Tag: race/ethnicity

Categories : GeneticsTags :

Genetic Variations Influence Drug Metabolism in Patients of African Descent

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Photo by Agung Pandit Wiguna

Investigators have identified new genetic variations that affect gene expression in the liver cells of patients of African ancestry, findings that provide insight into how drugs are metabolised differently in different populations, according to a study published in The American Journal of Human Genetics.

Expression quantitative locus (eQTL) studies use an individual’s genomic and transcriptomic data to uncover unique genetic variants that regulate gene expression. However, people of African descent have not been well represented in these databases.

Having this comprehensive, multiomic data is key to uncovering the mechanisms that regulate an individual’s genome and understanding how different groups of people respond to drugs differently, which can improve treatment strategies, according to Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

“We don’t have data from any historically excluded populations to run these analyses, so a big motivation of my lab is to create data in African ancestry populations so that they are represented in multiomics,” said Perera.

In the current study, the investigators treated hepatocytes from liver tissue samples from African American patients with six FDA approved drugs: Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital and Omeprazole.

The investigators then performed whole-genome genotyping and RNA sequencing on primary hepatocytes treated both with and without the drugs. They also mapped eQTLs, or single-nucleotide polymorphisms (SNPs) affecting gene expression, in the liver cells.

From this comprehensive analysis, they uncovered varying transcriptional changes in the cell lines across the different drug treatments and identified NRF2 as a potential gene transcription regulator.

“NRF2 has been already identified as a very important transcription factor for drug metabolism, but this is a much more comprehensive way to look at it,” Perera said.

The investigators also discovered nearly 3000 genetic variants that affect how well hepatocytes respond to external stimuli, including drugs, which the investigators called drug response eQTLs, or reQTLs. Notably, they discovered reQTLs for drug-metabolising genes such as CYP3A5.

Most individuals of European ancestry carry a specific genetic variant in CYP3A5 which results in no/low CYP3A5 enzyme, whereas individuals of African ancestry carry that variant at a lower frequency. According to Perera, this is a problem because most participants that are recruited for clinical trials are of European ancestry, and the findings from these trials directly inform how often and how much of a drug should be prescribed to all patients, regardless of their ancestry.

“When you test drugs in a group of people with limited diversity, and then say this is the dose, this is how fast it’s metabolised, this is how often you dose the drug and then you give this medication to the entire U.S. population, we don’t know for sure how accurate those measures are, and that’s just with one variant. Other variants that may influence how much or how little we up-regulate these important enzymes,” Perera said.

Perera said her team is now expanding their work by increasing the number of hepatocytes from African American participants they’re studying and incorporating other types of omics techniques, such as epigenetic profiling.

“Almost exclusively we’ve done epigenetic screenings in European populations, so what can we find in the epigenome that’s important for African Americans. Also, because there’s more genetic variation in individuals of African descent, would that change the epigenome in ways that we aren’t able to see in Europeans,” Perera said. “We hope that what we’re doing can help annotate new studies coming along for African ancestry populations.”

Source: Northwestern University

Categories : Ageing Cardiovascular DiseaseTags :

Increasing Age Blunts the Strength of Certain Stroke Risk Factors

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Photo by CDC on Unsplash

Hypertension and diabetes are known risk factors for stroke, but now a new study shows that the amount of risk may decrease as people age. The study is published in Neurology.

“High blood pressure and diabetes are two important risk factors for stroke that can be managed by medication, decreasing a person’s risk,” said study author George Howard, DrPH, of the University of Alabama at Birmingham School of Public Health. “Our findings show that their association with stroke risk may be substantially less at older ages, yet other risk factors do not change with age. These differences in risk factors imply that determining whether a person is at high risk for stroke may differ depending on their age.”

The study involved 28 235 people who had never had a stroke and were followed for 11 years. Risk factors included hypertension, diabetes, smoking, atrial fibrillation, heart disease and left ventricular hypertrophy. Because of the well-known higher stroke risk in Black people (comprising 41% of participants), race was also considered as part of the assessed risk factors, Howard added.

Researchers followed up with participants every six months, confirming strokes by reviewing medical records.

During the study, there were 1405 strokes over 276 074 person-years. Participants were divided into three age groups. The age ranges for those groups varied slightly depending on the data being analysed by researchers. In general, the younger group included participants ages 45–69, the middle group included people in their late 60s to 70s and the older group included people 74 and older.

Researchers found that people with diabetes in the younger age group were approximately twice as likely to have a stroke as people of similar age who did not have diabetes, while people with diabetes in the older age group had an approximately 30% higher risk of having a stroke than people of similar older age who did not have diabetes.

Researchers also found that people with high blood pressure in the younger age group had an 80% higher risk of having stroke than people of similar age without high blood pressure while that risk went down to 50% for people with high blood pressure in the older age group compared to people of similar age without high blood pressure.

With race/ethnicity as a risk factor, Black participants in the younger age group compared to White participants in that group, a difference which decreased in the older age group. For stroke risk factors such as smoking, atrial fibrillation and left ventricular hypertrophy, researchers did not find an age-related change in risk.

“It is important to note that our results do not suggest that treatment of high blood pressure and diabetes becomes unimportant in older age,” said Howard. “Such treatments are still very important for a person’s health. But it also may be wise for doctors to focus on managing risk factors such as atrial fibrillation, smoking and left ventricular hypertrophy as people age.”

Howard also noted that even where the impact of risk factors decreases with age, the total number of people with strokes at older ages may still be larger since overall risk of stroke increases with age. For example, in the younger age group for hypertension, researchers estimate that about 2.0% of normotensive people had a stroke, compared to 3.6% of hypertensive people. In the older age group, about 6.2% of normotensive people had a stroke, compared to 9.3% of hypertensive people.

A limitation of the research was that participants’ risk factors were assessed only once at the start of the study, and it’s possible they may have changed over time.

Source: American Academy of Neurology 

Categories : Cancer Ethics and LawTags :

Towards Larger, More Representative Lung Cancer Clinical Trials

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Source: NCI

Filling clinical trials and enrolling sufficiently diverse, representative groups of patients, has long been a challenge, partly due to stringent participation guidelines. In an effort to attain larger and more diverse trial groups, an international team of researchers and policymakers has written new recommendations on how to determine eligibility criteria for lung cancer clinical trials.

The group was led in part by David Gerber, MD, along with representatives from the Food and Drug Administration (FDA), National Cancer Institute, European Medicines Agency, pharmaceutical companies, and the LUNGevity Foundation.

The recommendations, published today in JAMA Oncology, offer the first publicly available outline of upcoming FDA draft guidance on lung cancer clinical trials that are expected to make it easier to include more patients.

“This paper is the public’s first look at the FDA’s proposed changes to how we determine who can participate in a lung cancer clinical trial,” said Professor Gerber in the Hematology/Oncology Division at UTSW. “If these changes are successful, they could make clinical trials for lung cancer as well as other cancers more powerful and more representative.”

Ensuring that people from diverse backgrounds join clinical trials is key to properly evaluating how a new treatment will work among patients of all races and ethnicities. But today, only about 5% of all cancer patients enrol in a clinical trial, and only 11% of cancer clinical trial participants identify as a racial or ethnic minority.

For patients with cancer, participation in clinical trials requires not just a decision to try an experimental treatment, but time and energy spent understanding the trial, enrolling in it, and often attending extra testing or clinic appointments. Many researchers agree that complicated, inconsistent, poorly explained, and overly strict eligibility requirements to join a cancer clinical trial exacerbate this problem and are a key reason for the low number of underrepresented minorities in clinical trials.

“So many clinical trials never finish enrollment, close prematurely, or don’t recruit a population that lets researchers generalise the results,” Dr. Gerber said. “I think there’s widespread recognition that eligibility criteria have become too stringent.”

Addressing this for one cancer subtype, advanced non-small cell lung cancer (NSCLC), – the LUNGevity Foundation convened a roundtable discussion with experts from academia, industry, and regulatory bodies. The team assembled a prioritised list of eligibility categories that should be included in the descriptions of all NSCLC clinical trials and recommended criteria for each category. Some suggestions were more lenient than what has typically been included in previous NSCLC trial eligibility criteria; for instance, the team recommended that most patients with prior or concurrent cancers, most patients with brain metastases, and most patients with mild liver impairment – all of whom would likely have been excluded in the past – still be included in trials.

The team also suggested that these categories be clearly laid out on public websites advertising clinical trials in an easily searchable format.

The FDA will be releasing draft guidance on NSCLC clinical trials in the near future and hold a public comment period before finalising them. Other interdisciplinary teams have already convened to standardise eligibility requirements for clinical trials of other cancer types.

If the new guidelines prove effective, Prof Gerber said that clinical trials will likely be easier to fill and provide more complete and timely data on new cancer interventions.

“If you can involve more patients in clinical trials, you’re more likely to complete those trials quickly. That’s going to lead to new treatments faster,” he said.

Source: UT Southwestern Medical Center

Categories : NeurologyTags :

Why do We Struggle to Recognise the Faces of People of Other Races?

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An Asian man and two white men enjoying St. Patrick’s Day Photo by Pressmaster on Pexels

In a study published in Scientific Reports, cognitive psychologists at the believe they have discovered the answer to a 60-year-old question as to why people find it more difficult to recognise faces from visually distinct racial backgrounds than they do their own.

This phenomenon named the Other-Race Effect (ORE) was first discovered in the 1960s. Humans seem to use a variety of markers to recognise people, instead of photographically memorising their faces, which may be based on what they observe in others around them. Hair and eye colour may be used by white people to tell apart other white people since those features vary considerably in that racial group. Setting may also be important: some people might not notice that the centre man in the picture above is Asian while his friends on either side are white.

The ORE has consistently been demonstrated through the Face Inversion Effect (FIE) paradigm, where people are tested with pictures of faces presented in their usual upright orientation and inverted upside down. Such experiments have consistently shown that the FIE is larger when individuals are presented with faces from their own race as opposed to faces from other races.

The findings spurred decades of debate, and social scientists took the view that indicates less motivation for people to engage with people of other races, making a weaker memory for them. Cognitive scientists posited it is down to a lack of visual experience of other-race individuals, resulting in less perceptual expertise with other-race faces.

Now, a team in the Department of Psychology at Exeter, using direct electrical current brain stimulation, has found that the ORE would appear to be caused by a lack of cognitive visual expertise and not by social bias.

“For many years, we have debated the underpinning causes of ORE,” said Dr Ciro Civile, the projects lead researcher.

“One of the prevailing views is that it is predicated upon social motivational factors, particularly for those observers with more prejudiced racial attitudes. This report, a culmination of six years of funded research by the European Union and UK Research and Innovation, shows that when you systematically impair a person’s perceptual expertise through the application of brain stimulation, their ability to recognise faces is broadly consistent regardless of the ethnicity of that face.”

The research was conducted at the University of Exeter’s Washington Singer Laboratories, using non-invasive transcranial Direct Current Stimulation (tDCS) specifically designed to interfere with the ability to recognise upright faces. This was applied to the participants’ dorsolateral prefrontal cortex, via a pair of sponges attached to their scalp.

The team studied the responses of nearly 100 White European students to FIE tests, splitting them equally into active stimulation and sham/control groups. The first cohort received 10 minutes of tDCS while performing the face recognition task involving upright and inverted Western Caucasian and East Asian (Chinese, Japanese, Korean) faces. The second group, meanwhile, performed the same task while experiencing 30 seconds of stimulation, randomly administered throughout the 10 minutes – a level insufficient to induce any performance change.

In the control group, the size of the FIE for own-race faces was found to be almost three times larger than the one found for other-race faces confirming the robust ORE. This was mainly driven by participants showing a much better performance at recognising own-race faces in the upright orientation, compared to other-race faces – almost twice as likely to correctly identify that they had seen the face before.

In the active tDCS group, the stimulation successfully removed the perceptual expertise component for upright own-race faces and resulted in no difference being found between the size of the FIE for own versus other-race faces. And when it came to recognising faces that had been inverted, the results were roughly equal for both groups for both races, supporting the fact that people have no expertise whatsoever at seeing faces presented upside down.

“Establishing that the Other-Race Effect, as indexed by the Face Inversion Effect, is due to expertise rather than racial prejudice will help future researchers to refine what cognitive measures should and should not be used to investigate important social issues,” said Ian McLaren, Professor of Cognitive Psychology. “Our tDCS procedure developed here at Exeter can now be used to test all those situations where the debate regarding a specific phenomenon involves perceptual expertise.”

Source: University of Exeter

Categories : CancerTags :

Parabens in Hair Products May Increase Breast Cancer Risk for Black Women

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Parabens, chemicals which are found in widely used hair and personal care products, cause harmful effects in breast cancer cells from Black women, according to a new study presented at ENDO 2022, the Endocrine Society’s annual meeting.

In the US, the lifetime risk of breast cancer is one in eight, and Black women are at a higher risk of getting breast cancer under the age of 40 than any other racial or ethnic group in that country. Breast cancer rates among Black South African women are also on the increase, but the cause remains unexplained and research in this area has been lacking.

“One reason for the higher risk of breast cancer may be exposure to harmful chemicals called endocrine-disrupting chemicals in hair and personal care products,” said lead researcher Lindsey S. Treviño, PhD. “These chemicals mimic the effects of hormones on the body.”

Parabens are endocrine-disrupting chemicals that are commonly used as preservatives in hair and other personal care products. Parabens cause breast cancer cells to grow, invade, spread, and express genes linked to cancer and to hormone action. Research showed that fewer paraben-free options are marketed to Black women.

“Black women are more likely to buy and use hair products with these types of chemicals, but we do not have a lot of data about how parabens may increase breast cancer risk in Black women,” Dr Treviño said. “This is because Black women have not been picked to take part in most research studies looking at this link. Also, studies to test this link have only used breast cancer cell lines from White women.”

The new study tested the effects of parabens on breast cancer cells from Black women. Parabens were found to increase the growth of a Black breast cancer cell line but not in the White breast cancer cell line. Parabens increased expression of genes linked to hormone action in breast cancer cell lines from both Black and White women. Parabens also promoted the spread of breast cancer cells, with a bigger effect seen in the Black breast cancer cell line.

“These results provide new data that parabens also cause harmful effects in breast cancer cells from Black women,” Dr Treviño said. 

The study is a part of a community-led project called the Bench to Community Initiative (BCI), which brings together scientists and community members (including breast cancer survivors) to create ways to reduce exposures to harmful chemicals in hair and personal care products in Black women with breast cancer. 

“While this project focuses on Black women, the knowledge we gain about the link between exposure to harmful chemicals in personal care products and breast cancer risk can be used to help all women at high risk of getting breast cancer,” Dr Treviño said.

Source: Endocrine Society

Categories : Allergies Cardiovascular DiseaseTags :

Allergies Linked to Increased Cardiovascular Risk

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Runny nose and sneezing symptoms
Photo by Britanny Colette on Unsplash

A national US health survey has revealed that adults with allergies are at an increased risk of hypertension and coronary heart disease, with the biggest risk increase seen in Black male adults. The study is presented at ACC Asia 2022 Together with the Korean Society of Cardiology Spring Conference.

“For patients with allergic disorders, routine evaluation of blood pressure and routine examination for coronary heart disease should be given by clinicians to ensure early treatments are given to those with hypertension or coronary heart disease,” said Yang Guo, PhD, the study’s lead author.

An association between allergic disorders and cardiovascular disease was detected in prior research, findings which remained controversial, Dr Guo explained. The present study sought to determine whether an increased cardiovascular risk exists in adults with allergic disorders.

The study used 2012 data from the National Health Interview Survey (NHIS), a cross-sectional survey of the US population. In the allergic group were adults with at least one allergic disorder, including asthma, respiratory allergy, digestive allergy, skin allergy and other allergy. The study included a total of 34 417 adults, over half of whom were women, average age 48.5 years. The allergic group included 10 045 adults. The researchers adjusted for age, sex, race, smoking, alcohol drinking and body mass index; they also examined subgroups stratified by demographic factors.

Having a history of allergic disorders was found to be associated with increased risk of developing hypertension and coronary heart disease. Further analysis showed that individuals with a history of allergic disorders between ages 18 and 57 had a higher risk of hypertension. An increased risk of coronary heart disease was seen in male Black/African American participants between ages 39-57. Asthma was the largest contributor of risk of hypertension and coronary heart disease.

Dr Guo said that to confirmed these findings, large cohort studies with long-term follow-up are required. Discovering the underlying mechanism could also help with management.

Source: American College of Cardiology

Categories : GeneticsTags :

The Need for an African Genetic Library

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Source: Mart Production on Pexels

Earlier this year, UCT professor Ambroise Wonkam published the Three Million African Genomes (3MAG) project in Nature, which he said started with a “crazy idea”. Now, it looks like his vision is starting to take shape.

The idea of creating a huge library of genetic information about the population of Africa emerged from his work on how genetic mutations among Africans contribute to conditions like sickle-cell disease and hearing impairments.

African genes contain great genetic variation, more than that seen outside of Africa. As he explained, “We are all African but only a small fraction of Africans moved out of Africa about 20–40 000 years ago and settled in Europe and in Asia.”

Another concern for Prof Wonkam is equity, saying: “Too little of the knowledge and applications from genomics have benefited the global south because of inequalities in health-care systems, a small local research workforce and lack of funding.”

Thus far only about 2% of genomes mapped are African, a good proportion of which are African American. This stes from a lack of prioritising funding, policies and training infrastructure, he says, but it also means the understanding of genetic medicine as a whole is lopsided. By studying African genomes, injustics can be corrected, such as finding that genetic risk profiles based on Europeans could be misleading for those of African descent.

To address these disparities, Prof Wonkam and other scientists are speaking to governments, companies and professional bodies across Africa and internationally, in order to build up capacity over the next decade to make the vision a reality.

He expects three million is the number needed to accurately map genetic variations across Africa. The project will take a decade, he says, costing around $450m per year, with industry already showing interest. 

Biotech firms welcome prospects of new data
The Centre for Proteomic and Genomic Research (CPGR) in Cape Town works with biotech firm Artisan Biomed on a variety of diagnostic tests. Gaps in the applicability of genetic data to the local population are a challenge for the firm, it said.

A genetic mutation in someone could be found but it would be uncertain if that variation is associated with a disease, especially as a marker for that particular population.

“The more information you have at that level, the better the diagnosis, treatment and eventually care can be for any individual, regardless of your ethnicity,” said Dr Lindsay Petersen, the company’s chief operations officer.

Artisan Biomed says the data it collects feeds back into CPGR’s research – allowing them to design a better diagnostic toolkit that is better suited to African populations, for instance.

Dr Judith Hornby Cuff said that the 3MAG project would help streamline processes and improve research, and one day could provide cheaper, more effective and more accessible health care, particularly in the strained South African system.

Prof Wonkam acknowledged that while the costs are huge, the project will “improve capacity in a whole range of biomedical disciplines that will equip Africa to tackle public-health challenges more equitably”.

“We have to be ambitious when we are in Africa. You have so many challenges you cannot see small, you have to see big – and really big,” he said.

Source: BBC News

Categories : Obstetrics & GynaecologyTags :

Black US Women at Increased Risk of Birth Complication

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Photo by SHVETS production from Pexels

Black US women are more likely than their white counterparts to experience a serious complication during labour or delivery, particularly due to systemic inflammation.

Systemic inflammation was one of four categories identified by the researchers when they looked for patterns in patients who experienced severe maternal morbidity (SMM) – an unexpected outcome of labour and delivery resulting in significant short- or long-term health consequences, including death. 

Women can experience multiple complications or events associated with SMM such as kidney failure and eclampsia. The study found these complications or events can occur within four categories: systemic inflammation (includes shock, abnormal blood clotting, adult respiratory distress syndrome [ARDS] and ventilation); cardiovascular events (includes kidney failure, eclampsia and cerebrovascular events such as aneurysm); admission to the intensive care unit; and haemorrhage leading to blood transfusion.

Black women were found to be at higher risk than white women in all four SMM categories, with the highest proportion experiencing SMM due to systemic inflammation.

“Previous studies have reported the higher the number of SMM complications or events a woman experiences, the higher the likelihood of death, but our study is the first to look at how these complications and events group together and their association with outcomes,” said lead author Andrea Ibarra, MD, MS, assistant professor of anesthesiology and perioperative medicine at the University of Pittsburgh School of Medicine. “We determined characteristics such as race, obesity and diabetes can identify which women are at higher risk of severe events, including death, in the various categories. That insight can spur efforts to develop new obstetric protocols and guidelines to improve care.”

Researchers reviewed records of 97 492 deliveries at one institution between 2008 and 2017 and determined that 2666 (2.7%) included an SMM event, with 49 women dying within a year of delivery. They found 44% of the deliveries associated with SMM were pre-term. Black women had higher rates of SMM (4.1%) than white women (2.4%).

Risk factors for all-category SMM included race, having pre-existing diabetes or having preeclampsia. Caesarean delivery was an additional risk factor for the haemorrhage category. Additional risk factors relating to women who fell in the systemic inflammation category were depression and social determinants, including low income or not graduating from high school.

“This research is crucial because most maternal morbidity is preventable,” said Dr Ibarra. “By identifying factors that put women at high risk of developing SMM complications or events, we can allocate more resources toward perinatal care.”

The findings were presented at the ANESTHESIOLOGY® 2021 annual meeting.

Source: American Society of Anesthesiologists