Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank.

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (ß=1.02 cm, p=3.91×10-68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (ß=19.36 mL, p=9.21×10-4) and FEV1/forced vital capacity (ß=0.0031, p=1.22×10-5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.

Variants associated with HHIP expression have sex-differential effects on lung function.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 -8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 -6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1) (P=3.15x10 -15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 ß=0.028 [SE 0.0022] litres) than females (ß=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Cardiometabolic phenotypes and mitochondrial DNA copy number in two cohorts of UK women.

The mitochondrial genome is present at variable copy number between individuals. Mitochondria are vulnerable to oxidative stress, and their dysfunction may be associated with cardiovascular disease. The association of mitochondrial DNA copy number with cardiometabolic risk factors (lipids, glycaemic traits, inflammatory markers, anthropometry and blood pressure) was assessed in two independent cohorts of European origin women, one in whom outcomes were measured at mean (SD) age 30 (4.3) years (N=2278) and the second at 69.4 (5.5) years (N=2872). Mitochondrial DNA copy number was assayed by quantitative polymerase chain reaction. Associations were adjusted for smoking, sociodemographic status, laboratory factors and white cell traits. Out of a total of 12 outcomes assessed in both cohorts, mitochondrial DNA copy number showed little or no association with the majority (point estimates were close to zero and nearly all p-values were >0.01). The strongest evidence was for an inverse association in the older cohort with insulin (standardised beta [95%CI]: -0.06, [-0.098, -0.022], p=0.002), but this association did not replicate in the younger cohort. Our findings do not provide support for variation in mitochondrial DNA copy number having an important impact on cardio-metabolic risk factors in European origin women.

Placental Size Is Associated Differentially With Postnatal Bone Size and Density.

We investigated relationships between placental size and offspring adolescent bone indices using a population-based, mother-offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual-energy X-ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z-scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (ß [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (ß [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (ß [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (ß [95% CI]: -0.11 [-0.20, -0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Prenatal alcohol exposure and offspring cognition and school performance. A 'Mendelian randomization' natural experiment.

BACKGROUND: There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. METHODS: We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. RESULTS: Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. CONCLUSIONS: Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.

Success of a multimodal program to improve hand hygiene compliance.

The purpose of this article was to describe the successful implementation of a quality improvement initiative focusing on a hand hygiene program that used the multimodal interventions of tailored education, monthly feedback, and reminders. Compliance rates improved from July 2011 to December 2012 by 57.4%. Efforts are continuing to ensure program sustainability.

Mapping cis- and trans-regulatory effects across multiple tissues in twins.

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data.

BACKGROUND: Oxidative stress is thought to be involved in the pathogenesis of asthma. Glutathione-S-transferase (GST) enzymes, which play an important role in antioxidant defences, may therefore influence asthma risk. Two common deletion polymorphisms of GSTM1 and GSTT1 genes and the GSTP1 Ile105Val polymorphism have been associated with asthma in children and adults, but results are inconsistent across studies. METHODS: Systematic review and meta-analysis of the effects of GST genes on asthma, wheezing and bronchial hyper-responsiveness (BHR), with inclusion of unpublished data from three studies, including the large Avon Longitudinal Study of Parents and Children (ALSPAC). Random effect or fixed effect models were used as appropriate, and sensitivity analyses were performed to assess the impact of study characteristics and quality on pooled results. RESULTS: The meta-analyses of GSTM1 (n = 22 studies) and GSTT1 (n = 19) showed increased asthma risk associated with the null genotype, but there was extreme between-study heterogeneity and publication bias and the association disappeared when meta-analysis was restricted to the largest studies. Meta-analysis of GSTP1 Ile105Val (n = 17) and asthma suggested a possible protective effect of the Val allele, but heterogeneity was extreme. Few studies evaluated wheezing and BHR and most reported no associations, although weak evidence was found for positive associations of GSTM1 null and GSTP1 Val allele with wheezing and a negative association of GSTP1 Val allele with BHR. CONCLUSIONS: Our findings do not support a substantial role of GST genes alone in the development of asthma. Future studies of large size should focus on interactions of GST genes with environmental oxidative exposures and with other genes involved in antioxidant pathways. Quality of study conduct and reporting needs to be improved to increase credibility of the evidence accumulating over time.

Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI.

The goal of this study is to investigate the relationship between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and body mass index (BMI) in two sizable and well-characterized populations of British women: the British Women's Heart and Health Study (BWHHS) (age 60-79 years) and the mothers from the Avon Longitudinal Study of Parents and Children (age 16-44 years). We genotyped the Val66Met polymorphism (rs6265) in these two populations, and conducted a linear regression analysis to test for an association between this polymorphism and BMI. Both study populations indicated an association between BMI and the Val66Met polymorphism, with individuals carrying the Met-Met genotype having a lower mean BMI than those with the Val-Met or Val-Val genotypes (in the BWHHS): mean BMI difference=-0.911 kg/m(2), 95% confidence interval (CI): -1.70 to -0.12, P=0.023; in the mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC): mean BMI difference=-0.57 kg/m(2), 95%CI: -1.08 to -0.054, P=0.03). In a pooled analysis of these two studies, together with one further published study that provided data in a suitable format for inclusion in our meta-analysis, we found a pooled difference of -0.76 (95% CI: -1.16, -0.036) for adult women; I(2)-test for heterogeneity=51%, P=0.13. Our study indicated an association between BDNF and BMI in two general population studies of women. The exact role of BDNF in weight regulation merits further investigation.

Improving reassessment and documentation of pain management.

BACKGROUND: The Joint Commission standards on pain management address the documentation of assessment and reassessment. Yet, little has been published to describe when and how nurses perform and communicate reassessment of pain. In 2005, the University of Wisconsin Hospital & Clinics (UWHC) was inconsistently reassessing pain after interventions, and documented reassessments were primarily confined to pain-intensity ratings. PLAN-DO-CHECK-ACT: A large-scale plan-do-check-act (PDCA) cycle was implemented to improve the documentation of pain reassessments, including development of an evidence-based administrative policy, repetitive education efforts with bedside coaching, changes in daily bedside documentation flow sheets, and audit and feedback. RESULTS: From May 29, 2006, through July 16, 2008, a cumulative rate of 94.9% appropriately documented pain reassessments was achieved. DISCUSSION: Despite implementation of an evidence-based policy to clarify requirements for pain reassessment, repetitive educational efforts, changes in daily bedside flow sheets, direct and extensive leadership involvement in the form of continuous bedside coaching, combined with more timely and persistent audit and feedback and clear accountability and alignment with goals, was necessary for substantial change. Strategies to sustain improvements include daily administrative and monthly staff documentation audits with prompt feedback to clinical nurse managers and staff. Nurses are instructed on the importance of pain reassessments and on the policy and specific documentation requirements. Reassessment of pain is a routine variable displayed on unit and departmental quality dashboards. Further study should examine if the intensity of this requirement for pain reassessment documentation ultimately facilitates the safety and effectiveness of pain management.

Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.

Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.