Epidemiological investigations into chronic inflammation using the novel biomarker Glycoprotein Acetyls

Chronic inflammation describes a state of long-term inflammation where levels of acute-phase proteins and cytokines are elevated over months to years. Epidemiological studies have provided evidence for the relationship between inflammation and adverse health outcomes, ranging from mental health disorders such as depression to physical health outcomes such as cardiovascular disease and even mortality. Additionally, studies have shown that genetic and environmental factors can influence levels of chronic inflammation. Given the proven detrimental outcomes of chronic inflammation, it is a public health concern to better understand its causes and consequences. In this thesis, I investigated whether Glycoprotein Acetyls (GlycA), a novel biomarker of chronic inflammation was more stable in the short and long term compared to C-reactive protein (CRP), an acute phase protein often studied as a marker of inflammation. I also explored several potential causes and consequences of chronic inflammation (as measured by GlycA), including adverse childhood experiences (ACEs), the mental health disorder depression, depressive symptoms and levels of circulating polyunsaturated fatty acids. I used data from two UK population-based studies: the Avon Longitudinal Study of Parents and Children and; UK Biobank. Where possible, I triangulated findings from multivariable models with Mendelian randomization analyses in order to overcome biases such as confounding and reverse causation. My findings suggest that GlycA behaves similarly to the biomarker CRP in response to pro-inflammatory factors, but that it is more stable than CRP over the long-term. I found that ACEs have a pro-inflammatory effect, but that this effect appears to only emerge in mid-adulthood. Contrary to previous literature, I did not find that inflammation causally increases levels of depression, instead my findings suggest that genetically determined depression causally increases levels of GlycA. I also found that genetically determined omega-3 fatty acid levels, which are posited to reduce inflammation, causally increase levels of CRP and GlycA, although this effect attenuated to the null when controlling for genetically determined omega-6 fatty acids. Finally, I found that genetically determined omega-6 fatty acids causally increase levels of CRP and GlycA and this effect was maintained when controlling for genetically determined omega-3 fatty acids. Results from my thesis suggest that several factors that occur across the life-course can influence levels of GlycA. My findings also highlight the importance of triangulation and replication in research given that, when using GlycA as a measure of inflammation, some of my findings contradict previously published and accepted inflammation-related relationships

Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort

BACKGROUND: Adverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. METHODS: ALSPAC offspring’s total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. RESULTS: Mean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. CONCLUSION: Results suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life

Comparison of the stability of Glycoprotein Acetyls and high sensitivity C-reactive protein as markers of chronic inflammation

It has been suggested that glycoprotein acetyls (GlycA) better reflects chronic inflammation than high sensitivity C-reactive protein (hsCRP), but paediatric/life-course data are sparse. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we compared short- (over weeks) and long-term (over years) correlations of GlycA and hsCRP, cross-sectional correlations between GlycA and hsCRP, and associations of pro-inflammatory risk factors with GlycA and hsCRP across the life-course. GlycA showed high short-term (weeks) stability at 15 years (r = 0.75; 95% CI = 0.56, 0.94), 18 years (r = 0.74; 0.64, 0.85), 24 years (r = 0.74; 0.51, 0.98) and 48 years (r = 0.82 0.76, 0.86) and this was comparable to the short-term stability of hsCRP at 24 years. GlycA stability was moderate over the long-term, for example between 15 and 18 years r = 0.52; 0.47, 0.56 and between 15 and 24 years r = 0.37; 0.31, 0.44. These were larger than equivalent correlations of hsCRP. GlycA and concurrently measured hsCRP were moderately correlated at all ages, for example at 15 years (r = 0.44; 0.40, 0.48) and at 18 years (r = 0.55; 0.51, 0.59). We found similar associations of known proinflammatory factors and inflammatory diseases with GlycA and hsCRP. For example, BMI was positively associated with GlycA (mean difference in GlycA per standard deviation change in BMI = 0.08; 95% CI = 0.07, 0.10) and hsCRP (0.10; 0.08, 0.11). This study showed that GlycA has greater long-term stability than hsCRP, however associations of proinflammatory factors with GlycA and hsCRP were broadly similar