Genetic Architecture, Clinical Phenotypes, and Complications of Familial Chylomicronaemia Syndrome in the United Kingdom

Abstract

Familial and multifactorial forms of hypertriglyceridaemia (HTG) are rare, heterogeneous disorders associated with substantial morbidity, particularly due to acute pancreatitis (AP) and recurrent AP (RAP). Emerging evidence also suggests an association between HTG and neurodegeneration in the presence of diabetes. This thesis investigates the genetic architecture, ethnic diversity, distinguishing features of familial and multifactorial chylomicronaemia syndromes, diagnostic strategies, and neurological consequences of HTG across different aetiologies. In the United Kingdom (UK), the genetic architecture of FCS is heterogeneous. Non-lipoprotein lipase (LPL)-FCS is common among individuals of non-European, particularly South-Asian ancestry, with Lipase maturation factor 1 (LMF1) and Glycosylphosphatidylinositol-anchored High-Density Lipoprotein-Binding Protein 1 (GPIHBP1) variants predominating in these populations. The prevalence of FCS varied across UK regions, which could reflect differences in detection rates. Individuals with FCS are at a higher risk of AP and RAP, whereas individuals with MCS, although also at risk for AP and RAP, have a comparatively lower burden of pancreatic complications and a relatively greater risk of atherosclerotic cardiovascular disease (ASCVD). The FCS score demonstrated robust performance across an ethnically diverse UK cohort. Beyond pancreatic complications, individuals with FCS had small fibre nerve damage, corneal nerve fibre loss, and cardiac autonomic dysfunction, with similar patterns observed in HTG of other aetiologies, independent of diabetes or other known causes of neuropathy. This doctoral work highlights the heterogeneous genetic and clinical landscape of severe HTG, examines the FCS score, and underscores the broader systemic and neurological complications associated with HTG.

Date of Award	28 Apr 2026
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Handrean Soran (Main Supervisor), Maryam Ferdousi (Co Supervisor), Rachelle Donn (Co Supervisor) & Rayaz Malik (Co Supervisor)