Protein-altering germline mutations implicate novel genes related to lung cancer development

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Environmental and dietary determinants of metal exposure in four-year-old children from a cohort located in an industrial area (Asturias, Northern Spain)

Urine samples from four-year-old children located in a heavily industrialized zone in Asturias (Spain) were collected between 2009 and 2012 (n = 334). Vanadium (V; median 54 μg/g creatinine), cobalt (Co; 1.0 μg/g c.), nickel (Ni; 3.8 μg/g c.), copper (Cu; 22 μg/g c.), zinc (Zn; 590 μg/g c.), arsenic (As; 64 μg/g c.), selenium (Se; 49 μg/g c.), molybdenum (Mo; 110 μg/g c.), cadmium (Cd; 0.27 μg/g c.), antimony (Sb; 1.0 μg/g c.), cesium (Cs; 14 μg/g c.), barium (Ba; 2.6 μg/g c.), thallium (Tl; 0.55 μg/g c.) and lead (Pb; 1.9 μg/g c.) were analysed. Comparison with children from other sites showed that this Asturias cohort was characterized by high levels of V, As, Sb, Cs and Tl. The concentrations of Co, Ni, Zn, Cu, Mo, Se, Cd, Ba and Pb were within the range of other cohorts. Terrestrial dietary items were most strongly related to increased urinary concentrations of metals in children, e.g., red meat with Ba and Ni, pasta/cereal with Ni and Zn, sweets with Zn, Co, and Cu, eggs with Mo, Cd, and Cs, and dairy products with Co and Sb. Seafood was the second group of dietary items significantly related to increased metals, e.g., shellfish with Ba, Cs, Pb, and V, fatty fish with As, and lean fish with As and Se. In contrast, higher fruit intake was significantly associated with decreased Cu and Sb, and higher legume intake with decreased Cu, Se and Cs. Higher intakes of other dietary items also led to significant decreases in some metals, such as vegetables and lower concentrations of Se and Mo, and dairy products with decreases in Cu and As. These negative correlations implied very low concentrations of the mentioned metals in these foods. Higher exposure to traffic was associated with higher concentrations of Ba, present in brake components. Children living outside urban areas had higher concentrations of Se. No association of metals with smoking in the family was found.The authors would particularly like to thank all the participants for their generous collaboration and the staff from Hospital San Agustin in Aviles for their effort. This study was funded by grants from CIBERESP, FIS-FEDER (PI04/2018, PI09/02311, PI13/02429, PI18/00909), Obra Social Cajastur/Fundación Liberbank and Oviedo University. This paper was also supported by funding from the European Union projects: EDCMET (H2020-HEALTH/0490–825762) and PARC (HLTH-2021-ENVHLTH-3:101057014).Peer reviewe

Maternal pre-pregnancy obesity and neuropsychological development in pre-school children: a prospective cohort study

BackgroundMaternal pre-pregnancy obesity may impair infant neuropsychological development, but it is unclear whether intrauterine or confounding factors drive this association.MethodsWe assessed whether maternal pre-pregnancy obesity was associated with neuropsychological development in 1,827 Spanish children. At 5 years, cognitive and psychomotor development was assessed using McCarthy Scales of Children's Abilities, attention deficit hyperactivity disorder (ADHD) symptoms using the Criteria of Diagnostic and Statistical Manual of Mental Disorders, and autism spectrum disorder symptoms using the Childhood Asperger Syndrome Test. Models were adjusted for sociodemographic factors and maternal intelligence quotient. We used paternal obesity as negative control exposure as it involves the same source of confounding than maternal obesity.ResultsThe percentage of obese mothers and fathers was 8% and 12%, respectively. In unadjusted models, children of obese mothers had lower scores than children of normal weight mothers in all McCarthy subscales. After adjustment, only the verbal subscale remained statistically significantly reduced (β: -2.8; 95% confidence interval: -5.3, -0.2). No associations were observed among obese fathers. Maternal and paternal obesity were associated with an increase in ADHD-related symptoms. Parental obesity was not associated with autism symptoms.ConclusionMaternal pre-pregnancy obesity was associated with a reduction in offspring verbal scores at pre-school age.This study was funded by grants from European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1

The INMA-INfancia y Medio Ambiente-(Environment and Childhood) project: more than 10 years contributing to environmental and neuropsychological research

BACKGROUND: In 2003 the INMA-INfancia y Medio Ambiente (Environment and Childhood) project, a Spanish national network of birth cohorts including more than 3500 participants, was set up with the aim to assess the health impacts of pre- and postnatal environmental exposures on children. The project has published more than 60 papers on maternal and environmental factors related to neuropsychological development in children, one of the main research interests within the project. With the present review, we evaluate the evidence provided by the INMA project on this topic and discuss how the data can contribute to cover the challenges that children's environmental health research will face in the coming years. RESULTS: The INMA project has contributed to provide increasing evidence of the association between prenatal exposure to persistent organic pollutants (POPs) and child neuropsychological development, but it has also shown, using innovative methodologies, that postnatal exposure to these compounds does not play a role in this association. The project has also contributed to show the detrimental influence of certain air pollutants on child neuropsychological development, as well as how a balanced maternal fish intake can protect from the potential adverse effects of prenatal exposure to mercury. Also, the project has contributed to the understanding of impacts of nutritional factors including supplement intake and vitamin D levels during pregnancy and the role of breastfeeding on the neuropsychological benefits. CONCLUSIONS: INMA findings underscore the importance of continued research on the delineation of the sensitive windows of exposure both during pregnancy and postnatally and on the combined effects of environmental exposures, denoted the exposome. In terms of health policy, INMA findings have important implications for the development of public health policies to advance the health and development of children.This study was supported Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, 97/0588, 00/0021-2, PI04/1436, PI06/1756, PI08/1151, PS09/01958, PI12/01890, PI14/00677, MS13/00054, CP13/00054 including FIS-FEDER funds 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02311, 09/02647, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 14/0891, 14/1687, and 16/1288) and Miguel Servet-FEDER MS15/00025, Spanish Ministry of Health - CIBERESP (FIS-97/1102, FIS-PS09/00362, FIS-07/0252, FIS-PI11/00610, FISPI07/0252, FISPI11/0610, FIS-PI04/2018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI06/0867, FIS-PS09/00090, FIS-PI13/02187, PI13/02406, MS13/00054), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Comission (QLK4-CT-2000-00263, QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502, FP7-ENV-2011 cod 282957, 261357, 308333 and 603794 and HEALTH.2010.2.4.5-1), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR501, 2014 SGR 822), Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221), Consejería de Salud de la Junta de Andalucía (grant number 183/07 and SAS-PI-0675-2010), Conselleria de Sanitat, Generalitat Valenciana, Andalusia Regional Government – Consejería de Salud (Grants P09-CTS-5488 Project of Excellence, and SAS PI-0133-2007; PI-0675–2010), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010), beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, Fundació La Caixa (97/009-00 and 00/077-00), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank and University of Oviedo, and annual agreements with the municipalities of the area of study (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain

Prenatal exposure to mixtures of xenoestrogens and repetitive element DNA methylation changes in human placenta

BACKGROUND: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. OBJECTIVES: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. METHODS: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated.RESULTS: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value<0.001), while no significant effects were found in girls (p-value=0.134). CONCLUSIONS: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.This work was supported by grants from the Spanish Ministry of Health (FIS-PI042018; FIS-PI060867; FIS-PI081151; FIS-PI09/02311; FIS-PI09/02647; FIS-PI11/00610); Instituto de Salud Carlos III [Red INMA G03/176 and CB06/02/0041]; the EU Commission (QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502), the Generalitat de Catalunya—CIRIT [1999SGR 00241]; the Consejería de Salud de la Junta de Andalucía (183/07 and 0675/10), the Diputación Foral de Gipuzkoa (DFG06/004), the Department of Health of the Basque Government (2005111093), and by the University of Oviedo, Obra Social Cajastur, the Fundación Roger Torné and La Fundació La Marató de TV3. NV was supported by an FPI Grant from the Spanish Ministry of Health (BES-2009-023933) and a Formación de Personal Investigador Grant for Short Research Stays in Foreign Institutions (BES-2009-023933). AA Baccarelli receives support from the Harvard School of Public Health and National Institute of Environmental Health Sciences Center for Environmental Health (R01 ES021357).The HUSC BioBank, integrated in the Andalusia Public Health System (SSPA) and the National Biobank Network, is financed by the Institute of Health Carlos III, (RD09/0076/00148) and the Regional Government of Andaluci

Lifelong Residential Exposure to Green Space and Attention: A Population-based Prospective Study

BACKGROUND: Natural environments, including green spaces, may have beneficial impacts on brain development. However, longitudinal evidence of an association between long-term exposure to green spaces and cognitive development (including attention) in children is limited. OBJECTIVES: We evaluated the association between lifelong residential exposure to green space and attention during preschool and early primary school years. METHODS: This longitudinal study was based on data from two well-established population-based birth cohorts in Spain. We assessed lifelong exposure to residential surrounding greenness and tree cover as the average of satellite-based normalized difference vegetation index and vegetation continuous fields, respectively, surrounding the child's residential addresses at birth, 4-5 y, and 7 y. Attention was characterized using two computer-based tests: Conners' Kiddie Continuous Performance Test (K-CPT) at 4-5 y (n=888) and Attentional Network Task (ANT) at 7 y (n=987). We used adjusted mixed effects models with cohort random effects to estimate associations between exposure to greenness and attention at ages 4-5 and 7 y. RESULTS: Higher lifelong residential surrounding greenness was associated with fewer K-CPT omission errors and lower K-CPT hit reaction time-standard error (HRT-SE) at 4-5 y and lower ANT HRT-SE at 7y, consistent with better attention. This exposure was not associated with K-CPT commission errors or with ANT omission or commission errors. Associations with residential surrounding tree cover also were close to the null, or were negative (for ANT HRT-SE) but not statistically significant. CONCLUSION: Exposure to residential surrounding greenness was associated with better scores on tests of attention at 4-5 y and 7 y of age in our longitudinal cohort