Smoking, blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people.

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75-0·89, P = 2·0 * 10-108 ) for leukocytes, 0·09 (-0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42-0·64, P = 8·0 * 10-22 ) for haematocrit, 0·42 (0·34-0·51, P = 7·1 * 10-21 ) for haemoglobin, 0·19 (0·08-0·31, P = 1·2 * 10-3 ) for mean corpuscular haemoglobin (MCH), 0·29 (0·19-0·39, P = 1·6 * 10-8 ) for mean corpuscular volume (MCV), and 0·04 (-0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33-1·56; P = 1·8 * 10-19 ; I2  = 0%] in current smokers, 1·29 (1·15-1·44; P = 8·0 * 10-6 ; I2  = 0%) in ex-smokers, 1·49 (1·26-1·77; P = 4·4 * 10-6 ; I2  = 0%) in light smokers and 2·04 (1·74-2·39, P = 2·3 * 10-18 ; I2  = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.

A Lower Maternal Cortisol-to-Cortisone Ratio Precedes Clinical Diagnosis of Preterm and Term Preeclampsia by Many Weeks.

CONTEXT: Previous studies have shown reduced placental levels of 11-ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) in preeclampsia (PE). However, it is unknown if the maternal cortisol-to-cortisone ratio is predictive of placental complications of pregnancy. OBJECTIVE: To determine the relationship between the maternal serum cortisol-to-cortisone ratio at different stages of pregnancy and the risk of PE or fetal growth restriction (FGR). DESIGN: Women from the Pregnancy Outcome Prediction Study experiencing PE (n = 194) or FGR (n = 185), plus a random sample of healthy controls (n = 279), were studied. Steroids were measured at ∼12, ∼20, ∼28, and ∼36 weeks of gestational age (wkGA). Separate analyses were performed for outcomes with term or preterm delivery. Associations were modeled using logistic regression. RESULTS: At 28 wkGA, the cortisol-to-cortisone ratio was negatively associated (OR per 1 SD increase, 95% CI)] with preterm PE (OR 0.33, 95% CI 0.19 to 0.57), term PE (OR 0.61, 95% CI 0.49 to 0.76), and preterm FGR (OR 0.50, 95% CI 0.29 to 0.85). At 36 wkGA, the cortisol-to-cortisone ratio was negatively associated with term PE (OR 0.42, 95% CI 0.32 to 0.55) but not term FGR (OR 1.07, 95% CI 0.87 to 1.31). Associations were not materially affected by adjustment for maternal characteristics. CONCLUSIONS: A lower maternal serum cortisol-to-cortisone ratio precedes clinical manifestation of PE and preterm FGR by many weeks, despite previous reports of reduced levels of placental 11ßHSD2 in these conditions. Our observations implicate enhanced maternal 11ßHSD2 activity or reduced 11ßHSD type 1 activity in the pathophysiology of PE.