Causal relevance of inflammation to cardiovascular disease

Thesis

Cardiovascular disease (CVD) is a major cause of premature deaths and disability globally. Inflammation, the response of the immune system to damaging stimuli, was reported to contribute to CVD risk, with key inflammation-associated proteins (e.g. interleukin-6 [IL-6] signalling) targeted in recent clinical trials. I investigated whether components (IL-6 and IL-6 receptor [IL-6R]) and markers (C-reactive protein [CRP] and fibrinogen) of the IL-6 signalling were associated with CVD risk, with the aim of identifying relevant therapeutic targets for CVD.

First, using a nested case-control study design in the prospective China Kadoorie Biobank (CKB), I reported that in Chinese adults higher plasma CRP concentrations, but not plasma fibrinogen levels, were log-linearly associated with higher risks of major coronary events, ischaemic stroke (IS), and intracerebral haemorrhage (ICH). However, prior genetic studies have reported null associations of plasma CRP- associated genetic variants with CVD risk, precluding CRP as a therapeutic target for CVD.

To investigate potential therapeutic targets, I used genome-wide association studies of CRP in CKB and in Europeans to derive genetic instruments representing the IL-6R and the IL-6 ligand. The IL-6R instrument was a non-synonymous genetic mutation in the IL6R locus (rs2228145-C) and reportedly mimicked the effects of tocilizumab (an IL-6R antagonist). The IL-6 instrument was composed of three genetic variants in CKB and a single genetic variant in Europeans (rs1880241-G) near the IL6 locus. The CKB/EUR IL-6 genetic instruments were, therefore, constructed to broadly represent effects of lower IL-6 signalling. Using a two-sample Mendelian randomization approach, I showed that although the IL-6R instrument, associated with lower plasma CRP, was associated with a lower risk of coronary heart disease (CHD) phenotypes in both CKB and Europeans, there was no evidence of an association of the IL-6 instrument with CHD in either population. Additionally, on trans-ethnic meta-analysis, there was weak evidence that the IL-6R instrument was associated with a lower risk of IS and a higher ICH risk but with consistent estimates observed with the IL-6 instrument.

In conclusion, although the observational study supported the role of inflammation in CVD, the null association of the IL-6 instrument with CHD in both the Chinese and Europeans with weak evidence of lower and higher risk of IS and ICH, respectively, questions the net therapeutic value of targeting IL-6 signalling for CHD.

Authors: Karim, MA

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cardiovascular disease; IL-6; mendelian randomization; inflammation; target validation using human genetics; interleukin-6; IL-6R; genetic epidemiology
• Subjects: Genetic epidemiology; Inflammation; Mendelian randomization; Human population genetics; Cardiovascular pharmacology; Cytokines