broad CRP strategies would make an additional 2.1 and 25.3 million Americans eligible for treatment, respectively. The latter strategy would make over half the adults age 35 and older eligible for lipid-lowering therapy, with most of the additionally eligible (57%) coming from the lowest NCEP heart risk category (i.e., 0–1 risk factors). CONCLUSION: There is substantial underuse of lipid lowering therapy for American adults at high risk for coronary disease. Rather than adopting CRP-based strategies, which would make millions more lower risk patients eligible for treatment (and for whom treatment benefit has not yet been demonstrated in a randomized trial), we should ensure the treatment of currently defined high-risk patients for whom the benefit of therapy is established

On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study

Testing for genetic effects on mean values of a quantitative trait has been a very successful strategy. However, most studies to date have not explored genetic effects on the variance of quantitative traits as a relevant consequence of genetic variation. In this report, we demonstrate that, under plausible scenarios of genetic interaction, the variance of a quantitative trait is expected to differ among the three possible genotypes of a biallelic SNP. Leveraging this observation with Levene's test of equality of variance, we propose a novel method to prioritize SNPs for subsequent gene–gene and gene–environment testing. This method has the advantageous characteristic that the interacting covariate need not be known or measured for a SNP to be prioritized. Using simulations, we show that this method has increased power over exhaustive search under certain conditions. We further investigate the utility of variance per genotype by examining data from the Women's Genome Health Study. Using this dataset, we identify new interactions between the LEPR SNP rs12753193 and body mass index in the prediction of C-reactive protein levels, between the ICAM1 SNP rs1799969 and smoking in the prediction of soluble ICAM-1 levels, and between the PNPLA3 SNP rs738409 and body mass index in the prediction of soluble ICAM-1 levels. These results demonstrate the utility of our approach and provide novel genetic insight into the relationship among obesity, smoking, and inflammation

Gene Variation of Endoplasmic Reticulum Aminopeptidases 1 and 2, and Risk of Blood Pressure Progression and Incident Hypertension among 17,255 Initially Healthy Women

Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic–epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women's Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified. Multivariable linear, logistic, and Cox regression analyses were performed to assess the relationship of genotypes with baseline BP levels, BP progression at 48 months, and incident hypertension assuming an additive genetic model. Linear regression analyses showed associations of four tSNPs (ERAP1: rs27524; ERAP2: rs3733904, rs4869315, and rs2549782; all p < 0.05) with baseline systolic BP levels. Three tSNPs (ERAP1: rs27851, rs27429, and rs34736, all p < 0.05) were associated with baseline diastolic BP levels. Multivariable logistic regression analysis showed that ERAP1 rs27772 was associated with BP progression at 48 months (p = 0.0366). Multivariable Cox regression analysis showed an association of three tSNPs (ERAP1: rs469783 and rs10050860; ERAP2: rs2927615; all p < 0.05) with risk of incident hypertension. Analyses of dbGaP for genotype–phenotype association and GTEx Portal for gene expression quantitative trait loci revealed five tSNPs with differential association of BP and nine tSNPs with lower ERAP1 and ERAP2 mRNA expression levels, respectively. The present study suggests that ERAP1 and ERAP2 gene variation may be useful for risk assessment of BP progression and the development of hypertension

Common Variants in CRP and LEPR Influence High Sensitivity C-Reactive Protein Levels in North Indians

BACKGROUND: High sensitivity C-reactive protein (hsCRP) levels are shown to be influenced by genetic variants in Europeans; however, little is explored in Indian population. METHODS: Herein, we comprehensively evaluated association of all previously reported genetic determinants of hsCRP levels, including 18 cis (proximal to CRP gene) and 73 trans-acting (distal to CRP gene) variants in 4,200 North Indians of Indo-European ethnicity. First, we evaluated association of 91 variants from 12 candidate loci with hsCRP levels in 2,115 North Indians (1,042 non-diabetic subjects and 1,073 patients with type 2 diabetes). Then, cis and trans-acting variants contributing maximally to hsCRP level variation were further replicated in an independent 2,085 North Indians (1,047 patients with type 2 diabetes and 1,038 non-diabetic subjects). RESULTS: We found association of 12 variants from CRP, LEPR, IL1A, IL6, and IL6R with hsCRP levels in non-diabetic subjects. However, only rs3093059-CRP [β = 0.33, P = 9.6×10⁻⁵] and the haplotype harboring rs3093059 risk allele [β = 0.32 µg/mL, P = 1.4×10⁻⁴/P(perm) = 9.0×10⁻⁴] retained significance after correcting for multiple testing. The cis-acting variant rs3093059-CRP had maximum contribution to the variance in hsCRP levels (1.14%). Among, trans-acting variants, rs1892534-LEPR was observed to contribute maximally to hsCRP level variance (0.59%). Associations of rs3093059-CRP and rs1892534-LEPR were confirmed by replication and attained higher significance after meta-analysis [β(meta) = 0.26/0.22; P(meta) = 4.3×10⁻⁷/7.4×10⁻³ and β(meta) = -0.15/-0.12; P(meta) = 2.0×10⁻⁶/1.6×10⁻⁶ for rs3093059 and rs1892534, respectively in non-diabetic subjects and all subjects taken together]. CONCLUSION: In conclusion, we identified rs3093059 in CRP and rs1892534 in LEPR as major cis and trans-acting contributor respectively, to the variance in hsCRP levels in North Indian population

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

&lt;p&gt;Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.&lt;/p&gt; &lt;p&gt;Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (&#60;2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).&lt;/p&gt; &lt;p&gt;Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).&lt;/p&gt

The Discovery of LOX-1, its Ligands and Clinical Significance

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and atherogenesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other atherogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardiovascular diseases. Further understandings of LOX-1 and its ligands as well as its versatile functions will direct us to ways to find novel diagnostic and therapeutic approaches to cardiovascular disease

Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy

Immune Responses Accelerate Ageing: Proof-of-Principle in an Insect Model

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies. Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology. Along with presenting a proof-of-principle study, we discuss a mechanism for the apparently counter-adaptive persistence of immunopathology in natural populations. If immunopathology from early immune response only becomes costly later in life, natural selection on reducing self-harm would be relaxed, which could explain the presence of immune self-harm in nature