Centre of Statistics and its Applications

Funder

Organizational Unit

Publications

Publication . Chora, Joana Rita; Alves, Ana Catarina; Mariano, Cibelle; Rato, Quitéria; Antunes, Marília; Bourbon, Mafalda

Background/Objectives: Incidence of cardiovascular disease (CVD) is increasing in low- and middle-income countries because of changing lifestyles. Since dyslipidaemia is a major independent cardiovascular risk factor, its correct identification is critical to implement specific interventions for CVD prevention. This study aimed to characterise the lipid profile of the Portuguese population. Methods: Overall, 1688 individuals from the general population (e_COR study, 2012-2014) were included. Population-specific percentiles for ten lipid biomarkers were estimated by bootstrapping methods to ensure national representativity. Statistical analyses were performed using RStudio. Results: The 50th percentile estimated for total cholesterol (TC), LDL-C, and non-HDL-C are similar to scientific societies recommended values for the general (low or moderate risk) population. National prevalence of having lipid parameters above recommended values was 64.6%, 66.9%, 51.3%, 68.9%, 17.8%, and 21.1% for TC, LDL-C, apoB, non-HDL-C, triglycerides, and Lp(a), respectively; these values are generally higher in men and increasing with age, except for Lp(a). A high prevalence of severe dyslipidaemia (>90th percentile) was identified, highest for small dense LDL-C (31.3%), apoB (30.4%), and LDL-C (30.3%). The national prevalence of CVD events was 5%. Three individuals were genetically identified with familial hypercholesterolemia, a high CVD risk condition. Conclusions: We provide for the first-time lipid biomarker percentiles for the general Portuguese population. Our results highlight that hypercholesterolemia is a neglected cardiovascular risk factor with over half of the population with TC, LDL-C, and apoB above recommended values. Since hypercholesterolemia is a modifiable risk factor, strategies to increase adherence to changes in lifestyle habits and medication need to be urgently discussed.

2024-11Journal article

Open access

Association between the adrenoreceptor β2 gene and pediatric asthma severity – a study of the PACMAN cohort

Publication . Caleiro, Maria Leonor; Soares, Patricia; Antunes, Marilia

"Pharmacogenetics of Asthma medication in Children: Medication with Anti-Inflammatory effects" (PACMAN) is an observational retrospective pharmacy-based study carried out in 2009, in the Netherlands, aiming to investigate the effects of genetic variation on treatment response to asthma medication in children and to identify (profiles of) SNPs that characterize response phenotypes. Data on respiratory symptoms and medication use, including medication type and amount, was collected from pharmaceutical records of asthmatic children and data on the children’s sex, age, genetic traits, and ethnicity. We aimed to assess the association between asthma severity and the Arg16Glu polymorphism of the β2 adrenoreceptor gene (ADRB2). This gene is expressed in bronchial muscle cells, which is involved in the physiological response of the airway response and has been associated with clinical drug response and asthma exacerbations. We used the PACMAN data and considered the dispensing of oral corticosteroid prescriptions as a proxy of the disease severity since corticoids are commonly used in uncontrolled asthmatic states (exacerbations). We considered two different genetic models – additive and genotypic, which can be translated for analysis purposes into a numeric format, corresponding to the number of copies of the minor allele, and categorical (each genotype representing a category), respectively. We used models of the class of the Generalized Linear Mixed Models for count data with excess of zeros, namely zero-inflated and hurdle models, considering a Negative Binomial distribution to account for overdispersion. Both models included the polymorphism in the zero and count components and were adjusted for children’s baseline characteristics. In both approaches to deal with the excess of zeros, a significant effect of the polymorphism was found only in the binary component of the models. In the count component, only sex and age showed a significant effect. This points towards the existence of an effect of the polymorphism in the presence of asthma exacerbations, with not shown effect in the frequency of OCS prescription.

2023-06Conference object

Open access

Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder

Publication . Santos, João Xavier; Sampaio, Pedro; Rasga, Célia; Martiniano, Hugo; Faria, Clarissa; Café, Cátia; Oliveira, Alexandra; Duque, Frederico; Oliveira, Guiomar; Sousa, Lisete; Nunes, Ana; Moura Vicente, Astrid

Early-life exposure to air pollutants, including ozone (O3), particulate matter (PM2.5 or PM10, depending on diameter of particles), nitrogen dioxide (NO2) and sulfur dioxide (SO2) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM2.5, PM10 and NO2 to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM2.5 and PM10 above the admissible threshold. A higher clinical severity was associated with higher exposure to PM2.5 (p = 0.001), NO2 (p = 0.011) and PM10 (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM2.5 exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05–1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00–1.15) and for PM10 (p = 0.02; OR = 1.07, 95%CI: 1.01–1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of earlylife exposure to PM in ASD clinical severity.

2023-04-05Journal article

Open access

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

Publication . Santos, João Xavier; Rasga, Célia; Marques, Ana Rita; Martiniano, Hugo; Asif, Muhammad; Vilela, Joana; Oliveira, Guiomar; Sousa, Lisete; Nunes, Ana; Vicente, Astrid M.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

2022-05-19Journal article

Open access