Research Strategy

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Research Strategy

Asthma, eczema and allergy are prevalent but poorly understood welfare diseases

The COPSAC study with its translational clinical research approach based on long-term studies of birth cohorts with deep phenotyping and exposure assessment, combined with genotyping and sequencing of the microbiome, insight into the genetic regulation of basic biological processes, and state-of-the-art systems biology methods holds the promise to improve our understanding of the processes causing disease in individual patients and the interaction between heredity and environment. Identification of the environmental factors that promote or protect against future disease raise realistic hope of prevention. This may provide the basis for the development of novel diagnostic tests, identification of molecular drug targets and the possibility of individualized treatment. This research program will eventually have significant effect on public health, as these diseases affect between one third to one fifth of all families in westernized countries.
Read more about the ‘COPSAC Vision’

Aims

The aim of COPSAC is to understand the origins of asthma, eczema and allergy in young children; and to translate this into clinical practice to improve disease prevention, diagnosis and treatment. It aims to identify endotypes of disease, defined by disease mechanism, and specifically it wants to understand the impact of the early human microbiome and maternal diet on disease development, and the interaction between such exposures and the genome and its effect on the early immune maturation.

Hypotheses

Asthma, eczema and allergies represent several specific endotypes, each associated with divergent underlying molecular mechanisms, distinct clinical features and individual treatment responses. Identifying these endotypes is essential for establishing effective preventive measures and determining appropriate individualized treatment. The diseases are programmed in the early life as the results of complex gene-environment interactions. The early human microbiome is an important environmental exposure, where an unbalanced composition may cause deregulation of the immature immune system leading to a trajectory towards the development of asthma, eczema and allergy, as well as other welfare diseases. Protective factors in maternal diet during pregnancy influence maturation and regulation of neonatal immune responses directly or through modification of the mucosal microbiome and provide an opportunity for preventive supplementation in pregnancy.

Research Strategy

The backbone of the COPSAC research strategy is longitudinal clinical studies of pregnancy and birth cohorts with deep phenotyping in disease and health and objective measurements of the exposome. COPSAC is de facto the health center for approximately 1,100 families who attend the clinic regularly and for acute symptoms. Clinical assessments, diagnoses and treatments are more difficult and imprecise in infants and young children than later in life, and information collected from community doctors and hospital records are of very low accuracy and precision. Therefore, COPSAC cohort studies of pregnant women and their children were planned as longitudinal clinical monitoring of symptoms, objective end-points and environmental exposures at a clinical research site with a standardised approach to diagnosis and treatment. Deep phenotyping allows new endotyping of these heterogeneous diseases and is a prerequisite to understanding the interactions between the genome, the exposome and the diet driving immune maturation towards these diseases.

Endotyping

The traditional disease classifications are symptom-driven based on a common symptom pattern but covering a number of different disease mechanisms. In contrast, an endotype is a subtype of disease defined by a molecular mechanism or by a treatment response. Asthma and related disorders are likely to represent several specific endotypes, each associated with distinct clinical features, divergent underlying molecular mechanisms, and individual treatment responses. Deep phenotyping in disease and health is needed to define the range of endotypes currently lumped together. This requires clinical data describing the disease continuum between disease and health instead of the traditional research on dichotomised disease definitions. It also requires longitudinal data increasing the temporal resolution of disease phenotypes and an understanding of the age-specific endotypes. By increasing the resolution of phenotyping from initiation, through propagation, to the onset of chronicity, COPSAC will be better placed to define clearer interactions between genetic susceptibility, environmental influence, and immune deviation in the transition from origins to chronicity. The expanding genetic information has presented the exciting perspective that the traditional clinical symptom-driven diagnostic classification may need to be revised. It is conceivable that by reversing the logic of genetic associations, we may redefine disease entities.

The Genome

Asthma, eczema and allergy are inheritable diseases and gene-environmental interactions are essential determinants of disease development. Human genomic research has recently provided insight into the genetic variants that cause asthma, eczema and allergy, and this has led to breakthroughs in the understanding of the aetiology and architecture of these traits. These disorders generally cluster on epithelial genes and genes affecting immunity, and importantly, this shows that different genes cause asthma, eczema and allergy. COPSAC pioneered genome-wide scans in the full birth cohort more than five years ago and has since contributed in the discovery of important genetic risk variants, such as: Filaggrin (FLG), a non-functional mutation in the filaggrin gene and a common risk factor for eczema. It is associated with an epithelial barrier defect, causing water loss through the skin and susceptibility to microbes, allergens, and toxic molecules.
DENND1B was discovered in one of the first genome-wide association studies (GWAS) of childhood asthma and may play a role in the adaptive immune response. Genes controlling the epithelial barrier of the airways was demonstrated by COPSAC in a GWAS study of severe asthma exacerbations in early childhood.
Meta-analysis of genome-wide data COPSAC is leading the asthma and atopy working group within the EAGLE (Early Genetics and Lifecourse Epidemiology).

The Human Microbiome

The microbiome inhabits the surfaces of the body, interfacing between the organism and its environment, and this silent organ has a complex reciprocal relationship with its host. The host-microbiome interaction is a complex bidirectional mechanism, as the microbes have the ability to modulate the epithelial barrier, mucosal immunity and immunological homeostasis. Given the right circumstances, the microbiome acts as a protector, while in chronic disease and in certain genetic phenotypes resulting in a barrier deficit, the microbes have the potential to cause or maintain disease. Thus, the microbiome may be a true intermediary in the interaction between the organism and its environment. COPSAC has found an increased risk of asthma in children of mothers who used antibiotics during third trimester of pregnancy and also found an increased risk of asthma in children born by Caesarean section, in agreement with other scientists. Both observations are compatible with a role of the microbiome in the disease origins. One of the most notable COPSAC discoveries has been the association between specific bacterial colonisation of the airways in neonates at one month, and development of asthma later in life. Recently, COPSAC used DNA-technology to demonstrate that limited diversity of the non-cultivable gut flora in neonates of its birth cohort was associated with increased risk of allergy at school age. The next-generation high-throughput sequencing techniques allow culture independent identification of ‘fingerprints’ of the complete microbiome. This will bring new insights into the mechanisms affecting the early immune function.

The Diet

Lifestyle changes in western countries have, among other changes, caused the insufficient intake of vitamin D and marine n-3 polyunsaturated fatty acids (n-3 PUFA). Insufficient vitamin D levels has been associated with risk of asthma, and COPSAC has found evidence of a link between low levels of vitamin D and an increase in asthma. Likewise, low levels of n-3 PUFA has been associated with increased risk of asthma. A randomized controlled trial suggested that a supplement of n-3 PUFA for pregnant mothers led to significant reduction in adolescent asthma. COPSAC chose to study key-dietary components through dietary intervention. COPSAC has performed a randomized, double-blind, controlled, factorial designed study with supplements of vitamin D and n-3 PUFA during 3rd trimester of pregnancy in a birth cohort of 700 pregnant women. Supplementation of these central dietary components will allow us to obtain higher separation between high and low exposure, and consequently reveal any possible effect on health outcome.

The Immune Maturation

The airway mucosal immunity is important in the study of gene-environmental interactions in early life, such as the immune response to the bacterial colonization of the neonatal airways. COPSAC therefore developed a method of harvesting undisturbed airway mucosal lining fluid from newborns aiming to characterize the immune and inflammatory signals at this interface between airway epithelium and environment. Analyzing the immune signatures in airway mucosal lining fluid in the unselected birth cohort of 700 asymptomatic newborns has provided insight into mechanisms affecting the early immune function. Neonates colonized with pathogenic bacteria in the upper airways exhibited a significant general up-regulation of their local immune signature. It seems more likely that such general up-regulation of immune mediators is a reaction to bacteria, than vice versa, supporting a role of the microbiome as an important trigger of asthma.

Beyond Asthma

The COPSAC research strategy focusing on the gene-environmental interactions determining immune maturation in early life is unlikely to be pivotal only in the origins of asthma, eczema and allergy. Such early gene- environment interactions with long-term effects on immune regulation may also cause, or contribute, to other lifestyle disorders including obesity, type-one diabetes, inflammatory bowel disease and others. Asthma, eczema and allergy represent a sensitive model of such welfare diseases. Because of their high prevalence in the first years of life asthma, eczema and allergies are easier to study compared to other welfare diseases that develop later in life with a longer lag time between the causative mechanisms and symptom debut. Both the microbiome and early nutrition seems to be important factors also for growth, bone mineralization, neurological development and other lifestyle disorders. The Rich data in COPSAC provide a unique resource also to study other health outcomes and well-fare diseases, and it may provide knowledge on shared disease mechanisms. COPSAC recently reported an association between anthropometrics of the newborn and the risk of developing asthma in childhood. COPSAC also contributed to recent discoveries of novel new genes determinant to head circumference, birth weight, birth length; infant obesity and BMI growth.

Perspectives

Evidence suggests that asthma is “the canary in the coalmine” as the earliest and most common immune disorder debuting in the first years of life as a marker preceding other more rare immune disorders with later occurrence. With a growing body of objective clinical assessment in health and disease from our two longitudinal birth cohorts, COPSAC is now in a unique position to redefine phenotypes accurately with optimal sensitivity and specificity. Ideally, this precise characterization will allow us to understand the basis for disease susceptibility and environmental influence; to offer an explanation for the heterogeneity of what is currently considered the same disease; to define disease prognosis with greater accuracy; to refine and to individualize treatment for optimal therapeutic safety and efficacy. COPSAC employs advanced bioinformatics and state-of-the-art systems biology approaches and chemometrics to optimize the value of these multi-dimensional data. By combining these research areas, scientists will learn how the gene-diet- microbiome interaction influences the immune maturation in early life and the development of disease. Genetic sequencing of the DNA from COPSAC’s cohorts, in international collaborations, provides insights into the genetic underpinnings of lifestyle diseases. Full sequencing of the samples of the microbiome from the birth cohorts will provide a cutting-edge resource to study the role of the early microbiome in immune maturation and disease development. Eventually, this holds promise that manipulation of resident microbial communities may provide preventive strategies. Intervention with dietary supplements will add to our understanding of the inter- actions between genetics, microbiome, diet and lifestyle diseases including asthma, eczema, and allergy, but also growth, obesity, bone mineralization and early neurological development. The human microbiome and the diet are possible foci for intervention, aiming to maintain good health in the general population.

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CHRONIC INFLAMMATORY DISEASES BEGINS IN EARLY LIFE

Research Strategy

Research Strategy

Asthma, eczema and allergy are prevalent but poorly understood welfare diseases

Aims

Hypotheses

Research Strategy

Endotyping

The Genome

The Human Microbiome

The Diet

The Immune Maturation

Beyond Asthma

Perspectives

CONTACT