Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND

Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

OBJECTIVE.— To deal with public and professional concern regarding possible overprescription of attention-deficit/hyperactivity disorder (ADHD) medications, particularly methylphenidate, by reviewing issues related to the diagnosis, optimal treatment, and actual care of ADHD patients and of evidence of patient misuse of ADHD medications. DATA SOURCES.— Literature review using a National Library of Medicine database search for 1975 through March 1997 on the terms attention deficit disorder with hyperactivity,methylphenidate, stimulants, and stimulant abuse and dependence. Relevant documents from the Drug Enforcement Administration were also reviewed. STUDY SELECTION.— All English-language studies dealing with children of elementary school through high school age were included. DATA EXTRACTION.— All searched articles were selected and were made available to coauthors for review. Additional articles known to coauthors were added to the initial list, and a consensus was developed among the coauthors regarding the articles most pertinent to the issues requested in the resolution calling for this report. Relevant information from these articles was included in the report. DATA SYNTHESIS.— Diagnostic criteria for ADHD are based on extensive empirical research and, if applied appropriately, lead to the diagnosis of a syndrome with high interrater reliability, good face validity, and high predictability of course and medication responsiveness. The criteria of what constitutes ADHD in children have broadened, and there is a growing appreciation of the persistence of ADHD into adolescence and adulthood. As a result, more children (especially girls), adolescents, and adults are being diagnosed and treated with stimulant medication, and children are being treated for longer periods of time. Epidemiologic studies using standardized diagnostic criteria suggest that 3% to 6% of the school-aged population (elementary through high school) may suffer from ADHD, although the percentage of US youth being treated for ADHD is at most at the lower end of this prevalence range. Pharmacotherapy, particularly use of stimulants, has been extensively studied and generally provides significant short-term symptomatic and academic improvement. There is little evidence that stimulant abuse or diversion is currently a major problem, particularly among those with ADHD, although recent trends suggest that this could increase with the expanding production and use of stimulants. CONCLUSIONS.— Although some children are being diagnosed as having ADHD with insufficient evaluation and in some cases stimulant medication is prescribed when treatment alternatives exist, there is little evidence of widespread overdiagnosis or misdiagnosis of ADHD or of widespread overprescription of methylphenidate by physicians