Obstetrician-assessed maternal health at pregnancy predicts offspring future health

Background: We aimed to examine the association between obstetrician assessment of maternal physical health at the time of pregnancy and offspring cardiovascular disease risk.<p></p> Methods and Principal Findings: We examined this association in a birth cohort of 11,106 individuals, with 245,000 person years of follow-up. We were concerned that any associations might be explained by residual confounding, particularly by family socioeconomic position. In order to explore this we used multivariable regression models in which we adjusted for a range of indicators of socioeconomic position and we explored the specificity of the association. Specificity of association was explored by examining associations with other health related outcomes. Maternal physical health was associated with cardiovascular disease: adjusted (socioeconomic position, complications of pregnancy, birthweight and childhood growth at mean age 5) hazard ratio comparing those described as having poor or very poor health at the time of pregnancy to those with good or very good health was 1.55 (95%CI: 1.05, 2.28) for coronary heart disease, 1.91 (95%CI: 0.99, 3.67) for stroke and 1.57 (95%CI: 1.13, 2.18) for either coronary heart disease or stroke. However, this association was not specific. There were strong associations for other outcomes that are known to be related to socioeconomic position (3.61 (95%CI: 1.04, 12.55) for lung cancer and 1.28 (95%CI:1.03, 1.58) for unintentional injury), but not for breast cancer (1.10 (95%CI:0.48, 2.53)).<p></p> Conclusions and Significance: These findings demonstrate that a simple assessment of physical health (based on the appearance of eyes, skin, hair and teeth) of mothers at the time of pregnancy is a strong indicator of the future health risk of their offspring for common conditions that are associated with poor socioeconomic position and unhealthy behaviours. They do not support a specific biological link between maternal health across her life course and future risk of cardiovascular disease in her offspring.<p></p&gt

Human cytomegalovirus uracil DNA glycosylase associates with ppUL44 and accelerates the accumulation of viral DNA

BACKGROUND: Human cytomegalovirus UL114 encodes a uracil-DNA glycosylase homolog that is highly conserved in all characterized herpesviruses that infect mammals. Previous studies demonstrated that the deletion of this nonessential gene delays significantly the onset of viral DNA synthesis and results in a prolonged replication cycle. The gene product, pUL114, also appears to be important in late phase DNA synthesis presumably by introducing single stranded breaks. RESULTS: A series of experiments was performed to formally assign the observed phenotype to pUL114 and to characterize the function of the protein in viral replication. A cell line expressing pUL114 complemented the observed phenotype of a UL114 deletion virus in trans, confirming that the observed defects were the result of a deficiency in this gene product. Stocks of recombinant viruses without elevated levels of uracil were produced in the complementing cells; however they retained the phenotype of poor growth in normal fibroblasts suggesting that poor replication was unrelated to uracil content of input genomes. Recombinant viruses expressing epitope tagged versions of this gene demonstrated that pUL114 was expressed at early times and that it localized to viral replication compartments. This protein also coprecipitated with the DNA polymerase processivity factor, ppUL44 suggesting that these proteins associate in infected cells. This apparent interaction did not appear to require other viral proteins since ppUL44 could recruit pUL114 to the nucleus in uninfected cells. An analysis of DNA replication kinetics revealed that the initial rate of DNA synthesis and the accumulation of progeny viral genomes were significantly reduced compared to the parent virus. CONCLUSION: These data suggest that pUL114 associates with ppUL44 and that it functions as part of the viral DNA replication complex to increase the efficiency of both early and late phase viral DNA synthesis

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women

STUDY QUESTION: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? SUMMARY ANSWER: We identified four loci associated with AMH levels at P < 5 × 10(−8): the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. WHAT IS KNOWN ALREADY: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10(−8)). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We identified four loci associated with AMH levels at P < 5 × 10(−8): the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (r(g) = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. LARGE SCALE DATA: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. WIDER IMPLICATIONS OF THE FINDINGS: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. STUDY FUNDING/COMPETING INTEREST(S): Nurses’ Health Study and Nurses’ Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.’s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Assessment of data quality in a multi-centre cross-sectional study of participation and quality of life of children with cerebral palsy

BACKGROUND: SPARCLE is a cross-sectional survey in nine European regions, examining the relationship of the environment of children with cerebral palsy to their participation and quality of life. The objective of this report is to assess data quality, in particular heterogeneity between regions, family and item non-response and potential for bias. METHODS: 1,174 children aged 8–12 years were selected from eight population-based registers of children with cerebral palsy; one further centre recruited 75 children from multiple sources. Families were visited by trained researchers who administered psychometric questionnaires. Logistic regression was used to assess factors related to family non-response and self-completion of questionnaires by children. RESULTS: 431/1,174 (37%) families identified from registers did not respond: 146 (12%) were not traced; of the 1,028 traced families, 250 (24%) declined to participate and 35 (3%) were not approached. Families whose disabled children could walk unaided were more likely to decline to participate. 818 children entered the study of which 500 (61%) self-reported their quality of life; children with low IQ, seizures or inability to walk were less likely to self-report. There was substantial heterogeneity between regions in response rates and socio-demographic characteristics of families but not in age or gender of children. Item non-response was 2% for children and ranged from 0.4% to 5% for questionnaires completed by parents. CONCLUSION: While the proportion of untraced families was higher than in similar surveys, the refusal rate was comparable. To reduce bias, all analyses should allow for region, walking ability, age and socio-demographic characteristics. The 75 children in the region without a population based register are unlikely to introduce bias

Notch-induced T cell development requires phosphoinositide-dependent kinase 1

Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development

Study protocol: Determinants of participation and quality of life of adolescents with cerebral palsy: a longitudinal study (SPARCLE2)

<p>Abstract</p> <p>Background</p> <p>Children and adults with impairments such as cerebral palsy have lower participation in life situations than able-bodied people. Less is known about their subjective perception of their lives, called their quality of life.</p> <p>During adolescence, rapid physical and psychological changes occur; although these may be more difficult for disabled than for able-bodied adolescents, little research has examined the lives of disabled adolescents.</p> <p>In 2003-4 a European Union funded project, SPARCLE, visited 818 children aged 8-12 years with cerebral palsy, sampled from population-based registers in nine European regions. The quality of life reported by these disabled children was similar to that of the general population but their participation was lower; levels of participation varied between countries even for children with similar severity of cerebral palsy.</p> <p>We are currently following up these children, now aged 13-17 years, to identify (i) to what extent contemporaneous factors (pain, impairment, psychological health and parental stress) predict their participation and quality of life, (ii) what factors modify how participation and quality of life at age 8-12 years are associated with participation and quality of life in adolescence, and (iii) whether differences between European countries in participation and quality of life can be explained by variations in environmental factors.</p> <p>Methods/Design</p> <p>Trained researchers will visit families to administer questionnaires to capture the adolescents' type and severity of impairment, socio-demographic characteristics, participation, quality of life, psychological health, pain, environmental access and parental stress. We will use multivariable models (linear, logistic or ordinal) to assess how adolescent participation, quality of life, psychological health, pain, environmental access and parental stress, vary with impairment and socio-demographic characteristics and, where possible, how these outcomes compare with general population data. For participation and quality of life, longitudinal analyses will assess to what extent these are predicted by corresponding levels in childhood and what factors modify this relationship. Structural equation modelling will be used to identify indirect relationships mediated by other factors.</p