Beyond genome wide association studies in celiac disease by exploring the non-coding genome

Rodrigo de Almeida

Beyond genome wide association studies in celiac disease by exploring the non-coding genome

Vertaalde titel van de bijdrage: De volgende stap na genoom-wijde associatie studies: de rol van het niet-coderende genoom

Rodrigo de Almeida

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Coeliakie is de meest voorkomende voedselintolerantie wereldwijd. Coeliakie patiënten ontwikkelen een ernstige darm ontsteking als reactie op gluten die voorkomen in granen die worden gebruikt in het Westerse dieet. Er wordt geschat dat Coeliakie bij 1% van de bevolking voorkomt, maar ook dat waarschijnlijk slechts 1 van de 8 Coeliakie patiënten correct wordt gediagnosticeerd. Daarnaast is beschreven dat >10% van de bevolking aan glutengevoeligheid lijdt, een mildere ziekte dan Coeliakie, en dat het voorkomen van glutengevoeligheid aan het stijgen is. De enige behandeling voor Coeliakie is het volgen van een levenslang glutenvrij dieet. Het volhouden van dit dieet is echter moeilijk en verlaagt de kwaliteit van leven van de patiënt behoorlijk. Er is daarom grote behoefte aan het verkrijgen van nieuwe inzichten in het ontstaan van Coeliakie, wat hopelijk gaat leiden tot betere diagnostische testen en behandelingsmethoden. Recente studies hebben 40 DNA varianten geïdentificeerd die bijdragen aan het ontstaan van Coeliakie. In dit proefschrift heb ik populatie-genetische methoden en kennis over moleculaire signaleringsroutes gebruikt om te onderzoeken hoe deze 40 varianten bijdragen aan Coeliakie. Ik beschrijf nieuwe functionele varianten, genen en signaleringsroutes. Een van de nieuw ontdekte genen behoort tot een recent ontdekte groep van RNA moleculen, de zogenaamde ‘long non-coding RNAs’. Een veelbelovende ontwikkeling is dat circulerende micro-RNA moleculen een nieuwe klasse van bio-markers kunnen zijn voor immuun-gemedieerde ziektes. Ik beschrijf micro-RNAs die misschien gebruikt kunnen worden als bio-markers voor Coeliakie ontwikkeling en voor het monitoren van het correct volgen van het glutenvrije dieet.

Vertaalde titel van de bijdrage	De volgende stap na genoom-wijde associatie studies: de rol van het niet-coderende genoom
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Wijmenga, Cisca, Supervisor Withoff, Sebo, Co-supervisor
Datum van toekenning	25-mrt.-2015
Plaats van publicatie	[S.l.]
Uitgever	[S.n.]
Gedrukte ISBN's	978-90-367-7718-6
Elektronische ISBN's	978-90-367-7760-5
Status	Published - 2015

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Title and contents Final publisher's version, 411 KB
Chapter 1 Final publisher's version, 1,13 MB
Chapter 2 Final publisher's version, 4,54 MB
Chapter 3 Final publisher's version, 1,07 MB
Chapter 4 Final publisher's version, 2,23 MB
Chapter 5 Final publisher's version, 3,41 MB
Chapter 6 Final publisher's version, 1,03 MB
Chapter 7 Final publisher's version, 1,67 MB
Chapter 8 Final publisher's version, 2,47 MB
AppendicesFinal publisher's version, 2,52 MB
Complete dissertationFinal publisher's version, 8,9 MB
PropositionsFinal publisher's version, 129 KB

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title = "Beyond genome wide association studies in celiac disease by exploring the non-coding genome",

abstract = "Celiac disease is the most prevalent food intolerance known. Individuals suffering from celiac disease develop a severe intestinal inflammation in response to gluten proteins that are present in the grains that form the basis of the Western diet. Although the incidence of celiac disease is 1%, it is thought that only 1 in 8 celiac patients is, in fact, diagnosed correctly. The only treatment for celiac disease is a life-long, gluten-free diet. Compliance is difficult and significantly affects the patient{\textquoteright}s overall quality of life. This all means there is an urgent need to gain a better understanding of celiac disease and its mechanisms, which we hope will lead to the development of better diagnostic tools and/or treatment options.Recent studies have identified 40 regions in the human genome that predispose to the development of celiac disease. In this thesis, I applied statistical genetics and pathway analysis methods to gain a better understanding of how the predisposing genetic factors contribute to celiac disease. I prioritize functional variants, genes and pathways affected in celiac disease, including a long non-coding RNA that is regulated by a celiac-associated genetic variant. An exciting development is that circulating micro-RNA molecules have been identified as a new class of biomarkers for immune-mediated diseases. I found microRNAs candidates that can be used as novel biomarkers for celiac disease development and to monitor a patient{\textquoteright}s adherence to the gluten-free diet. These biomarkers can be developed into useful clinical tests.",

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N2 - Celiac disease is the most prevalent food intolerance known. Individuals suffering from celiac disease develop a severe intestinal inflammation in response to gluten proteins that are present in the grains that form the basis of the Western diet. Although the incidence of celiac disease is 1%, it is thought that only 1 in 8 celiac patients is, in fact, diagnosed correctly. The only treatment for celiac disease is a life-long, gluten-free diet. Compliance is difficult and significantly affects the patient’s overall quality of life. This all means there is an urgent need to gain a better understanding of celiac disease and its mechanisms, which we hope will lead to the development of better diagnostic tools and/or treatment options.Recent studies have identified 40 regions in the human genome that predispose to the development of celiac disease. In this thesis, I applied statistical genetics and pathway analysis methods to gain a better understanding of how the predisposing genetic factors contribute to celiac disease. I prioritize functional variants, genes and pathways affected in celiac disease, including a long non-coding RNA that is regulated by a celiac-associated genetic variant. An exciting development is that circulating micro-RNA molecules have been identified as a new class of biomarkers for immune-mediated diseases. I found microRNAs candidates that can be used as novel biomarkers for celiac disease development and to monitor a patient’s adherence to the gluten-free diet. These biomarkers can be developed into useful clinical tests.

AB - Celiac disease is the most prevalent food intolerance known. Individuals suffering from celiac disease develop a severe intestinal inflammation in response to gluten proteins that are present in the grains that form the basis of the Western diet. Although the incidence of celiac disease is 1%, it is thought that only 1 in 8 celiac patients is, in fact, diagnosed correctly. The only treatment for celiac disease is a life-long, gluten-free diet. Compliance is difficult and significantly affects the patient’s overall quality of life. This all means there is an urgent need to gain a better understanding of celiac disease and its mechanisms, which we hope will lead to the development of better diagnostic tools and/or treatment options.Recent studies have identified 40 regions in the human genome that predispose to the development of celiac disease. In this thesis, I applied statistical genetics and pathway analysis methods to gain a better understanding of how the predisposing genetic factors contribute to celiac disease. I prioritize functional variants, genes and pathways affected in celiac disease, including a long non-coding RNA that is regulated by a celiac-associated genetic variant. An exciting development is that circulating micro-RNA molecules have been identified as a new class of biomarkers for immune-mediated diseases. I found microRNAs candidates that can be used as novel biomarkers for celiac disease development and to monitor a patient’s adherence to the gluten-free diet. These biomarkers can be developed into useful clinical tests.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-7718-6

PB - [S.n.]

CY - [S.l.]

ER -

Beyond genome wide association studies in celiac disease by exploring the non-coding genome

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