DrEoin Brennan

My group in the UCD Diabetes Complications Research Centre are interested in unraveling the complex mechanisms underpinning the pathophysiology of diabetes-associated vascular complications, including diabetes-associated atherosclerosis and kidney disease. These represent signficant burdens on individuals with long-standing diabetes mellitus. Ongoing research projects in my group include:

1. Dark-side of the genome: non-coding RNA drivers in CVD.
An estimated 97% of the human genome consists of non-protein-coding sequences. For many decades, this genetic ‘dark matter’ was written off as junk sequence with little or no relevance to the human organism or human evolution. However, as our understanding of the human genome improved, along with advances in sequencing technologies, a major shift in our understanding of genome regulation has emerged. This has led to the characterization of a diverse array of non-coding RNA (ncRNA) genes.

Atherosclerosis is a complex multifactorial disease that, despite advances in lifestyle management and drug therapy, remains to be the major cause of high morbidity and mortality rates from cardiovascular diseases (CVDs). In particular, individuals with diabetes are at an increased risk of cardiovascular disease. Atherosclerosis is characterized by the formation of lesions associated with subendothelial lipid accumulation and low-grade inflammation within arterial walls. Lipid lowering therapy (e.g. statins) has been the mainstay of cardiovascular risk reduction and prevention, resulting in atherosclerotic plaque regression as well as stabilization of high-risk plaques. Despite the success of statins, a significant proportion of statin-treated patients remain at substantial risk of CVD, and many patients cannot tolerate statins or reach acceptable LDL cholesterol levels on treatment. Therefore, on a healthcare and economic basis there is a need for innovative targets beyond LDL to make further inroads against atherosclerotic complications. One possible solution to improve the use of statins in primary prevention is to apply a stratified treatment strategy involving the tailoring of type and dosage of statin, as well as investigating drug combination therapies alongside statins. Hence, a new drug class targeting atherosclerosis could synergise with statin therapy to optimise outcomes. We are now beginning to unravel the role of non-coding RNAs as important regulators of pathophysiological cellular effects in CVD. We have recently investigated the functional consequences of dual miRNA/statin therapy in human aortic smooth muscle cells, by simultaneously targeting the let-7 miRNA family. We show that targeting this miRNA networks can disrupt pro-inflammatory signalling pathways (e.g. IL-6, IL1β) in vascular cells, tissues and animal models.


Ongoing research projects in my lab include:

1. Mapping global coding/non-coding RNA responses in human carotid plaque lesions.
2. Investigating the role of let-7 miRNA in modulating vascular smooth muscle cells plasticity.
3. Multi-miRNA/statin dual therapies targeting atherosclerosis.


2. GENIE Consortium: unravelling the genetics of diabetic nephropathy.
Diabetes is responsible for a large proportion of chronic kidney disease (CKD), end-stage kidney disease (ESKD), blindness, amputation, heart disease and stroke. Tight glycemic control in type 1 diabetes or type 2 diabetes can delay or arrest the progression of microvascular complications. How hyperglycemia leads to complications, and why some patients with long-standing diabetes are relatively spared, remains largely unknown, limiting the ability to target and improve preventive strategies. Inherited variation in DNA sequence contributes to individual risk of diabetic complications. Familial aggregation of diabetic complications confirms the influence of inherited risk factors, but until recently few specific genes or variants were known. In the past few years, genome-wide association studies (GWAS) have begun to identify the genetic factors that influence diabetic kidney disease (DKD) . In a global collaboration, we founded the GEnetics of Nephropathy–an International Effort (GENIE) consortium, which found several associations with ESKD. Together with the Diabetic Nephropathy Collaborative Research Initiative (DNCRI), we have completed a much larger GWAS meta-analysis of ~20,000 samples with or without DKD in T1D. We identified 16 genome-wide significant loci, including a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a key structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies.


While these findings are encouraging, additional work is required to realize the hope placed in genetic discoveries in DKD. First, these initial results only capture a small proportion of the heritability of this phenotype, and as commonly observed with most other complex phenotypes they confer modest effects; much larger sample sizes are needed to reach the level of genetic discovery achieved for other metabolic diseases. Second, most of these genetic associations lie in non-coding regions, necessitating an assessment of regulatory mechanisms and a systematic search for the effector transcripts that mediate the genetic associations. In this quest, targeted approaches to identify low-frequency or rare variants directly altering the protein structure are needed. And third, in cases where such effector transcripts are known or highly suspected, functional validation in relevant model systems is required to prove and fully characterize the molecular mechanisms by which these genes affect DKD. Our group in UCD is developing functional pipelines to screen genetic and epigenetic candidates. We are using our established cell models, human stem cell-derived kidney organoids and in vivo model organisms such as zebrafish to interrogate the effects of modulating genes and regulatory elements identified in our ongoing work on functional DKD readouts.