Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents

Background: While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. Methods: In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). Results: The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value ,0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and selfmedication phenotypes were both 0.076. Conclusions: Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Impact: Dopaminergic pathways may be salient during early smoking and the development of ND

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

SNPs Associated with Early Smoking and Nicotine Dependence Phenotypes (P-value from Linear Mixed Model <0.01) (n = 544).

<p>NDIT Study, 1999–2008.</p><p>Abbreviations: ICD-10, International Classification of Disease, 10^th Revision; mFTQ, Modified Fagerstrom Tolerance Questionnaire; NDIT, Nicotine Dependence In Teens; ND, nicotine dependence; No., number; SNP, single-nucleotide polymorphism.</p><p>*Based on 88,326 permutations **Also known as DAT1.</p><p>SNPs Associated with Early Smoking and Nicotine Dependence Phenotypes (P-value from Linear Mixed Model <0.01) (n = 544).</p

Presence/Absence of Nominally Statistically Significant Associations^** Between 16 SNPs from Seven Genes and Early Smoking and Nicotine Dependence Phenotypes (n = 544).

<p>NDIT Study, 1999–2008.</p><p>Abbreviations: ICD-10, International Classification of Diseases. 10th Revision; mFTQ, Modified Fagerstrom Tolerance Questionnaire; NDIT, Nicotine Dependence in Teens; ND, nicotine dependence; No., number; SNP, single-nucleotide polymorphism.</p><p>*Also known as <i>DAT1</i>.</p><p>**p-value from linear mixed models <0.01.</p><p>Presence/Absence of Nominally Statistically Significant Associations^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115716#nt114" target="_blank">**</a>} Between 16 SNPs from Seven Genes and Early Smoking and Nicotine Dependence Phenotypes (n = 544).</p

Selected Characteristics of NDIT Participants Who Smoked Cigarettes and Had DNA Genotyped.

<p>NDIT Study, 1999–2008.</p><p>Abbreviations: DNA, deoxyribonucleic acid; ICD-10, International Classification of Disease, 10th Revision;</p><p>IQR, interquartile range; mFTQ, Modified Fagerstrom Tolerance Questionnaire; ND, nicotine dependence; NDIT, Nicotine Dependence in Teens; No., number; sd, standard deviation; y, year.</p><p>*Includes participants of Chinese, South Asian, Black, Latin American, South-East Asian, Arabic, West Asian, Japanese and mixed ethnicity descent.</p><p>Selected Characteristics of NDIT Participants Who Smoked Cigarettes and Had DNA Genotyped.</p

Biological System, Minor and Major Alleles and Minor Allele Frequency of 16 SNPs from Seven Genes (n = 544). NDIT Study, 1999–2008.

<p>Abbreviations: NDIT, Nicotine Dependence In Teens; SNP, single-nucleotide polymorphism; MAF, Minor allele frequency.</p><p>*Includes French-Canadian and other European ethnicities only.</p><p>**Also known as <i>DAT1</i>.</p><p>Biological System, Minor and Major Alleles and Minor Allele Frequency of 16 SNPs from Seven Genes (n = 544). NDIT Study, 1999–2008.</p

Optical and Near-Infrared Observations of the Peculiar Type Ia Supernova 1999ac

We present 39 nights of optical photometry, 34 nights of IR photometry, and 4 nights of optical spectroscopy of the Type Ia supernova 1999ac. This supernova was discovered 2 weeks before maximum light, and observations were begun shortly thereafter. At early times its spectra resembled the unusual SN 1999aa and were characterized by very high velocities in the Ca II H and K lines but very low velocities in the Si II λ6355 line. The optical photometry showed a slow rise to peak brightness but, quite peculiarly, was followed by a more rapid decline from maximum. Thus, the B- and V-band light curves cannot be characterized by a single stretch factor. We argue that the best measure of the nature of this object is not the decline rate parameter Δm15(B). The B - V colors were unusual from 30 to 90 days after maximum light in that they evolved to bluer values at a much slower rate than normal Type Ia supernovae. The spectra and bolometric light curve indicate that this event was similar to the spectroscopically peculiar slow decliner SN 1999aa