Background C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels. Methods and Results We performed a genome wide association (GWA) analysis of CRP in 66,185 participants from 15 population-based studies. We sought replication for the genome wide significant and suggestive loci in a replication panel comprising 16,540 individuals from ten independent studies. We found 18 genome-wide significant loci and we provided evidence of replication for eight of them. Our results confirm seven previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2), immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1), or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found significant interaction of body mass index (BMI) with LEPR (p<2.9×10−6). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximately 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusion We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. MG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, statins, are highly effective drugs for the treatment of hypercholesterolemia, a major risk factor of cardiovascular disease. Statins inhibit the synthesis of mevalonate, the rate-limiting step in cholesterol biosynthesis. 1,2 Although statins are generally well tolerated, 3 skeletal muscle side effects are commonly reported among those treated. One such side effect, myalgia, which is defined as muscle aches or weakness in the absence of blood creatine kinase elevation, occurs in 5% to 15% of statin-treated patients. 2,4 -8 In rare cases, potentially life-threatening statin-induced rhabdomyolysis may occur, a condition characterized by acute muscle damage, resulting in pronounced elevation in creatine kinase levels and possible renal failure. 9 The pathophysiology of statin-induced myopathy is not completely understood. The leading mechanism suggests a role for cellular depletion of secondary metabolic intermediates of mevalonate in the development of statin-induced myotoxicity. 10 In addition to decreased cholesterol synthesis, HMG-CoA reductase inhibition by statins causes a commensurate reduction in the levels of downstream metabolic products including isoprenoids, dolichol, and ubiquinone (coenzyme Q10). 10 -13 Among these are the isoprenoid secondary metabolic intermediates geranylgeranylpyrophosphate and farnesylpyrophosphate that are involved in protein isoprenylation and activation of small GTPases such as Rho and Rab. The important role for diminished isoprenylation in the mechanism of statin myotoxicity is related to induction of the muscle atrophy-linked protein atrogin-1. 12 This is highlighted by the findings that supplementation of geranylgeranylpyrophosphate to cultured skeletal myotubes or isolated myofibers treated with statins leads to attenuation of toxicity, 11,13-15 whereas inactivation of a Rab and RhoA induces toxicity. 11,13 Decreased geranylgeranylation of small GT-

The ligand-activated nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of drug metabolizing enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in breast cancer. However, the relevant pathway or target genes of PXR in breast cancer biology and progression have not yet been fully clarified. In this study, we show that mRNA expression of organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in breast cancer tissue. Interestingly, treatment of breast cancer cells in vitro with the PXR agonist rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located f5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the rifampin effect on the cellular uptake of E 1 S. These data provide important new insights into the interplay between a xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of breast cancer and may also prove to be heretofore unrecognized targets for breast cancer treatment. [Cancer Res 2008;68(22):9338-47]