ROLE OF ALLERGIC SENSITIZATION, FILAGGRIN VARIANTS, AND DNA

Background: Allergic disorders, including eczema, asthma, and rhinitis, have emerged as a global public health concern due to their elevated prevalence and the associated clinical morbidity. Environmental, immunologic, and genetic factors have been implicated in the pathogenesis of allergic disorders. Allergic sensitization (representing deviated immune responses) and filaggrin gene (FLG) variants (leading to dysfunctional epidermal barrier) have shown to be common predisposing factors in the development of allergic disorders. However, there is a lack of knowledge on their joint effects on the development of single and multiple (coexistence) allergic disorders. More recently, epigenetic mechanisms, such as DNA methylation, have emerged as potentially important factors in the development of such complex diseases; however, the extent to which DNA methylation associates with allergic disorders is unclear. Objectives: This dissertation sought to (i) determine whether eczema and/or allergic sensitization is an effect modifier of the association between ‘FLG variants and asthma’ and ‘FLG variants and rhinitis’, (ii) test whether FLG variants and allergic sensitization jointly predispose to the comorbidity of eczema, asthma and rhinitis, and (iii) examine associations between DNA methylation across the epidermal differentiation complex (EDC) genomic region with eczema status. Methods: The Isle of Wight (IOW) birth cohort, a population-based sample of 1,456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10, and 18 years. Repeated measurements of eczema, asthma, rhinitis, and allergic sensitization (documented by skin prick tests) were available for all follow-ups. FLG variants R501X, 2282del4, and S3247X were genotyped in 1,150 participants. Logbinomial regression models were applied to test for associations and statistical interactions on multiplicative scale. On the other hand, DNA methylation was measured in a subsample (n = 367) of the IOW participants at age 18 years (discovery cohort) and in two semi-independent samples (replication cohorts I and II). Associations between eczema status and DNA methylation were assessed using linear regression. Results: FLG variants were associated with increased risk of asthma and rhinitis. Both eczema status (RRinteraction = 1.96, Pinteraction = 0.006) and allergic sensitization (RRinteraction= 1.58, Pinteraction = 0.013) modified the association between FLG variants and asthma, but not the association with rhinitis. The combined effect of both risk factors increased the risk of coexisting “eczema and asthma” (RR = 13.67, 95% CI: 7.35 – 25.42), “asthma andrhinitis” (RR = 7.46, 95% CI: 5.07 – 10.98), and “eczema, asthma, and rhinitis” (RR =23.44, 95% CI: 12.27 – 44.78). On the other hand, Differential DNA methylation of CpG site cg12048339 (located within promoter of S100A6 gene) was associated with eczema specifically among female participants of all study cohorts; whereas, aberrant DNA methylation of cg10959711 (located within promoter of S100A11 gene) associated with eczema among male participants in all study samples. Conclusions: Allergic sensitization and eczema modulated the association between FLG variants and asthma, but not rhinitis; implying that the mechanisms and pathways through which FLG variants predispose to increased risk of asthma and rhinitis may be different. Moreover, the coexistence of allergic disorders is frequent and allergic sensitization and FLG variants jointly increased risk of allergic comorbidities, which may represent more severe and complex clinical phenotypes. Results of an exploratory investigation demonstrated that DNA methylation of the EDC locus could be an important factor in the development of eczema in a sex-specific manner. Future studies corroborating our findings are needed

Exposure to Household Secondhand Smoke Among Adolescents in Kuwait: Results From Two School-Based Cross-Sectional Studies

INTRODUCTION: Detrimental effects of secondhand smoke (SHS) exposure are well established; however, data on SHS exposure among adolescents in Kuwait are lacking. Hence, this study sought to estimate the prevalence of household SHS exposure among two samples of adolescents in Kuwait and assess its variation by socioeconomic status and parental education level. METHODS: Data from two large school-based cross-sectional studies were analyzed. Adolescents attending public middle (n=3864; aged 11-14 years) and high (n=1959; aged 14-19 years) schools throughout Kuwait were enrolled in 2016-2017, and parental self-reported household SHS exposure was ascertained. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (APRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Overall, 45.8% (1755/3836; 95% CI: 44.2-47.3%) of the enrolled middle school students and 51.6% (998/1936; 95% CI: 49.3-53.8%) of the enrolled high school students were exposed to household SHS. Among middle and high school students, the prevalence of household SHS exposure increased as maternal/paternal education level and family income decreased. Among middle school students, paternal educational attainment of middle school or less compared to bachelor\u27s degree or higher was associated with 1.60 times (95% CI: 1.44-1.79) higher household SHS exposure. Similarly, in the sample of middle school students, the prevalence of household SHS exposure significantly increased from 35.8% among children from families reporting the highest household income to 50.5% among children from families with the lowest reported household income (p-trend\u3c0.001). CONCLUSIONS: Household SHS exposure is substantially high among adolescents in Kuwait. Enrolled adolescents from families with low socioeconomic status or with low parental education level have the highest household SHS exposure. These findings highlight the need for national comprehensive tobacco control policies and increasing parental awareness of the impact of SHS exposure on children

Sex Differences in the Association of Sibship Size and Position in Sibship with Lipid Profile During Adolescence: A Cross-Sectional Study

Background. Epidemiologic studies have reported associations of sibship size and position of the child in the sibship with multiple health outcomes, including adiposity and diabetes. However, little is known about sibling effects on lipids. Hence, this study sought to evaluate associations of the number of total, older, and younger siblings with lipid profile among adolescents. Methods. In a cross-sectional study among high school students aged 14 to 19 years, lipid levels were measured in capillary blood. Parents reported the number of siblings (total, older, and younger). Geometric means of lipids were calculated, and linear regression was used to estimate the ratio of geometric means (RoGM) and 95% confidence intervals (CI). Analyses were sex stratified. Results. Of the total study sample (n = 1,584), 758 (47.9%) were boys and 826 (52.1%) were girls, with median age of 16.0 years. Total cholesterol (TC) was lower by 8% (adjusted-RoGM = 0.92, 95% CI: 0.88–0.96) among boys with ≥3 older siblings compared to those with no older siblings. Similarly, boys with ≥3 younger sibling compared to those with no younger siblings had reduced TC by 7% (adjusted-RoGM = 0.93, 0.87–0.99). Moreover, an increased number of total siblings (≥4 vs. 0/1: adjusted-RoGM = 0.80, 0.67–97) and older siblings (≥3 vs. 0: adjusted-RoGM = 0.90, 0.82–0.98) were associated with reduced low-density lipoprotein cholesterol (LDL-C) among boys. Similarly, lower levels of triglycerides (TG) were seen among boys with ≥3 older siblings compared to those with no older siblings (adjusted-RoGM = 0.87, 0.78–0.96). A higher number of younger siblings was associated with increased high-density lipoprotein cholesterol (HDL-C) among boys (≥3 vs. 0: adjusted-RoGM = 1.08, 1.01–1.17). Sibship characteristics were not associated with lipids among girls. Conclusions. Increased number of total, older, and younger siblings were associated with favorable lipid profiles among adolescent boys, but not girls. Mechanisms underlying these associations need further investigations

Exposure to household secondhand smoke among adolescents in Kuwait: Results from two school-based cross-sectional studies

INTRODUCTION: Detrimental effects of secondhand smoke (SHS) exposure are well established; however, data on SHS exposure among adolescents in Kuwait are lacking. Hence, this study sought to estimate the prevalence of household SHS exposure among two samples of adolescents in Kuwait and assess its variation by socioeconomic status and parental education level. METHODS: Data from two large school-based cross-sectional studies were analyzed. Adolescents attending public middle (n=3864; aged 11-14 years) and high (n=1959; aged 14-19 years) schools throughout Kuwait were enrolled in 2016-2017, and parental self-reported household SHS exposure was ascertained. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (APRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Overall, 45.8% (1755/3836; 95% CI: 44.2-47.3%) of the enrolled middle school students and 51.6% (998/1936; 95% CI: 49.3-53.8%) of the enrolled high school students were exposed to household SHS. Among middle and high school students, the prevalence of household SHS exposure increased as maternal/paternal education level and family income decreased. Among middle school students, paternal educational attainment of middle school or less compared to bachelor's degree or higher was associated with 1.60 times (95% CI: 1.44-1.79) higher household SHS exposure. Similarly, in the sample of middle school students, the prevalence of household SHS exposure significantly increased from 35.8% among children from families reporting the highest household income to 50.5% among children from families with the lowest reported household income (p-trend<0.001). CONCLUSIONS: Household SHS exposure is substantially high among adolescents in Kuwait. Enrolled adolescents from families with low socioeconomic status or with low parental education level have the highest household SHS exposure. These findings highlight the need for national comprehensive tobacco control policies and increasing parental awareness of the impact of SHS exposure on children

Time Trends of Overweight and Obesity Among Schoolchildren in Kuwait Over a 13-Year Period (2007-2019): Repeated Cross-Sectional Study

Objectives: This study aimed to examine age-specific trends in the prevalence of overweight and obesity in schoolchildren in Kuwait over a 13-year period (2007 to 2019) using the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC) and the International Obesity Taskforce (IOTF) definitions. Design: Using cross-sectional approach, Kuwait Nutrition Surveillance System (KNSS) objectively measured weight and height of schoolchildren over a 13-year period. Log-binomial regression models were used to examine age-specific trends of obesity and overweight over the study period. Setting: Public primary, middle, and high schools in all provinces of Kuwait. Participants: Schoolchildren aged 5-19 years (n 172 603). Results: According to the WHO definition, the prevalence of overweight and obesity in schoolchildren respectively increased from 17.73% and 21.37% in 2007 to 20.19% and 28.39% in 2019 (P for trend\u3c0.001). There is evidence that the obesity in females (but not males) has levelled off in the period 2014-2019 according to the three definitions of obesity, which is corroborated by a similar trend in the mean of BMI-for-age Z score. Conclusion: The prevalence of obesity and overweight in schoolchildren in Kuwait has risen over the last 13 years and trends are similar across all definitions. Obesity is no longer increasing at the same pace and there is evidence that the prevalence of obesity in females has plateaued. The current level of childhood overweight and obesity is too high and requires community-based and school-based interventions

Sex Differences in the Association of Sibship Size and Position in Sibship with Lipid Profile during Adolescence: A Cross-Sectional Study.

Background: Epidemiologic studies have reported associations of sibship size and position of the child in the sibship with multiple health outcomes, including adiposity and diabetes. However, little is known about sibling effects on lipids. Hence, this study sought to evaluate associations of the number of total, older, and younger siblings with lipid profile among adolescents. Methods: In a cross-sectional study among high school students aged 14 to 19 years, lipid levels were measured in capillary blood. Parents reported the number of siblings (total, older, and younger). Geometric means of lipids were calculated, and linear regression was used to estimate the ratio of geometric means (RoGM) and 95% confidence intervals (CI). Analyses were sex stratified. Results: Of the total study sample (n = 1,584), 758 (47.9%) were boys and 826 (52.1%) were girls, with median age of 16.0 years. Total cholesterol (TC) was lower by 8% (adjusted-RoGM = 0.92, 95% CI: 0.88-0.96) among boys with ≥3 older siblings compared to those with no older siblings. Similarly, boys with ≥3 younger sibling compared to those with no younger siblings had reduced TC by 7% (adjusted-RoGM = 0.93, 0.87-0.99). Moreover, an increased number of total siblings (≥4 vs. 0/1: adjusted-RoGM = 0.80, 0.67-97) and older siblings (≥3 vs. 0: adjusted-RoGM = 0.90, 0.82-0.98) were associated with reduced low-density lipoprotein cholesterol (LDL-C) among boys. Similarly, lower levels of triglycerides (TG) were seen among boys with ≥3 older siblings compared to those with no older siblings (adjusted-RoGM = 0.87, 0.78-0.96). A higher number of younger siblings was associated with increased high-density lipoprotein cholesterol (HDL-C) among boys (≥3 vs. 0: adjusted-RoGM = 1.08, 1.01-1.17). Sibship characteristics were not associated with lipids among girls. Conclusions: Increased number of total, older, and younger siblings were associated with favorable lipid profiles among adolescent boys, but not girls. Mechanisms underlying these associations need further investigations

Interactive effect of STAT6 and IL13 gene polymorphisms on eczema status: results from a longitudinal and a cross-sectional study

BACKGROUND: Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13, and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk.METHODS: Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema.RESULTS: Under a dominant genetic model, the interaction term [IL13 (rs20541) x STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted Pinteraction = 0.046; PAPA: Pinteraction = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 -- 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 -- 3.12; P = 0.002) in the PAPA study population.CONCLUSIONS: Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis)

Sleep Patterns, Insomnia, and Well-Being Among Female High School Students: A Population-Based Study

Background and Objective The role of insomnia in the well-being of school children has not been sufficiently examined in the literature. We aimed to explore the prevalence of clinical insomnia and its relationship to the health-related quality of life among female high-school students. Methods In a cross-sectional study in 2018, 300 students from five female high-schools in the Kurdistan Region were randomly included, regardless of age and other socio-demographic characteristics. The Personal Wellbeing Index, General Health Questionnaire–12, and Insomnia Severity Index were used to measure the personal and general well-being, and insomnia of school children, respectively. Results The students were categorized into short sleepers (2.0%), normal sleepers (51.0%), and long sleepers (47.0%), and age range is 14–19 years (mean: 16.22 years). The mean value of general well-being and insomnia severity was 6.89 and 11.42, respectively. We found that 25.0% of the students had no clinically significant insomnia, 47.7% had subthreshold insomnia, 24.0% had clinically moderate insomnia, and 3.3% had clinically severe insomnia. The mean value of the personal well-being of students was 7.91 out of 10. The mean value of personal well-being was significantly lower among students with more severe insomnia. The mean values of personal well-being were 8.61 (no clinically significant insomnia), 7.87 (subthreshold insomnia), 7.49 (clinically moderate insomnia), and 6.91 (clinically severe insomnia). The worse sleep situations and smoking were the main independent controlling factors for lower personal well-being. Conclusions The study documented that female students are at risk of being clinical insomniacs, and are at risk of the development of lower well-being

Epistasis between FLG and IL4R genes on the risk of allergic sensitization: results from two population-based birth cohort studies

Immune-specifc genes as well as genes responsible for the formation and integrity of the epidermal barrier have been implicated in the pathogeneses of allergic sensitization. This study sought to determine whether an epistatic efect (gene-gene interaction) between genetic variants within interleukin 4 receptor (IL4R) and flaggrin (FLG) genes predispose to the development of allergic sensitization. Data from two birth cohort studies were analyzed, namely the Isle of Wight (IOW; n=1,456) and the Manchester Asthma and Allergy Study (MAAS; n=1,058). In the IOW study, one interaction term (IL4R rs3024676×FLG variants) showed statistical signifcance (interaction term: P=0.003). To illustrate the observed epistasis, stratifed analyses were performed, which showed that FLG variants were associated with allergic sensitization only among IL4R rs3024676 homozygotes (OR, 1.97; 95% CI, 1.27–3.05; P=0.003). In contrast, FLG variants efect was masked among IL4R rs3024676 heterozygotes (OR, 0.53; 95% CI, 0.22–1.32; P=0.175). Similar results were demonstrated in the MAAS study. Epistasis between immune (IL4R) and skin (FLG) regulatory genes exist in the pathogenesis of allergic sensitization. Hence, genetic susceptibility towards defective epidermal barrier and deviated immune responses could work together in the development of allergic sensitization