Approved Research
Assessing the directionality of effects between obesity, inflammation and cardiovascular and renal disease
Lay summary
We now wish to expand this scope to assess the directionality of effects between obesity, inflammation and cardiovascular and renal disease. We have now established a collaboration between Dr. Dash, Dr. paterson, Dr. Linda Hiraki and Dr. Moumita Barua. Dr. Dash a cohort of 350 patients with extreme obesity. Dr. Hiraki has a cohort of 500 paediatric and 700 adult SLE patients, while Dr. Barua has a cohort of 300 patients with focal segmental glomerulosclerosis, a known complication of obesity. The commonest genetic cause for focal segmental sclerosis is Alport syndrome.
Our preliminary data that likely deleterious variants previously associated with neuropsychiatric disease, autoimmune disease and renal disease may be increased in patients with obesity. Further inflammatory conditions such as SLE are associated with obesity and cardiovascular and renal disease, independent of established risk factors. Additionally focal segmental glomerulosclerosis is a known complication of obesity. Therefore, we will assess these associations in more detail.
1. In addition to assessing the association between coding variants in genes influencing inflammatory pathways on metabolic disease, we will assess whether coding and non-coding variants associated with inflammatory conditions such as SLE associate with cardiovascular, metabolic, neuropsychiatric and renal complications in patients with obesity. We are also interested in understanding the gene-gene effects in patients with SLE and whether they predipose to complications such as osteonecrosis, obesity and cardiovascular disease, all more common among people with SLE compared to those without.
2. Most cases of focal segmental glomerulosclerosis including Alport syndrome represent an extreme phenotype and the available evidence suggests milder forms likely exist. We aim to assess for the prevalence of variants in genes associated with Alport syndrome and focal segmental glomerulosclerosis and assess associated renal and ocular phenotypes as well as presence of comorbdities such as obesity, type 2 diabetes and cardiovascular disease. We will focus on all known genes including collagen IV related variants.
Additional Approaches
1. Test the correlation of SLE and kidney function variants individually and as a genetic risk score (GRS), in association with end-stage kidney disease and dialysis among both patients with SLE.
2. Assess the effects of these variants in patients with obesity and CKD.
3. Explore the interaction and shared effects of other complex genetic phenotypes such as obesity and cardiovascular disease, on these outcomes among people with SLE.
4. Correlate rare genetic changes in the Type IV collagen with phenotypic data including hearing loss, ocular defects and renal function tests in UK Biobank participants and whether these associate with BMI and cardiovascular disease
5. Apply a polygenic risk score (PRS) to UK Biobank participants with deleterious Type IV collagen gene variants to determine if it influences disease severity
6. Additionally we will assess whether this PRS influences risk of CKD in people with obesity.