You eat your veggies, opt for whole grains, and religiously check your fiber intake. You’ve been told for years that a fiber-rich diet is key to a healthy heart, and you’ve done your best to follow that advice. But what if, despite your best efforts, your genes are quietly undermining all that good work? A groundbreaking study from Monash University suggests that for some people, rare genetic glitches can prevent their bodies from reaping the full cardiovascular benefits of dietary fiber, significantly increasing their risk of high blood pressure and serious heart problems.
This research dives deep into the intricate connection between our gut bacteria, the food we eat, and our cardiovascular health, revealing a surprising vulnerability that could affect a small but important segment of the population. It zeroes in on specific receptors in our bodies that act as crucial communicators, interpreting signals from beneficial substances produced by our gut microbes. When these receptors are faulty due to rare genetic variations, it’s like a broken telephone line between your healthy diet and your heart, potentially leaving you exposed to cardiovascular disease even if you’re hitting your fiber targets.
Think of your gut as a bustling city, and dietary fiber as the raw material for a vital industry within that city. Certain friendly gut bacteria ferment this fiber, producing beneficial byproducts called short-chain fatty acids, or SCFAs. These SCFAs are like tiny messengers, and they travel throughout your body, sending signals to various organs, including your heart and blood vessels. Previous research has already shown that these SCFAs can help lower blood pressure in humans and protect against heart damage in mice. The new study, however, takes this understanding a crucial step further, investigating the human “receivers” for these SCFA messages – a group of proteins known as G-protein coupled receptors (GPCRs), particularly FFAR3 (GPR41), FFAR2 (GPR43), and HCAR2 (GPR109A).
For the first time in humans, this large-scale population-based study explored whether rare, harmful changes (what scientists call “rare pathogenic variants” or RPVs) in the genes that make these SCFA-sensing GPCRs could increase a person’s risk of developing hypertension (high blood pressure) and major adverse cardiac events (MACE), which include serious conditions like acute coronary syndrome (heart attacks), heart failure, and ischemic stroke. The results are a stark reminder that even with a perfect diet, our genetic makeup can play a powerful and sometimes unforeseen role in our health.
To uncover these insights, the researchers delved into a massive trove of health data: the UK Biobank. This incredible resource contains healthcare information, lifestyle details, and whole-exome sequencing data (which looks at all the protein-coding genes in a person’s DNA) from nearly 400,000 participants of white-European genetic ancestry. This enormous sample size is a significant strength of the study, allowing researchers to identify patterns and associations that might be missed in smaller groups.
The team specifically looked for rare genetic variants – those found in less than 1% of the population – within the FFAR3, FFAR2, and HCAR2 genes. They then meticulously identified a subset of 158 of these rare variants that were predicted to have a major negative impact on how these genes function, essentially making them “pathogenic” or disease-causing. This careful filtering ensured they were focusing on genetic changes most likely to disrupt the SCFA signaling pathway.
To determine if these rare genetic glitches were indeed linked to heart disease, the researchers compared individuals who carried at least one of these rare pathogenic variants (referred to as “carriers”) with those who did not (the “non-carriers”). They identified cases of hypertension and MACE (acute coronary syndrome, heart failure, and ischemic stroke) using detailed medical records, including hospital diagnoses, self-reported health information, surgical histories, and even death registries.
Using sophisticated statistical models, the researchers adjusted for various factors that could also influence cardiovascular risk, such as age, sex, and body mass index (BMI). Their initial analyses revealed that the prevalence of individuals carrying these rare GPCR variants was significantly higher among those with hypertension and MACE compared to healthy controls. This was a crucial first hint that these genetic variations might be playing a role.
Understanding that MACE is often linked to common cardiovascular risk factors like hypertension, diabetes, high cholesterol, and smoking, the researchers took their analysis a step further. They adjusted their models to account for these “standard modifiable cardiovascular risk factors” (SMURFs). Even after these stringent adjustments, the increased risk of MACE among GPCR RPV carriers remained statistically significant, suggesting that the genetic variations were contributing to cardiovascular disease independently of these well-known risk factors. As Dr. Leticia Camargo Tavares, the study’s leading author, stated, “The study found that disruption in these receptors is associated with up to 20 per cent increased prevalence of hypertension and heart disease or stroke – even after accounting for other risk factors like body weight and smoking.”
When the researchers looked at the individual GPCR genes, they found even more specific associations. Carrying rare pathogenic variants in the HCAR2 (GPR109A) gene was particularly linked to a significantly increased risk of heart failure. Meanwhile, genetic variations in the FFAR2 (GPR43) gene were associated with a higher risk of hypertension. These findings were strong enough to remain significant even after correcting for multiple comparisons, adding confidence to their specific implications.
The study also explored comorbidities, looking for other diseases more common in hypertension and MACE patients who carried these GPCR RPVs. They examined an enormous amount of hospital inpatient records, analyzing over 39 million data points across thousands of disease codes. What they found was striking: cardiomyopathy, a serious condition affecting the heart muscle, was more than twice as common in hypertensive patients carrying GPCR RPVs. This finding aligns with previous mouse studies, where a lack of SCFA-sensing GPCR genes led to cardiac hypertrophy (enlargement of the heart) and fibrosis (scarring of heart tissue).
Perhaps the most compelling part of the study explored the direct interaction between genetics and diet. Given that SCFAs are primarily produced when gut microbes break down dietary fiber, the researchers investigated whether carrying these GPCR RPVs made individuals more susceptible to hypertension and MACE, even if they were consuming enough fiber. This was a critical test of their hypothesis: that fiber’s heart-protective effects rely on proper GPCR signaling.
To assess fiber intake, a subset of UK Biobank participants had provided dietary data through 24-hour food recalls. An adequate fiber intake was defined based on nutritional recommendations: over 25 grams per day for women and at least 30 grams per day for men. The results were eye-opening. Consistent with their hypothesis, the prevalence of hypertension was significantly higher among GPCR RPV carriers who were consuming an adequate-fiber diet. This strongly suggests that for these individuals, the cardiovascular benefits of fiber intake are indeed diminished or even lost due to their genetic impairments in SCFA-related GPCR signaling. As Dr. Tavares stated, “Consistent with our hypothesis, the prevalence of hypertension was significantly higher in this cohort, even among those who ate a diet rich in fibre.”
Interestingly, no significant associations were observed for MACE in this specific fiber analysis subgroup, which the authors attribute to the smaller sample size available for that particular dietary assessment. Furthermore, in the subgroup of individuals who did not consume enough fiber, the prevalence of hypertension was still higher in carriers versus non-carriers, but the difference was no longer statistically significant. This makes sense: if there isn’t enough fiber to begin with, SCFA production is minimal, and thus, the potential benefits from SCFA signaling are largely absent for everyone, regardless of their genetic predisposition.
In essence, these findings highlight a powerful gene-by-environment interaction. While a healthy, fiber-rich diet is undeniably beneficial for most, this study reveals that for a small number of people with specific genetic variations, their bodies might not be able to fully utilize those benefits. This underscores the potential for personalized medicine approaches, where genetic screening could one day help identify individuals who might need alternative or supplementary strategies to protect their cardiovascular health.
This study serves as a potent reminder that the intricate dance between our diet, our gut microbiome, and our genes is far more complex than we often imagine. For the small percentage of people carrying these specific rare genetic variants, the pathway to heart health might require more than just a high-fiber diet; it might necessitate new therapeutic strategies that can bypass these genetic roadblocks and directly activate the beneficial SCFA signaling pathways.
Paper Summary
Methodology
This study utilized data from the UK Biobank, analyzing nearly 400,000 participants of white-European genetic ancestry. Researchers identified 158 rare pathogenic variants (RPVs) in three specific genes (FFAR3, FFAR2, and HCAR2) that are involved in sensing short-chain fatty acids (SCFAs) produced by gut bacteria. They compared the prevalence of these RPVs in individuals with hypertension and major adverse cardiac events (MACE) against healthy controls. Statistical models adjusted for factors like age, sex, BMI, and common cardiovascular risk factors. A subgroup analysis also examined the impact of these genetic variants on individuals consuming adequate dietary fiber.
Results
The study found that individuals with these rare genetic variants (RPVs) had a significantly higher prevalence of hypertension and MACE, even after accounting for other known cardiovascular risk factors. Specifically, genetic variations in HCAR2 were linked to an increased risk of heart failure, and FFAR2 variations were associated with higher blood pressure. Cardiomyopathy was also found to be more than twice as common in hypertensive RPV carriers. Crucially, RPV carriers who consumed an adequate-fiber diet still showed a significantly higher prevalence of hypertension, suggesting their bodies could not fully utilize fiber’s cardiovascular benefits.
Limitations
Key limitations include the smaller sample size for the dietary fiber analysis, which may have limited the detection of associations with MACE. Additionally, the study primarily involved participants of white-European genetic ancestry, meaning the findings may not be directly applicable to other populations.
Funding and Disclosures
The research received funding from fellowships provided by the Sylvia and Charles Viertel Charitable Foundation, the National Heart Foundation, and an Emerging Leader Fellowship from the National Health & Medical Research Council (NHMRC). The authors reported no conflicts of interest.
Publication Information
This research utilized data from the UK Biobank (Application Number 86879). The preprint is titled “Rare pathogenic variants in G-protein coupled receptor genes involved in gut-to-host communication are associated with cardiovascular disease risk”. The corresponding authors are Dr. Leticia Camargo Tavares and Professor Francine Marques, both from Monash University, Australia. The preprint was posted on medRxiv on January 29, 2025. The full methods are available at medRxiv Preprint: Gut-to-Host Receptors and Cardiovascular Disease Risk.