Māori and Pacific people have long been told that the state of their health is their fault. Now, genetics is giving scientists new tools to both improve health and fight discrimination. And the results could help us all.
They’re part of a research programme being run by scientists who say genetics plays a much bigger role in metabolic diseases than it’s given credit for, and sufferers are being unfairly stigmatised when people blame their condition solely on diet and lifestyle. This year, Auckland Girls’ Grammar is one of about 50 schools whose Year 9 or 10 students will discover how they respond to fructose in their diet – it’s estimated between 20 and 25% will be defined as fructose malabsorbers, which is linked to a lower body mass index (BMI) and may protect against diabetes.
The experiment, part of Tātai Oranga, a grassroots-research programme linking communities with scientists, is being run by the Maurice Wilkins Centre, one of the country’s Centres of Research Excellence. The nationwide group of researchers is investigating genetic and other factors that increase or reduce risk of diabetes and change the way patients respond to common treatments.
The Moko Foundation in Kaitaia, founded by GP and former New Zealander of the Year Dr Lance O’Sullivan, is a partner in the Sugar in Schools programme, and other studies that are providing new data linking genetic and other personalised patient-health information in a bid to revolutionise treatment options.
“The opportunity here is exciting,” says O’Sullivan. “We have limited resources as a country and targeting risk-reduction strategies universally gives us really mediocre outcomes, whereas if we have precise information about individual risk through genetic information, we can be really clear about people who need customised treatment.”
At least half his diabetic patients have a problem with side effects of metformin, the mainstay of treatment before insulin. “Māori patients tend to need high doses, which come with a lot of complications, including chronic diarrhoea. Often with these patients we don’t have a second chance. You give them something for their diabetes that’s horrible and has bad side effects and you never see them again, so we should be trying our best option first.”
Knowledge about the triggers for diabetes and gout is expanding rapidly, outpacing what doctors learnt in medical school. “I compare what we are learning now about gout, for example, with what we knew then. We know now it’s a very genetically driven condition in Māori, yet for decades the advice from doctors was, ‘You’ve eaten too much kai moana and you drink too much, so you’ve got to change your lifestyle.’
“I saw a patient yesterday who said, ‘Yeah, it’s my fault, I’m eating and drinking too much.’ The reality is that’s probably not the case, but you’re genetically programmed to process uric acid differently and, regardless of what you eat, you are going to have problems with gout. We can manage it a bit differently. Patients get sick of being told off and treated like a naughty kid, so that’s why I’m excited about these initiatives.”
University of Auckland-based Maurice Wilkins Centre (MWC) deputy director Professor Peter Shepherd hopes the research will break long-held stereotypes. “There’s no doubt exercise and a good diet are helpful, but there are people, including scientists, who will look at the data and say, ‘Well, that’s all very interesting, but we know people can still control their food intake and should be able to’, because for them it’s not a problem. It’s the skinny-white-men-in-bicycle-shorts syndrome – they would never get fat in their life if they tried. You can’t just choose the facts you like if you want to solve the problem.”
Up to 20% of Māori and Pacific people are thought to have a genetic variant that may make them process metformin differently, and another, which occurs in about 15% of men, that increases the risk of high blood pressure. “Anecdotally, there is evidence Māori and Pacific people do worse on metformin, but no one has done the studies in New Zealand because the medical system just says, ‘Here’s a pill, everyone take it.’ Doctors figure we’ll give it to everyone and it’ll work in 80% and that’s good enough. The problem is, a lot of Western medicines were trialled on Western people and we don’t know if they are going to work the same way in Māori and Pacific people.”
Bigger not fatter
Another variant, known as CREBRF, which is found in about 30% of Māori and Pacific people but not in Europeans, is associated with higher BMI – usually a measure of obesity and associated ill-health. However, the variant is remarkably protective against diabetes, and recent unpublished research from the MWC indicates that the higher BMI is the result of more muscle, not fat.
“It’s not making people fatter; it’s making them bigger,” says Shepherd. He also points out that BMI varies widely in different ethnic groups, showing again the effect of genetics. People of Asian origin, for example, have very high rates of type 2 diabetes at much lower BMI. The research may have wider implications – another recently identified gene variant that was more common in Māori and Pacific people, but also moderately common in East Asian people, has been found to be associated with increased risk of hypertension. Shepherd believes this will reveal a mechanism that’s never been identified before to regulate blood pressure. It raises the hope of not only early intervention with current drugs, but also a new group of medicines being developed to treat it.
“We have been stigmatising whole parts of the population by BMI,” says MWC and University of Otago researcher Tony Merriman, who has sequenced the genome of dozens of Māori and Pacific people to find genetic information unique to those populations.
“A lot of academic colleagues have this perception that Māori and Pacific people are not comfortable about having their genomes sequenced, but that’s just rot, really. When you get out to the communities, they say, ‘We want you to do this research. But we want you to do it in a way that we have governance and we trust each other.’”
From Auckland north, the Sugar in Schools work is being run by health-science graduate Conor Watene-O’Sullivan, Lance O’Sullivan’s son, out of Waharoa ki te Toi in Kaitaia, a research centre set up in another Moko Foundation-MWC partnership. South of Auckland it is headed by Waikato-based teacher-scientist Crystal Gerring.
Waharoa ki te Toi runs the school-based work, but is also recruiting for a Health Research Council-funded study on genetics and outcomes in diabetes. About 250 Māori and Pacific men and women have so far joined the study, which aims to recruit 1000 participants from Kaitaia, Auckland, Gisborne and Wellington. Participants are phenotyped locally and have their DNA sequenced in Auckland and Otago. “One of the key aspirations is to build a lasting organisation in the Kaitaia community run by people from there to play a deep, meaningful role in the research, rather than having it all done in an ivory tower in Auckland behind closed doors,” says Shepherd.
Bringing jobs back
At Te Puia Springs Hospital on the East Coast, the work is being done from Te Rangawairua o Paratene Ngata, named after Māori health advocate Dr Paratene Ngata. It’s a joint research centre run by the MWC and Ngāti Porou. “It’s a real partnership and it’s bringing jobs back to these communities, which haven’t had a stake in the game,” says Shepherd. “We want this to work on multiple levels, so the mana and the prestige come back to these communities as well as health benefits.”
Anezka Hoskin, a post-graduate genetics student in Merriman’s lab at the University of Otago and Ngāti Porou herself, although she was born overseas, has been investigating genetic variants specific to Māori and Pacific people, but very rare in other populations, to find out if they might have a role in type 2 diabetes.
Otago has the DNA of about 3000 Māori and Pacific people, of whom about 500 are from Ngāti Porou. Hoskin is comparing the genetic information with the physical characteristics of the sample donors. “I’ve learnt an increase in BMI doesn’t necessarily mean an increase in disease burden in these populations, and that’s an assumption we currently hold in clinical healthcare. The correlation is not as strong as it may be in other populations.” Part of the problem is that the genetics of type 2 diabetes before now have all been based on European and Asian populations rather than indigenous minority groups.
“It’s really special being able to walk past the lab and know there is the DNA of 500 people sitting there that is our whakapapa; it is a huge honour. I feel such a responsibility and I want to make sure that it is protected and used in the right way, for research that will help our people, empower our people and increase our knowledge about our health and how our body works and encourage people to take ownership of their health.”
Hoskin chose a career in health and genetics after her sister was diagnosed with type 1 diabetes. She says she’s also faced stigmatisation on the basis of her BMI. “I’ve been at the doctor and my BMI has been calculated and they’ve wagged their finger at me and told me to lose weight and get to the gym. It’s infuriating – I know I have no health issues whatsoever.”
Shepherd says although DNA from 3000 people is stored, the genomes of only 170 have been fully sequenced so far in the Health Research Council-funded research. “From that, decisions are made as to where to focus – dealing with three billion bits of information per person is really hard, so we focus on places where there are gene variants, particularly differences that are statistically associated with risk of disease. In future, we will be looking routinely at only about 300 of the three billion points in the genome for the studies we need to do.”
Bringing the research findings from the laboratory into the doctor’s surgery is a key task for Auckland-based MWC scientist-clinician Dr Rinki Murphy, a diabetes expert who leads its genetic predisposition to obesity and diabetes programme. She’s heading a study investigating how patients respond to two medicines for type 2 diabetes, vildagliptin and pioglitazone, which act on different pathways. Vildagliptin promotes more insulin being released on eating, whereas pioglitazone increases insulin sensitivity in muscle and fat.
She says if doctors can understand which patients will respond better or worse to the medications, based on factors such as age, gender, obesity, lipid profile and ethnicity, they can prescribe more rationally. The study aims to recruit 300 patients by the end of the year, with study sites in Auckland, Kaitaia, Gisborne and Waikato. Anyone being treated with tablets for diabetes, but who is not on insulin, vildagliptin or pioglitazone, can contact the study if they’re interested in taking part, at T2Dmed@auckland.ac.nz.
The study will also look at whether people who develop diabetes despite carrying CREBRF, the normally protective variant, respond to one medicine better than the other. People who carry the variant have a 40% lower risk of developing type 2 diabetes. Women who have it seem to also be protected against gestational diabetes.
If the finding is confirmed, it means Māori and Pacific women may be able to be tested for the variant as part of their routine clinical care and those who have it may need fewer of the burdensome glucose-tolerance tests traditionally given to overweight Māori and Pacific women during pregnancy.
“Being judged by size and ethnicity can be really demotivating,” says Murphy. “We want to be more precise in our estimations of diabetes risk and treatment and to be more compassionate about where different people are at with regard to body weight and health. We’ve always recognised that people vary in their weight threshold before developing diabetes, but we didn’t have a genetic marker.”
The search for genetic pointers for better-targeted treatment is also spreading to general practice. In May, the innovation arm of Midlands Health Network, Pinnacle, which has about half a million patients on its books, launched a programme aimed at using patients’ genetic makeup to drive prescribing decisions. It plans to have about 5000 patients gene-tested in the next year, and although many of these will be self-funding, the network will pay for tests for some of its highest-risk patients. Information from the gene tests will be embedded in patients’ electronic records and linked to a tool that helps doctors decide which drugs are best for patients with certain genetic variants.
“This is Star Trek – not in my lifetime”
Pinnacle chief executive John Macaskill-Smith says that comes with education to better equip GPs who often didn’t learn too much about genetics at medical school. “When you bring it up, they get a bit pale and pasty. Half will go ‘This is Star Trek – not in my lifetime’, and the other half will generally look uncomfortable because they know it’s there and don’t know enough about how pharmacogenomics works.”
He says the primary healthcare organisation decided it needed to be proactive about patient health rather than running clinics like mini emergency departments that waited for sick people to turn up. “We said, ‘How can we keep people well and healthy?’, and one of the things that came up very clearly was personalised, precision medicine, and pharmacogenomics is a big part of that.”
Pinnacle is one of the country’s largest health providers for Māori, who make up more than a quarter of its patient population. “We can see where medical regimes are not working. In some cases, we are getting better results from community coaches and lifestyle interventions than we are from some traditional medicines, so that’s reinforcing some of the work that the Maurice Wilkins Centre is doing.”
He hopes Pinnacle can work with the researchers to help scientists get answers to their questions. “They are excited because no one else is at this scale and co-ordination in introducing pharmacogenomics in New Zealand.”
Says Shepherd: “We have huge numbers of people with diabetes, but we are using stone-age tools to treat it, and health authorities are just shutting their eyes and hoping it will go away, when we could do so much better.”
For some people, it's a "bloody struggle".
The genetic profile of overweight people with diabetes such as Chetham, who tipped the scales at 253kg between 2005 and 2007, and now weighs 119kg, will be compared with those of middle-aged people who are neither obese nor diabetic. The research may find he’s inherited an increased risk of obesity, but Chetham thinks his weight is “100% in my control, even with the genes. It’s a bloody struggle, but it’s still up to you. You can’t expect doctors to give you a quick-fix pill.”
Unfortunately for Chetham, the researchers aren’t able to release individual results because of concerns that the genetic-risk information could be misunderstood and negatively affect participants’ health behaviour.
Chetham, who works at North Port as a facilities service officer, has lost 30kg in four years. He is not on diabetes medication, after his metformin caused liver damage.
He hopes to work with the Maurice Wilkins Centre to set up a community research base at the Patuharakeke iwi’s Takahiwai marae in Bream Bay for sugar-absorption testing. “This is a two-way street – open communication between science and medicine for our well-being. Knowledge is power and it’s giving people choices backed up by the science.”
Clinician-scientist Dr Rinki Murphy, one of the lead diabetes investigators in the original research, wants to followup Chetham and other participants and randomly assign them to receive lifestyle information with their genetic results, or lifestyle information alone, to see how they fare three months and a year later.
How do Pacific populations differ?
“The view without much data is that all Polynesians will be the same [genetically],” Professor Lisa Matisoo-Smith says. “We are not seeing that. It helps us tease apart some of the evolutionary history, and the causes for the different mutations when populations adapt in different ways.”
European diseases, for example, had a greater impact in east Polynesia than in the west. “That might have been a selective force that shaped east Polynesian genomes, or [it could be] that there is a different source population for the two groups.”
Her research group wants to compare the Polynesian genome with that of other Pacific populations to try to understand the driving forces that shaped it. That understanding will help remove some of the blame-and-shame mentality that can accompany diagnoses of gout and diabetes. “We can say in our current environment it’s having a negative effect on your health, but perhaps it’s a genetic predisposition that allowed your ancestors to survive malaria or other infectious diseases.
“Modern people carry portions of genome of ancient hominins and Pacific populations carry some of the highest frequencies of these. As anthropologists, we look at that and ask if that’s contributing to the disease and genetic profiles we see in them and the relationship with disease in the Pacific – that’s a deep history a medical doctor wouldn’t consider.”
This article was first published in the June 29, 2019 issue of the New Zealand Listener.