Relationship of atopic dermatitis with obesity and its related inflammatory metabolic disturbances in an adult general population cohort

Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant patient and population burden. It has been observed that obesity is associated with a higher risk of AD. However, the underlying mechanisms are not clear. The purpose of this thesis is to assess the relationship of AD and obesity in a general adult population cohort and explore possible underlying mechanistic links. Specifically, there are five different aims to determine epidemiological associations, skin physiology differences, skin microbiome diversity, serum inflammatory biomarkers profile and genomic associations between AD and obesity. These are specifically to address the various hypotheses based on our current understanding of AD’s pathophysiological mechanisms. Participants of the Health for Life in Singapore (HELIOS) study cohort, aged 30 to 85 years old from the general population, were included in the analysis. Participants were screened for AD using the modified UK Working Party criteria and obesity classified according to anthropometric, bio-impedance and dual x-ray absorptiometry measures. Skin physiology parameters such as trans epidermal water loss (TEWL), skin surface moisture and pH were also measured for all participants. In addition, skin microbiome profiling and serum inflammatory biomarkers proteomics analysis were performed in 300 selected Chinese participants (150 AD participants age and gender matched in a 1:1 ratio with healthy controls). Genetic associations and the concept of Mendelian randomisation (MR) were also used to explore causal relationship between obesity, and AD using genetic data published in public domain. Finally, analysis was performed to integrate results from the skin microbiome and serum proteomic studies to evaluate interactions between the various omics platforms. A total of 5560 participants were recruited from initiation till January 2020. About 8.8% of participants had AD while 40.2% were overweight or obese. Participants with higher visceral fat mass were more likely to have AD after adjusting for age, gender and ethnicity (Odds Ratio (OR): 1.52; p=0.028). Skin physiology, skin microbiome and serum proteomic profile related to AD were found to be significant with increasing body mass index (BMI). Obese participants (BMI ≥ 30 kgm-2 had a significantly higher trans-epidermal water loss (TEWL) values (Beta=0.059 p < 0.001) while having a lower skin surface hydration (Beta= - 0.047 p = 0.003). Serum proteomic analysis revealed that levels of 98 specific serum biomarkers were significantly different with increasing BMI. Known biomarkers of obesity such as serum leptin and IL6 and several AD related chemokines such as CCL17, CCL20, CCL3 and CCL4 were among these significantly different serum biomarkers. The IL18 family of cytokines, previously hypothesized to play a role in initiating AD like dermatitis, were also found to be significantly elevated with increasing BMI. While the diversity of the skin microbiome was similar between the obese and the lean, there were increased proportions of Corynebacterium species, Staphylococcus hominis and Malassezia globosa and reduced proportions of Propionibacterium (Cutibacterium) acnes in participants with increasing BMI. Finally, with MR analysis, it has been observed that genetically determined increase in obesity is associated with increased risk of AD (OR of AD 1.08; p = 0.015). This study provided new evidence to improve our understanding of how obesity is associated with the risk of AD. Obesity, particularly abdominal/visceral obesity was associated with an increased risk of AD. It was established by the MR analyses that the direction of this relationship likely reflects an effect of obesity on the risk of developing AD. This was further reinforced by the observations that obese participants exhibited features of skin barrier dysfunction. Serum proteomic and skin microbiome analyses also revealed unique profile among obese participants. These findings provided basis for future studies to evaluate possible underlying mechanistic pathways of this relationship.Doctor of Philosoph