Akl Fahed, MD, MPH, Interventional Cardiologist at Massachusetts General Hospital and Instructor in Medicine at Harvard Medical School.

Multi-Ancestry Genetic Risk Score Shows Value of Global Collaboration in Metabolic Disease, With Akl Fahed, MD, MPH

A multi-ancestry metabolic polygenic risk score (PRS) of 20 metabolic traits from over 8.5 million individuals points to the utility of global collaboration in genetic research.

The metabolic PRS outperformed existing ones in predicting obesity and T2D across 6 ancestries, effectively identifying individuals at high risk for metabolic multimorbidity and predicting clinical outcomes, including GLP-1 receptor agonist initiation.

“We haven’t yet seen this level of integration for diabetes and obesity. However, these scores are becoming more widely available,” Akl Fahed, MD, MPH, Interventional Cardiologist at Massachusetts General Hospital and Instructor in Medicine at Harvard Medical School, said in an interview. “Many health systems are beginning to implement them, and individuals can also access them through direct-to-consumer approaches.”

The metabolic diseases, obesity, and T2D have a shared pathophysiology. Traditionally, previous polygenic risk scores focused on them separately, with study investigators noting that the single-disease approach has fallen short in capturing the full dimension of metabolic dysfunction.

To address this gap in research, investigators derived a biologically enriched metabolic PRS, composite score that uses multi-ancestry genome-wide association studies of 20 metabolic traits from over 8.5 million individuals, optimized to predict obesity and T2D.

The model was trained and tested in the UK Biobank before being externally validated in 3 multi-ethnic cohorts comprising up to 300,000 participants. According to investigators, the risk scores identified individuals at high risk for clinical outcomes such as cardiovascular disease and stroke. In a median 5.5 years follow-up, even individuals with a high PRS who were healthy at baseline were approximately 2 times as likely, specifically, those in the top decile compared to the middle quintile, to eventually receive GLP-1 agonist medications or bariatric surgery.

Investigators see the biologically enriched metabolic PRS as an opportunity to work together with traditional metrics, such as body mass index, to add more information to disease prediction and management approaches for metabolic diseases.

As uptake of these tools grows, additional clinical trials will be needed to guide how clinicians should respond to elevated genetic risk. Fahed noted that while identifying individuals at high risk for obesity may support earlier lifestyle intervention, it remains unclear whether this should also prompt earlier use of pharmacologic options, including GLP-1–based therapies or other incretin agents, an area that will require further study. He also emphasized that the findings reflect a large-scale international effort, with contributions from researchers across the United States, the Middle East, China, and other regions.

"We relied on harmonizing data from multiple large biobanks and working closely with methodological experts. The field of genomics depends on this kind of global collaboration and access to shared data. Without publicly available datasets, work like this simply wouldn’t be possible.”

, where he discusses efforts to address longstanding Eurocentric bias in genomics. He explains how expanding genomic datasets to include more non-European populations, alongside advances in analytic methods, is helping improve the accuracy and generalizability of polygenic risk scores across diverse ancestries.

Editor’s Note: Fahed reports relevant disclosures with Goodpath, MyOme, HeartFlow, and Foresite Labs.

New genetic risk score better predicts diabetes, obesity and downstream complications. EurekAlert! Published March 16, 2026. 

https://www.eurekalert.org/news-releases/1119751

Ghatan S, Jeroen van Rooij, Mandy van Hoek, et al. Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations. 

https://doi.org/10.1186/s13073-023-01255-7

Videos

Fahed explains how a multi-ancestry metabolic poly genetic risk score from over 8.5 million individuals points to the utility of global collaboration in genetic research. 


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Dietary Epitopes Drive Oral Tolerance, With Jamie Blum, PhD

New translational research is beginning to clarify a long-standing gap in immunology: which specific food-derived antigens drive oral tolerance. A study identified discrete dietary epitopes from common seed storage proteins that are recognized by intestinal regulatory T (Treg) cells, offering mechanistic insight into how the immune system classifies foods as “safe.”

, Jamie Blum, PhD, of the Salk Institute, emphasized that advancing understanding of tolerance is critical to addressing

“While we understand more and more about food allergies, we actually know comparably little about oral tolerance,” Blum said. “What is it? How does it develop? So, I think my study is starting to identify what are the protein antigens that are recognized, and if we understand how those antigens are normally seen through the tolerance response, we might be able to apply those same principles to allergy cases to help better prevent food allergies.”

Using murine models fed standard chow, investigators isolated intestinal Treg cells and identified their cognate antigens through T cell receptor (TCR) mapping. The analysis revealed 3 key epitopes derived from seed storage proteins in corn, wheat, and soybean.

 One of the most robust responses was directed against a maize protein, α-zein, a digestion-resistant storage protein.

“When we started the study, I had expected we might find dozens of different epitopes, and it was unexpected and striking that we saw the strong convergence on just 1 protein, which may suggest that a few key proteins in diet are… are garnering most of the immune response,” Blum said. “If you can tune how the immune response sees those proteins, you can set the overall tone for interpretation of the food.”

These proteins are highly abundant and resistant to digestion, allowing prolonged exposure in the gut for immune sampling. As Blum noted, they “resist proteases,” enabling their role in tolerance induction. Clinically, this convergence suggests a small number of dietary antigens may disproportionately shape immune tolerance.

The study also provides insight into the ontogeny of tolerance. Blum and colleagues observed that antigen-specific Treg populations emerge around the time of weaning, coinciding with initial exposure to solid foods.¹ Blum noted that this developmental window aligns with clinical data supporting early allergen introduction for immune tolerance. This paradigm is supported by the Learning Early About Peanut Allergy (LEAP) trial, which demonstrated that early peanut exposure significantly reduces the risk of peanut allergy and informed current guideline recommendations to introduce allergens between 4 and 6 months of age.

Mechanistically, the identified Treg cells exhibited canonical immunosuppressive functions, including secretion of anti-inflammatory cytokines and inhibition of effector T cell proliferation.

 These cells help maintain immune homeostasis.

An additional finding is the potential for cross-tolerance. The study demonstrated that TCRs recognizing a soybean-derived epitope also responded to structurally similar proteins in other foods, including sesame and quinoa.

 This suggests that exposure to 1 food antigen could confer tolerance to related proteins, even in the absence of direct exposure.

“What this could suggest, and my lab is working on this a bit now, is perhaps if we could map cross reactivity for things like a peanut, you could become tolerant to peanut by eating something that has those shared proteins without actually having the peanut exposure,” Blum said.

Blum JE, Kong R, Schulman EA, et al. Identification and characterization of dietary antigens in oral tolerance. 

. 2026;11(117):eab4684. doi:10.1126/sciimmunol.aeb4684. 

https://www.science.org/doi/10.1126/sciimmunol.aeb4684

Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. 

. 2015;372(9):803-813. doi:10.1056/NEJMoa1414850. 

https://www.nejm.org/doi/full/10.1056/NEJMoa1414850

New research identifies dietary epitopes driving oral tolerance, offering insight into Treg responses, early exposure, and future food allergy therapies.

Food Allergy

Allergy

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Experts discuss therapeutic switching in patients already on biologic therapy and adherence challenges specific to oral agents.

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration 

For patients currently well-controlled on omalizumab or dupilumab, routine therapeutic switching is not indicated and may introduce unnecessary disruption to a successful regimen. The clinical rationale for switching or adding remibrutinib is strongest in patients experiencing breakthrough disease where BTK inhibition offers a mechanistically distinct intervention. The availability of 3 step-up agents also creates a practical bridging opportunity: remibrutinib's rapid onset makes it well-suited for patients experiencing a flare while pursuing prior authorization for a long-term biologic. For new patients, presenting all 3 options with a clear explanation of their respective profiles supports genuine shared decision-making without defaulting to a prescribing hierarchy that the evidence does not support.

Adherence to a twice-daily oral regimen presents a real-world challenge distinct from the adherence profile of injectable biologics. Patients managed with injections typically have adherence supported by clinic-based or pharmacy-based administration schedules; oral agents depend entirely on patient behavior. This is compounded by a disease-specific dynamic: patients who achieve rapid symptom control on remibrutinib may question the need for continued therapy precisely because the treatment has worked. Clinicians should proactively address this at initiation, counseling patients that symptom improvement does not signal that therapy is no longer necessary and that premature discontinuation will likely result in recurrence. A structured re-evaluation at 6 to 12 months of complete control is a reasonable framework for discussing a monitored discontinuation attempt in appropriate patients.

In this video segment, Nicole Chase, MD, and Jason Hawkes, MD, examine spontaneous remission as the key variable underlying discontinuation decisions. Without a validated biomarker to predict its onset, the only practical way to determine whether a patient has remitted is to attempt discontinuation after a defined period of disease control. Chase suggests a minimum of 6 months of sustained control, and ideally 1 year, before considering this step in patients with severe disease, framing the continued treatment period as suppression of the underlying pro-inflammatory state rather than simply symptom management. Both experts agree that patients who discontinue and experience recurrence typically return to therapy quickly, because the memory of symptomatic disease reasserts itself rapidly once hives return — a self-correcting dynamic that reduces the clinical stakes of a monitored discontinuation attempt while reinforcing the importance of patient education about the likely outcome.

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration

Experts address how quickly clinicians should escalate from antihistamines to step-up therapy and examine remibrutinib's clinical trial data on speed of response.

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action

The guidelines support prompt escalation from antihistamines to step-up therapy in patients who demonstrate inadequate response. Evidence for adding leukotriene receptor antagonists or other antihistamine-adjacent agents to improve CSU control is weak, and prolonged sequential antihistamine trials delay access to effective targeted therapy without meaningful clinical benefit. The guidelines make clear that combining multiple antihistamine mechanisms does not improve outcomes in patients already inadequately controlled on a core regimen. A practical and time-efficient approach is to establish fourfold high-dose antihistamine therapy, assess response within 2 to 4 weeks, and proceed to step-up therapy if control is inadequate. Importantly, the majority of patients presenting to specialist practices have already tried antihistamines, often at above-labeled doses, well before their appointment, making the escalation question largely moot; the clinical record itself documents the non-response.

Remibrutinib's onset of action profile is clinically distinctive. Approximately 50% reductions in UAS7 scores within the first 1 to 2 weeks of treatment represent a faster response trajectory than has been observed with dupilumab, which typically requires approximately 1 month to produce comparable early-phase improvements. Some clinical trial participants experienced measurable relief within hours to days of initiation. The 12-week timepoint marks a practical efficacy plateau for remibrutinib; patients who have not responded substantially by this point are unlikely to achieve further benefit without a change in management strategy. This is analogous to the 12-week assessment used for omalizumab and should be incorporated into patient communication at the time of prescribing. For remibrutinib specifically, the fast onset may also be leveraged as a bridge strategy in patients who require quick relief while awaiting insurance authorization for a longer-term biologic therapy.

In this video segment, Nicole Chase, MD, notes that she approaches remibrutinib's onset data conservatively, advising patients to expect meaningful improvement within a month while acknowledging that some may see relief considerably sooner. Hawkes frames this as a case where the clinical data genuinely support optimism: roughly a 50% reduction in disease activity within the first 1 to 2 weeks is a response profile that few therapies in any specialty can match. Setting appropriate patient expectations at the initiation of step-up therapy is a clinically undervalued element of CSU management. Patients who have been inadequately controlled have often experienced prolonged suffering, and providing a realistic but optimistic framing — meaningful improvement likely within weeks, with full assessment at 12 weeks — supports adherence and reduces premature discontinuation driven by impatience or unrealistic short-term benchmarks.

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action 

Updated ACC/AHA Dyslipidemia Guidelines Incorporate LDL-C Goals, Lp(a) Focus, With Deepak Bhatt, MD, MPH

On March 13, 2026, the American College of Cardiology (ACC) and American Heart Association (AHA) released an updated clinical guideline for the management of 

, replacing the 2018 Guideline on the Management of Blood Cholesterol.

Among some of the most significant changes, the new guidelines encourage clinicians to enhance their focus on lipoprotein(a), or Lp(a). This updated version suggests clinicians measure Lp(a) ≥1 time in all adults when addressing 

atherosclerotic cardiovascular disease (ASCVD) 

risk. This suggestion is now a Class of Recommendation (COR) 1 suggestion.

“I’ve been a believer in measuring Lp(a) for a long time, way before it was in vogue. I used to test it in patients who came in with premature MI,” Deepak Bhatt, MD, MPH, director of Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, told 

 in an exclusive interview. “I think one can debate the exact level of evidence – we’re all eagerly awaiting, probably later this year, the first randomized clinical trials looking at Lp(a) drugs. If those trials are positive, that validates that specific therapeutics lowering Lp(a) as clinically useful.”

Additionally, the 2026 guidelines have shifted from percent reduction of LDL-C back to specific, targeted goals. The previous 2018 version introduced the use of percent LDL-C reductions as a method of monitoring lipid levels and guiding lipid-lowering therapy (LLT). This method was widely considered vague, as these percentages were inherently subjective between patients. Goals, however, establish concrete targets. Although percentage risk reduction in LDL-C was retained as a priority for individuals, LDL-C and non-HDL-C treatment goals are reclaiming their spot as the backbone of LLT guidance.

Specific goals are determined by PREVENT risk tier, with those at borderline risk – between 3 and <5% - having a goal LDL-C of <100 mg/dL and a goal non-HDL-C of <130 mg/dL. Those at intermediate risk – 5 to <10% - have a goal LDL-C of <100 mg/dL, while those at high risk - ≥10% - have a goal LDL-C of <70 mg/dL and a non-HDL-C goal of <100 mg/dL.

Secondary prevention also incorporates LDL-C goals based on these new guidelines; those with high risk, defined as ≥2 major ASCVD events or 1 event and ≥2 high-risk features have a goal LDL-C of <55 mg/dL and non-HDL-C <85 mg/dL. These patients should also receive ezetimibe in addition to maximum tolerated statin. However, those not at very high risk have an LDL-C goal of <70 mg/dL and non-HDL-C of <100 mg/dL.

“I do like the fact that targets are clearly back in the guidelines,” Bhatt said. “That was a real backward step some years ago when the guidelines eliminated targets for LDL. It’s a good illustration of the fact that the guidelines are not always sacrosanct. If you look at different times and places, guidelines have made mistakes. They don’t replace good clinical judgment or individualized patient care.”

Editors’ Note: Bhatt reports disclosures with GSK, Merck, Cereno Scientific, Angiowave, Boehringer Ingelheim, Novo Nordisk, and others.

Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online March 13, 2026. 

Livingston R. AHA/ACC Dyslipidemia Guidelines Reinstate LDL-C Goals, With Viet Le, DMSc, PA-C. 

. March 17, 2026. Accessed March 25, 2026. 

https://www.hcplive.com/view/aha-acc-dyslipidemia-guidelines-reinstate-ldl-c-goals-with-viet-le-dmsc-pa-c

Bhatt shares his thoughts on the recently released dyslipidemia guidelines, highlighting the return of goal-based LDL-C therapy and Lp(a) receiving a COR 1 suggestion.

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Allergist-immunologist at Yale New Haven Hospital

Su emphasized how care should be shifted to reflect known impacts of NNAALs on obstetric care.

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The Case for Delabeling NNAALs in Obstetric Care, With Chang Su, MD

Andres Gelrud, MD, is a gastroenterologist at Baptist Health Miami Cancer Institute, part of Baptist Health South Florida

Gerlud explains why exocrine pancreatic insufficiency is often missed, even in high-risk patients. 


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, IBS and IBD, Crohn's disease, and more.

Why Exocrine Pancreatic Insufficiency Is Frequently Underdiagnosed, With Andres Gelrud, MD

Piotr Witkowski, MD, PhD, is a professor of surgery in the Transplantation Institute at the University of Chicago.

Witkowski discusses the data presented at ATTD 2026, highlighting the investigative anti-CD40L monoclonal antibody in facilitating insulin independence.

Type 1 Diabetes

Tegoprubart Improves Glycemic Control Following Islet Transplantation for T1D, With Piotr Witkowski, MD, PhD

Julia W. Angkeow, a PhD candidate and former research technologist at Johns Hopkins Medicine

Angkeow discusses a recent study finding that PhIP-Seq analysis links diverse IgG responses to food allergy phenotypes.

IgG Reactivity Patterns in Pediatric Food Allergy, With Julia Angkeow

Learn how clinicians confirm iron deficiency anemia, interpret ferritin, and trace dietary, menstrual, or GI causes for targeted treatment.

Video Series

Diagnosing Iron Deficiency Anemia — Ferritin Thresholds, Confirmatory Testing, and Workup 

Abdallah Geara, MD, is an Associate Professor of Clinical Medicine at the University of Pennsylvania.

Articles

Geara breaks down the clinical framework for the modern era of IgA nephropathy. 


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Stratifying Risk, Optimizing Therapy in IgA Nephropathy, With Abdallah Geara, MD

Mark Taylor, MD, a consultant psychiatrist from The Edinburgh Practice and a professor in the school of medicine and dentistry at Griffith University.

National cohort study finds semaglutide tied to reduced depression, anxiety, and self-harm risk in patients with diabetes and comorbid mental illness.
 

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Semaglutide Linked to Lower Suicidality Risk in Diabetes, With Mark Taylor, MD

Discover how new IBD therapies, combo drugs, and microbiome research aim to predict response, prevent Crohn’s complications, and expand trial options.

Advancing Gastroenterology from the Frontlines of Patient Care 

Su discussed the role of delabeling non-narcotic analgesic allergy labels in obstetrics care.

Why De-Labeling NNAALs Should Be Routine Obstetrics Care, With Chang Su, MD

Mercedes Martinez, MD, is a professor of pediatrics and medicine, medical director of the intestinal transplant program at the Center for Liver Disease and Abdominal Organ Transplantation, and medical director of the pediatric abdominal organ transplantation program at NewYork-Presbyterian.

Martinez discusses unmet needs in pruritus management and maralixibat’s potential to expand treatment of itch across rare cholestatic liver diseases.

Latest News

Multi-Ancestry Genetic Risk Score Shows Value of Global Collaboration in Metabolic Disease, With Akl Fahed, MD, MPH

Dietary Epitopes Drive Oral Tolerance, With Jamie Blum, PhD

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action

Updated ACC/AHA Dyslipidemia Guidelines Incorporate LDL-C Goals, Lp(a) Focus, With Deepak Bhatt, MD, MPH