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ORIGINAL CONTRIBUTION: Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease

Context Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. Objective To investigate association of genetic loci with CRP levels and risk of coronary heart disease. Design, Setting, and Participants We first carried out a genome-wide association (n = 17 967) and replication study (n = 13 615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28 112 cases and 100 823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14 365 cases and 32 069 controls. Main Outcome Measure Risk of coronary heart disease. Results Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (–14.8%; 95% confidence interval [CI], –17.6% to –12.0%; P = 6.2 x 10–22), rs4537545 in IL6R (–11.5%; 95% CI, –14.4% to –8.5%; P = 1.3 x 10–12), rs7553007 in the CRP locus (–20.7%; 95% CI, –23.4% to –17.9%; P = 1.3 x 10–38), rs1183910 in HNF1A (–13.8%; 95% CI, –16.6% to –10.9%; P = 1.9 x 10–18), and rs4420638 in APOE-CI-CII (–21.8%; 95% CI, –25.3% to –18.1%; P = 8.1 x 10–26). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, –3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. Conclusion The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

ORIGINAL CONTRIBUTION: Novel and Conventional Biomarkers for Prediction of Incident Cardiovascular Events in the Community

Context Prior studies have demonstrated conflicting results regarding how much information novel biomarkers add to cardiovascular risk assessment. Objective To evaluate the utility of contemporary biomarkers for predicting cardiovascular risk when added to conventional risk factors. Design, Setting, and Participants Cohort study of 5067 participants (mean age, 58 years; 60% women) without cardiovascular disease from Malmö, Sweden, who attended a baseline examination between 1991 and 1994. Participants underwent measurement of C-reactive protein (CRP), cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide (N-BNP) and underwent follow-up until 2006 using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register for first cardiovascular events (myocardial infarction, stroke, coronary death). Main Outcome Measures Incident cardiovascular and coronary events. Results During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had C statistics of 0.758 (95% confidence interval [CI], 0.734 to 0.781) and 0.760 (0.730 to 0.789) for cardiovascular and coronary events, respectively. Biomarkers retained in backward-elimination models were CRP and N-BNP for cardiovascular events and MR-proADM and N-BNP for coronary events, which increased the C statistic by 0.007 (P = .04) and 0.009 (P = .08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). Net reclassification improvement was nonsignificant for cardiovascular events (0.0%; 95% CI, –4.3% to 4.3%) and coronary events (4.7%; 95% CI, –0.76% to 10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%; 95% CI, 0.7% to 14.1%; P = .03; coronary events: 14.6%; 95% CI, 5.0% to 24.2%; P = .003). However, correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events. Conclusions Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.

ORIGINAL CONTRIBUTION: Prevalence, Complications, and Hospital Charges Associated With Use of Bone-Morphogenetic Proteins in Spinal Fusion Procedures

Context No national data exist to examine use of bone-morphogenetic proteins (BMPs) in spinal fusion surgery. Objective To determine the patterns of use and rates of complications and financial charges associated with BMP use in spinal fusion nationally. Design, Setting, and Patients Retrospective cohort study of 328 468 patients undergoing spinal fusion procedures from 2002-2006 identified from the Nationwide Inpatient Sample database, a 20% sample of US community hospitals. Main Outcome Measures The rates of use of BMP among patients undergoing spinal fusion procedures are examined along with complications, length of stay, and hospital charges associated with use of this fusion adjunct. Results The nationwide usage of BMP has increased from 0.69% of all fusions in 2002 to 24.89% of all fusions in 2006. Use of BMP varied by patient sex, race, and primary payer with increased use seen in women (56.26% with BMP vs 53.35% without BMP; odds ratio [OR], 1.12; 95% confidence interval, [CI], 1.09-1.16) and Medicare patients (29.62% with BMP vs 27.16% without BMP; OR, 1.43; 95% CI, 1.31-1.56) and decreased use in nonwhite patients (8.69% with BMP vs 10.23% without BMP; OR, 0.80; 95% CI, 0.75-0.85). When comparing immediate postoperative, in-hospital rates of complications for the year 2006 among patients undergoing spinal fusion by BMP use status, no differences were seen for lumbar, thoracic, or posterior cervical procedures. On univariate analysis and after multivariable adjustment, the use of BMP in anterior cervical fusion procedures was associated with a higher rate of complication occurrence (7.09% with BMP vs 4.68% without BMP; adjusted OR, 1.43; 95% CI, 1.12-1.70) with the primary increases seen in wound-related complications (1.22% with BMP vs 0.65% without BMP; adjusted OR, 1.67; 95% CI, 1.10- 2.53) and dysphagia or hoarseness (4.35% with BMP vs 2.45% without BMP; adjusted OR, 1.63; 95% CI, 1.30-2.05). Bone-morphogenetic protein use was associated with greater inpatient hospital charges across all categories of fusion. Increases between 11% and 41% of total hospital charges were reported, with the greatest percentage increase seen for anterior cervical fusion. Conclusion Bone-morphogenetic protein was used in approximately 25% of all spinal fusions nationally in 2006, with use associated with more frequent complications for anterior cervical fusions and with greater hospital charges for all categories of fusions.

SPECIAL COMMUNICATION: The Obligation to Participate in Biomedical Research

The current prevailing view is that participation in biomedical research is above and beyond the call of duty. While some commentators have offered reasons against this, we propose a novel public goods argument for an obligation to participate in biomedical research. Biomedical knowledge is a public good, available to any individual even if that individual does not contribute to it. Participation in research is a critical way to support an important public good. Consequently, all have a duty to participate. The current social norm is that individuals participate only if they have a good reason to do so. The public goods argument implies that individuals should participate unless they have a good reason not to. Such a shift would be of great aid to the progress of biomedical research, eventually making society significantly healthier and longer lived.

CLINICAL CROSSROADS: A 70-Year-Old Woman With Shingles: Review of Herpes Zoster

Herpes zoster is a common late complication of varicella-zoster virus exposure and can be further complicated by postherpetic neuralgia. Ms A is a 70-year-old woman with shingles and Ramsay-Hunt syndrome who presented to the emergency department with a few days of earache followed by pain in the back of her head. Using her case as a springboard, the diagnosis, natural history, and treatment of herpes zoster and postherpetic neuralgia in immunocompetent older adults are reviewed, in addition to the effectiveness of the herpes zoster vaccine.

CLINICAL CROSSROADS UPDATE: Update: A 59-Year-Old Man Considering Implantation of a Cardiac Defibrillator

COMMENTARY: Ethical Collection, Storage, and Use of Public Health Data: A Proposal for a National Privacy Protection

COMMENTARY: Building Bridges Between Medical Care and Public Health

COMMENTARY: The Case for Public Ownership of Patient Data

COMMENTARY: Exploring the Harmful Effects of Health Care

EDITORIAL: Biomarkers and Cardiovascular Disease: Determining Causality and Quantifying Contribution to Risk Assessment

LETTERS: Adverse Outcomes Associated With Use of Proton Pump Inhibitors and Clopidogrel

LETTERS: Adverse Outcomes Associated With Use of Proton Pump Inhibitors and Clopidogrel--Reply

LETTERS: Proton Pump Inhibitors and the Risk for Clostridium difficile Infection

LETTERS: Proton Pump Inhibitors and the Risk for Clostridium difficile Infection--Reply

LETTERS: Employment Status Among Cancer Survivors

LETTERS: Employment Status Among Cancer Survivors--Reply

LETTERS: State Licensure and Professional Monopolies in Medicine

MEDICAL NEWS & PERSPECTIVES: New Pain Guideline for Older Patients: Avoid NSAIDs, Consider Opioids

MEDICAL NEWS & PERSPECTIVES: Groups Back Telemedicine for Stroke Care

MEDICAL NEWS & PERSPECTIVES: Clinical Trials Registry Expands

FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION: Novel Influenza A (H1N1) Virus Infections in Three Pregnant Women--United States, April-May 2009

FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION: Errata: Vol. 58, No. 18

FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION: Malignant Mesothelioma Mortality--United States, 1999-2005

THE COVER: The Cannon Shot

A PIECE OF MY MIND: The Quiet Storm

POETRY AND MEDICINE: Reprieve

JAMA 100 YEARS AGO: AMETHYST-TINTED LENSES

BOOK AND MEDIA REVIEWS: The Processes of Life: An Introduction to Molecular Biology

BOOK AND MEDIA REVIEWS: Aging, Biotechnology, and the Future

BOOK AND MEDIA REVIEWS: Your Health in the Information Age: How You and Your Doctor Can Use the Internet to Work Together

BOOK AND MEDIA REVIEWS: Evolution: The First Four Billion Years

CORRECTION: Misspelled Name in Photo Credit in: Albany Prize Honors Immunology Studies

JAMA PATIENT PAGE: Shingles

ABOUT THIS JOURNAL: About This Journal