genetic risk

Largest study of its kind finds new genetic risk factors for type 2 diabetes.

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Largest ever genome-wide association study reveals fresh insights about type 2 diabetes risk.

  • The risk factors for type 2 diabetes are both environmental and genetic, and researchers have identified many genetic risk factors to date.
  • Now, however, the largest ever genome-wide association study of people with type 2 diabetes has discovered even more locations of risk variants than before.
  • It has also identified different clusters of variants that contribute to the risk of developing the disease, revealing more about the different mechanisms that underpin the disease.

Genome-wide association studies have been possible since the human genome was first sequenced in 2003. They allow us to understand which regions of the genome and genetic variants are associated with increased risk of certain conditions.

Coupled with the advent of cell maps and genomic libraries, it is now possible for researchers to identify not only the variants that could impact risk, but also understand what they control and the cellular mechanisms that they play a role in.

So what can genetic markers teach us about widespread conditions, such as type 2 diabetes? That is what the researchers conducting a new study — whose results now appear in NatureTrusted Source — set out to reveal.

What genetics teach us about type 2 diabetes 

Type 2 diabetes is characterized by reduced insulin sensitivity of cells, which means they are less able to take up glucose in the bloodstream.

This leads to the chronically elevated blood glucose (sugar) levels, which can increase the risk of complications, such as cardiovascular disease and nerve damage.

There are many known risk factors for type 2 diabetes, including family members having it, being of African or Asian ancestry, high blood pressure, obesitym and polycystic ovary syndrome (PCOS), among others.

Genome-wide association studies have revealed some other interesting links between type 2 diabetes and other conditions. For example, a study in 2023 showed that a number of genetic risk variants were shared by type 2 diabetes and depressive symptoms.

Prof. Inga Prokopenko, who studies the impact of genetics on diabetes and glycaemic control from the University of Surrey told Medical News Today that the way we look at type 2 diabetes has changed in recent years:

“A final very important point is that many previous large scale GWAS [genome-wide association studies] meta-analyses in type 2 diabetes have been focusing on [type 2 diabetes] as an outcome, but it was clear that as [type 2 diabetes], as a disease, progresses there are many complications of this disease.These major complications are very important, such as diabetic nephropathy, retinopathy, etc.”

New genetic variants tied to complications of diabetes

The study recently published in Nature is the largest genome-wide association study of type 2 diabetes to date, and it included genomic data from 2,535,601 individuals, of whom 428,452 had type 2 diabetes.

Many genome-wide association studies feature data from a predominantly white European dataset, but this study featured data from six ancestral groups, namely: European, East Asian, African American, South Asian, South African, and Hispanic with American, West African and European ancestry.

However, the majority of participants were still predominantly European in ancestry, with 60% of the cohort made up of this group.

A global consortium of researchers discovered 1,289 genetic variants, at 611 areas of the genome known as loci, of which 145 were new discoveries.

They then mapped these variants to 37 cardiometabolic phenotypes, including waist-height ratio, liver fat percentage, LDL and HDL cholesterol, blood pressure, fasting insulin and others, to discover if certain variants were associated with certain phenotypes, or traits.

They then identified eight nonoverlapping “clusters” characterized by subsets of variants associated with certain cardiometabolic traits.

These clusters included beta-cell dysfunction, obesity, and liver and lipid (fat) metabolism, among others, and also characterized whether people with these clusters exhibited increased or decreased insulin secretion, or increased or decreased insulin sensitivity.

One of the corresponding authors, Dr. Benjamin F. Voight, of the University of Pennsylvania–Perelman School of Medicine, told MNT that “[i]t turns out the genetic variants that contributed to our clusters do not overlap [with] one another — so patients have their disease risk influenced to different extents by these clusters.”

Can genetics predict cardiovascular outcomes in diabetes?

Next, researchers looked at whether the eight clusters they had determined could be used to predict cardiovascular disease outcomes in these participants.

They developed polygenic scores in a further 279,552 individuals for whom they had genomic data, including 30,288 with type 2 diabetes, and investigated whether there was an association with cardiovascular outcomes and genetic variant clusters.

The most significant associations discovered showed risk of hospitalization for heart failure was increased by 15% in people positive for the obesity cluster of genetic variants.

They also found that having the beta cell proinsulin positive cluster of genetic variants decreased a person’s risk of hospitalization for heart failure by 10%. This cluster was also associated with 10% lower risk of cardiovascular death and 6% lower risk of major cardiovascular events and heart attack.

Dr Voight said:

“I think the potential doorway that this type of work opens is where one can start to dissect how different genetic ‘subtypes’ of type 2 diabetes could modulate risk to complications of diabetes — either a little or a lot. Moreover, genetic subtyping might also give us better clues about the underlying genes and biology that contributes most importantly to those complications.”

Prof. Prokopenko, who was not involved in this research, said it represented significant advancement in analyses of large data sets and increased the number of risk variants we are aware of by a quarter.

“For us scientists, this is an important resource, and it will enable a many follow-up studies, experiments, etc., and further drug discovery,” she told MNT.

“The results of this study and generated information will empower us to improve the lives of people with diabetes with new treatments, new ways of care, new ways of [treating] it in the future, through prediction of individual susceptibility or ability to distinguish potential subtypes of diabetes,” Prof. Prokopenko noted.

Is a treatment for those at genetic risk of Alzheimer’s on the horizon?

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Animal research may be bringing us a step closer to new treatments for those genetically predisposed to Alzheimer’s disease.

  • Alzheimer’s disease is the commonest form of dementia, causing up to 70% of the 55 million dementia cases worldwide.
  • Around half of those who develop Alzheimer’s disease have a variant of one gene — APOEe4— that increases the risk of developing the condition.
  • This gene variant prevents cells clearing the beta-amyloid plaques that are characteristic of Alzheimer’s disease.
  • Now, a study in nematodes and mice has identified a molecule that can inhibit APOEe4 and allow the cells to clear these beta-amyloid deposits, and potentially alleviate Alzheimer’s disease symptoms.

With an aging global population, dementia is a growing concern worldwide. A recent forecast by The LancetTrusted Source estimated that the worldwide burden of dementia is set to almost triple by 2050.

Of these dementia cases, according to the World Health Organization (WHO)Trusted Source, 60–70% are due to Alzheimer’s disease.

For dementia, the greatest risk factor is aging — with the likelihood of developing dementia increasing each year from the age of 65Trusted Source.

Genetics can also influence whether a person develops dementia: About 1% of cases of Alzheimer’s disease are entirely caused by genes, and other genes increase the risk of developing Alzheimer’s.

The gene that expresses apolipoprotein ETrusted Source, the APOE gene, influences Alzheimer’s disease risk. One variant, or alleleTrusted Source, of this gene, APOEe4, increases the risk of Alzheimer’s disease, with between 40–65% of people with Alzheimer’s disease having at least one copy of this allele.

Dr. Emer MacSweeney, CEO and medical director at Re:Cognition Health, told Medical News Today:

“In 2018, it was shown those with an APOEe4 gene are less able to clear waste products from the brain and, therefore, more susceptible to building up toxic levels of amyloid and tau protein, which is the hallmark of Alzheimer’s disease. The toxic amyloid and tau protein relentlessly destroy further brain cells, with the progression of the characteristic symptoms of [Alzheimer’s disease].”

Now, a team led by researchers at the University of Arkansas for Medical Sciences have found a molecule that binds to APOEe4and inhibits its harmful effects. They suggest it may form the basis for a new treatment for Alzheimer’s disease with a genetic basis.

The research is published in Communications Biology.

Dr. MacSweeney, who was not involved in the research, welcomed the study.

She said: “This study focuses on the role of the APOE gene, specifically the APOEe4 allele, in Alzheimer’s disease and explores a potential therapeutic strategy using small molecules to target APOEe4. The research combines genetic association studies, cellular mechanism investigations, computational modelling, and experimental validation.”

APOEe4 gene variant linked to amyloid plaques

Studies have shown that APOEe4 has several effects, including disrupting lipid metabolismTrusted Source and driving beta-amyloid pathologyTrusted Source. Both of these can increase the risk of dementia, but for Alzheimer’s disease, beta-amyloid pathology is key.

This latest study found that APOEe4 blocks genes responsible for autophagyTrusted Source — the breakdown and recycling of worn out cell parts and macromolecules in cells. If these genes are inhibited, molecules such as beta-amyloid build up rather than being recycled.

When beta-amyloid builds up it forms plaques on and around nerve cells, which is thought to drive the cognitive impairment and other symptoms that are characteristic of Alzheimer’s disease.

The researchers used in vitro and in vivo models in both Caenorhabditis elegansTrusted Source — a nematode worm widely used in genetic research — and mice.

In molecular models, they first identified the site on DNA where APOEe4 binds to inhibit autophagy. They then investigated molecules that could block this region to prevent APOEe4 binding, allowing autophagy of beta-amyloid to continue.

One molecule — CBA2 — bound to a stable “pocket“ region on APOEe4, blocking its activity.

Dr. Heather M. Snyder, Ph.D., Alzheimer’s Association vice president of Medical and Scientific Relations, not involved in this study, commented on its findings, noting that:

“It is exciting to see advances in technology that may accelerate therapy discovery. And it is exciting that this newly announced research is looking at a novel and understudied therapeutic target — APOEe4 and its actions in the brain. But the research is very preliminary; it is being conducted in mouse and other animal models of Alzheimer’s. We are still far from knowing whether this experimental treatment will be safe and effective in people.”

Molecule inhibits APOEe4 to prevent amyloid build-up

Once the molecule bound to the stable region, it inhibited the gene, as Dr. MacSweeney explained to MNT: “The lead compound, CBA2, is found to selectively bind to this pocket, demonstrating efficacy in restoring autophagic transcription in APOEe4-expressing models, including primary astrocyte cultures and T98G cells.”

In C. elegans nematodes genetically altered to show Alzheimer’s disease-like changes, CBA2 significantly reduced the build up of beta-amyloid, and reversed the decline in chemotaxisTrusted Source, the worms’ response to a chemical stimulus.

When researchers treated the mice modified to express APOEe4, expression of the autophagy genes increased. Dr. MacSweeney told MNT that the results were encouraging, but urged caution.

“In mice with APOEe4, CBA2 boosts the activity of key genes linked to cleaning up harmful substances in the brain, an important part of Alzheimer’s. However, the effects are stronger in mice with APOEe4 than in those with APOEe4,” she explained.

“While these findings are positive, more research and testing in humans are needed to confirm CBA2’s potential benefits for Alzheimer’s,” she added.

Potential new treatment target for those genetically at risk

The researchers suggest that CBA2 might form the basis of treatment to help avoid amyloid build up in people with the gene.

“CBA2, identified as a promising therapeutic compound, demonstrated effectiveness in mitigating APOEe4-associated issues in both worms and mice. If proven safe and effective in humans, CBA2 could represent a targeted treatment to address molecular and behavioural aspects of [Alzheimer’s disease], particularly for individuals carrying the APOEe4 allele.”

– Dr. Emer MacSweeney

Dr. MacSweeney welcomed the findings, saying that “[t]his is the first time a potential compound to specifically block the harmful effects of APOEe4 has been described.”

“These results suggest hope, particularly for the 25% of the population who inherit one copy of the APOEe4 gene and are three times more likely to develop [Alzheimer’s disease] between ages 65-85, than an individual who does not have an APOEe4 gene. And the 2-3% of the population who inherit two APOEe4 genes; these individuals are 12-15 times more likely to develop [Alzheimer’s disease] than the general population,” she told us.

This optimism was echoed by Dr. Snyder, who suggested that targeting APOEe4 might form part of a multifaceted approach to Alzheimer’s disease treatment.

“We know the underlying biology of Alzheimer’s is complex, and therefore that effective treatment is likely going to be a combination approach that will be personalized to each individual,” said Dr. Snyder.

“The Alzheimer’s Association envisions a time in the relatively near future when there are many approved treatments that address Alzheimer’s in multiple ways across the entire course of the disease, and that can be combined into powerful combination therapies that more effectively slow and even stop the disease,” she added.

Frequent aspirin use lowers ovarian cancer risk regardless of genetic risk

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Daily or near daily aspirin use reduced the risk for nonmucinous ovarian cancer across most strata of genetic risk based on a polygenic score, according to a case-control study published in JAMA Network Open.

“While aspirin is a promising chemopreventive agent for ovarian cancer, its use remains limited by several factors. First, serious adverse events can occur with aspirin use, including gastric ulcer and hemorrhagic stroke; although rare, these risks are nonnegligible. Second, the incidence of ovarian cancer in the general population is low; thus, the number needed to treat to prevent one case of ovarian cancer is high,” Lauren M. Hurwitz, PhD, MHS, postdoctoral fellow in thedivision of cancer epidemiology and genetics at the National Cancer Institute, and colleagues wrote. “Targeting chemoprevention programs to individuals at higher risk of ovarian cancer could reduce the number needed to treat and improve the benefit-harm profile.”

aspirin

Researchers pooled individual-level data from eight population-based case-control studies from the Ovarian Cancer Association Consortium in the U.S., U.K. and Australia between 1995 and 2009. In total, 4,476 patients with nonmucinous ovarian cancer (median age, 58 years) and 6,659 control participants (median age, 57 years) with both genetic data and frequent aspirin use data were included.

The primary outcome was nonmucinous epithelial ovarian cancer with frequent aspirin use defined as daily or almost daily use for 6 months or more.

Overall, frequent aspirin use was reported among 13% of patients with ovarian cancer and 15% of control participants. Polygenic score did not modify the 13% reduction in risk for ovarian cancer associated with frequent aspirin use (OR = 0.87; 95% CI, 0.76-0.99).

Researchers observed similar associations between frequent aspirin use and ovarian cancer risk among those with a polygenic score less than (OR = 0.85; 95% CI, 0.7-1.02) and greater than the median (OR = 0.86; 95% CI, 0.74-1.01) with results similar by histotype.

According to the researchers, these results are consistent with previous analyses including mucinous ovarian cancer cases.

“This work expands on the evidence base to suggest that chemoprevention programs could target individuals at higher risk of ovarian cancer, as defined by epidemiologic risk factors, polygenic risk, or both, to improve the benefit-harm profile of frequent aspirin use for ovarian cancer prevention,” the researchers wrote.

Excess weight increased risk for colorectal cancer, independent of genetic risk

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Excess weight, regardless of polygenic risk score, correlated with an increased risk for colorectal cancer, according to results from a population-based, case-control study.

“Accumulated evidence has shown that a high BMI, as a proxy for excess body weight, is associated with increased CRC risk,” Xuechen Chen, MMed, of the division of clinical epidemiology and aging research at the German Cancer Research Center, and colleagues wrote in JAMA Network Open. “Polygenic risk scores (PRSs), the combination of multiple single nucleotide variations identified in genome-wide association studies, are increasingly used for CRC risk stratification and also are useful to improve limited statistical power in gene-environmental studies that often suffer from weak effects of single risk loci and harsh penalty of multiple comparison corrections.

HGI0123Chen_Graphic_01

“Another important issue is that CRC risks associated with excess weight and genetic risk factors are often evaluated separately, and how to communicate CRC risk increased by excess weight compared with the risk associated with background genetic profiles remains to be solved.”

To evaluate both individual and joint associations between BMI and PRSs with CRC, Chen and colleagues evaluated 9,169 participants (median age, 69 years; 61% men), of whom 5,053 had CRC and 4,116 were controls. Study analysis showed PRS and BMI independently associated with risk for CRC.

Compared with the lowest tertile, having a PRS in the top tertile correlated with “significantly increased” odds for a CRC diagnosis (adjusted OR = 2.27; 95% CI, 2.02-2.55), as did a BMI of 25 to 29 (aOR = 1.31; 95% CI, 1.18-1.46) and a BMI of 30 or greater (aOR = 1.71; 95% CI, 1.49-1.97) approximately 10 years prior to diagnosis compared with normal weight.

The risk for CRC increased among individuals with a BMI of 30 or more with low (adjusted OR = 1.97; 95% CI, 1.53-2.56), medium (aOR = 2.79; 95% CI, 2.19-3.56) or high PRSs (aOR = 3.82; 95% CI, 3.03-4.83) compared with individuals who with normal weight and low PRS. Further, those with a high PRS had increased risk for CRC with increasing BMI (<25: aOR = 2.41; 95% CI, 1.98-2.93; 25 to <30: aOR = 3.14; 95% CI, 2.6-3.79 and 30: aOR = 3.82; 95% CI, 3.03-4.82) compared with those who had a low PRS and normal weight.

Researchers estimated that the association between a BMI greater than 30 and the risk for CRC was “equivalent” to having a 41-percentile (95% CI, 29-53) higher PRS. Additionally, researchers noted a BMI of at least 30 had the greatest correlation with stage IV CRC (aOR = 2.21; 95% CI, 1.71-2.84).

“The findings of this case-control study add to the limited evidence on the individual and joint associations of BMI and PRS with CRC,” Chen and colleagues concluded. “The absence of interaction on a multiplicative scale between PRS and BMI, two significant CRC risk factors, provides a great potential for CRC risk classification through their joint consideration, and also underlines the importance of keeping a healthy weight.”