Returning to Philadelphia, Lillias (Lily) H. Maguire, MD, brings a background in genetic investigation to the role of Director of Research, Division of Colon and Rectal Surgery at Penn Medicine.
Trained at the Perelman School of Medicine, Dr. Maguire has returned to Penn Medicine to join the Division of Colon and Rectal Surgery as the Director of Research and the Measey Surgical Faculty Career Development Endowed Professor.
A specialist whose concentrations include open and minimally invasive surgeries for colon and rectal cancers, and inflammatory bowel disease, Dr. Maguire brings an interest in genetics, acquired in part from a research interest in diverticulitis, to her role as Research Director.
Parsing the etiology, pathology and therapeutic guidelines for diverticular disease has captured the interest of gastroenterologists and surgeons for decades, if the 1229 reports published since 1964 (and listed on PubMed) are a reliable indication. Understanding the disease, its causes and risk factors, can be seen as a means to achieve a wider discernment of the general pathophysiology of colonic disease.
Diverticulitis — Who, What and When?
Diverticulitis is the inflammatory manifestation of diverticulosis, an asymptomatic disorder characterized by numerous bulb-like protuberances, or diverticula, in the wall of the sigmoid colon. Exceptionally common in older individuals, diverticulosis affects about a third of U.S. adults between the ages of 50 and 60, rising to greater than 70 percent of persons older than 80 years. Although most affected individuals will remain asymptomatic, ~5 percent will eventually develop diverticulitis and its symptoms, including left-sided pain, nausea, vomiting, constipation and diarrhea. About a third of this segment will develop complicated disease and its associated risks, including inflammation, bleeding, abscess, fistula, perforation, and obstruction. Statistically, diverticulitis is more common among men in populations younger than age 50, but more common in women in persons aged 50 or more.
The course of treatment for uncomplicated disease is typically conservative; that for complicated serious disease usually involves surgery.
Unfortunately, from this point, little else about diverticular disease — it's etiology, risk factors, prognosis, pathologic course, heritability — is incontrovertible. Recent studies have challenged elements long thought to be settled fact — including, for example, the thought that younger patients and male patients were more likely to experience a more aggressive form of diverticulitis. Suspected risk factors for the disease linked to lifestyle, including high-fat, low fiber intake, obesity, constipation, and laxative use, have either been contradicted in studies or negated by lack of evidence.
That the answers to these mysteries might lie with genetics is a new idea, Dr. Maguire said in a recent interview adds, but the weight of evidence is beginning to accrue, in part thorough her own efforts. Dr. Maguire has studied and published on the genetic risk factors, genomics and pharmacogenomics of diverticular disease.
Diverticulitis and the Genome
The understanding of diverticular pathogenetics gathered shape with the discovery about a decade ago of an association between diverticulitis and a set of diseases with well-described genetic mutations, including the Williams-Beuren and Ehlers-Danlos syndromes, Marfan's, and other disorders.
Other studies followed, including genetic epidemiology investigations in Europe, where a sharp rise in the incidence of diverticular disease among migrant populations supported a role for environment in diverticulitis, and a series of twin studies, which found an estimated heritability of 40 – 53 percent in the general population. With this new understanding of a shared etiology for the disease, investigators, including Dr. Maguire, began to focus upon the genetic architecture of diverticular disease.
In 2017, Dr. Maguire and colleagues at the University of Michigan (including Elizabeth K. Speliotes, MD, PHD, MPH, of the Department of Computational Medicine and Bioinformatics), initiated a large, genome-wide association (GWAS) clinical study to elucidate the genetic etiology of diverticulitis. In GWAS studies, whole genomic sequencing is used to identify single nucleotide polymorphisms associated with a phenotype.
Using two large data sources, the team identified 42 loci associated with diverticular disease, 39 of them novel, and with further definition of these loci, identified trends, including genes identified with connective tissue, the extracellular matrix, and intestinal motility.
Among other interesting discoveries, Dr. Maguire notes, a phenome-wide association analysis of the variants showed a shared etiology for diverticular disease, obesity, hernia, rectal and uterine prolapse and varicose veins conditions, like Ehlers-Danlos syndrome and the other earlier-noted disorders linked to diverticular disease defined by the presence of connective tissue.
Having established a genomic landscape for diverticulitis, the pallet of genetic variations could now be sifted and interpreted to render a profile of the likely contributors to the disease and its risk. To this end, Dr. Maguire is currently involved in an NIH-funded clinical research to examine risk prediction in diverticulitis through the application of polygenic risk scoring.
"Polygenic risk scoring is for common diseases where no big driver mutation exists," she explains. 'Driver' mutations appear in cystic fibrosis and hemophilia, among other diseases, and can be readily identified to arrive at individual risk predictions. Because diverticulitis is a polygenic disease, determining an individual's future risk is achieved by establishing a weighted sum of the number of risk alleles an individual carries. This value is then used to create a risk score to predict an individual's lifetime genetic risk for disease.
Dependent upon the availability of genome-wide associated study data (such as that gathered in Dr. Maguire's previous investigation) polygenic risk scores are useful in the early stages of disease to assist in diagnosis and inform treatment.
The treatments for diverticular disease range from conservative management with antibiotics and dietary interventions (e.g., fiber supplements and probiotics) for diverticulosis and mild diverticulitis, to surgery, which among persons with a history of serious disease has the object of preventing recurrence and avoiding future emergent procedures. In these described contexts, general consensus can be found for conservative therapy, but not for surgery.
"Right now, the recommendations for surgery are clear for people in crisis," Dr. Maguire says. But questions arise, she adds, with the intermediate cases, such as a 40-year-old who's had two acute flares.
In the past, two acute events were considered the tipping point for surgical intervention, and younger age was considered an indication for more aggressive surgery. While these recommendations are now considered obsolete, the inability to gauge the risk for surgery in the vast population of persons at the intermediate stage of diverticulitis remains a complex and troubling issue for colon and rectal surgeons.
Thus, among the goals of Dr. Maguire's study is to use polygenic risk scoring as a predictive tool for medical and surgical therapy, particularly for patients with complicated histories of diverticulitis and those with troubling intermediate disease.
"The point is to minimize unnecessary surgery for disease that's going to run a benign course and avoid under-treatment for patients who inevitably go on to have surgery," Dr. Maguire says. "What we'd like to be able to say to a patient is we think you're at high risk based on your score and should be thinking about surgery, or you're at low risk and don't need to worry about surgery."
A further objective for Dr. Maguire at Penn Medicine involves the creation of a bench lab to investigate the possibility of drug development for diverticulitis. At this time, drug therapy for the disorder is limited to antibiotic therapy. In recent years, two much hoped-for therapies, mesalazine, for the prevention of recurrence and rifaximin, for symptomatic relief in uncomplicated diverticular disease, have failed in clinical trials.
Dr. Maguire's interest involves the evolving field of pharmacogenomics.
"One of the targets that arose from our polygenic study was an association between diverticulitis and G-protein coupled receptors, which are the end target for about 30 percent of the pharmaceuticals on the market today," she explains. "If we could find an orphan G-protein receptor and trace down a drug to turn it on and off, it could be a major advance, especially if we could find a preventative for high-risk events and recurrence."
This effort will involve tracing down drugs and examining their downstream effects in murine models and cell lines in existing biobanks, and will be a collaborative Dr. Maguire adds. and will involve collaboration with researchers in researchers across Penn Medicine and the Perelman School of Medicine.
About Dr. Maguire
A graduate of the University of Pennsylvania School of Medicine (now the Perelman School of Medicine), Lillias H. Maguire, MD, completed a residency in general surgery at Massachusetts General Hospital in Boston, and a fellowship in colon and rectal surgery at the University of Minnesota School of Medicine in Minneapolis.
A colon and rectal surgeon, Dr. Maguire's particular clinical interests include the genomic epidemiology and determinants of diverticular disease, as well as the pharmacogenomics and management of the condition — topics about which she has published book chapters and numerous journal articles.
Board certified in colon and rectal surgery and general surgery, Dr. Maguire sees patients at Penn Colon and Rectal Surgery Perelman. She joins a strong team of board-certified, fellowship trained colon and rectal surgeons at Penn Medicine.