Author Identifiers

Alyce Russell
ORCID: 0000-0002-1667-7601

Date of Award

2020

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Professor Wei Wang

Second Advisor

Associate Professor Simon Laws

Third Advisor

Dr Ivo Ugrina

Fourth Advisor

Dr Michael Hunter

Fifth Advisor

Dr Jennie Hui

Abstract

The use of immunoglobulin G N-glycomics to study chronic non-communicable disorders and other complex phenotypes emerged following the Human Genome Project. The consortium discovered that most phenotypes were too complex to be explained by genetics alone. Thus, the biological importance of epigenetics was recognised; heritable modifications to gene expression rather than the genome itself. Nglycosylation is a form of epigenetic regulation known as a post-translational modification. It stabilises the immunoglobulin G structure and alters downstream responses elicited by the antibody and is extensively studied as a candidate biomarker in the post-genomic era.

The N-glycosylation of immunoglobulin G itself is complex, with glycosyltransferases and glycosylhydrolases influencing the biosynthesis of the branching structures. Moreover, altered N-glycosylation is associated with an array of phenotypes. Our research team considers the N-glycome as an interphenotype of subclinical health status; an amalgamation of genetic predisposition, environmental exposure and health behaviours over the life-course. This underscores the value of the immunoglobulin G N-glycome in the shift towards predictive, preventive and personalised medicine. However, there is still considerable heterogeneity even among individuals with the same disorder, which warrants further investigation to improve precision of the biomarker.

This thesis aimed to determine the degree the underlying genome and clinical factors explain the heterogeneity of the immunoglobulin G N-glycome. I used a subset of the cross-sectional population-based Busselton Healthy Ageing Study (n=637, 54.0% female, 46.2 to 68.3 years of age). The participants represent a highly homogenous population (99% identify as Caucasian with Caucasian parents), and all noninstitutionalised ‘Baby-boomers’ (adults born between 1946 and 1964) listed on the electoral roll in the City of Busselton between 2010 and 2016 were eligible to participate.

Three studies were designed to address the thesis aim. Firstly, previous IgG-related genetic polymorphisms were successfully validated using association studies of the N-glycan features. Secondly, next-generation sequencing of leucocyte mRNA was modelled with the N-glycome. Differentially expressed genes were identified, as well as the implementation of a multivariate model to integrate the ‘omics datasets. Finally, clinical factors and health behaviours were modelled using various statistics, extending on previous research. Collectively, however, the three studies evidenced potential utility of the immunoglobulin G N-glycome in identifying cardiometabolic disorders and associated risk factors. A polymorphism with genome-wide significance had pleiotropy to type 2 diabetes mellitus. Additionally, the clinical studies correlated cardiometabolic risk factors (central adiposity, blood pressure, C-reactive protein, triglycerides, fasting blood glucose and insulin) as well as the health behaviours excessive alcohol consumption and current smoking status (both associated with increased risk of cardiometabolic disorders) to an increase in pro-inflammatory immunoglobulin G glycoforms, thus potentiating involvement of immunoglobulin G in the pathophysiology of these phenotypes. Overall, this data-driven thesis identified several factors explaining immunoglobulin G N-glycome heterogeneity. These should be considered in subsequent translational research, to improve the precision of this complex biomarker when stratifying populations of interest.

Access Note

Sections 4.2, 5.2 and 5.2 are not available in this version of the thesis

Available for download on Thursday, March 10, 2022

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