For thousands of years, the indigenous people of the far north survived the extreme cold of their environment with a diet of fat and protein and hardly any carbohydrates.
Now, there is evidence that the historic diet based on foods like muktuk and seal and walrus meat has been imprinted on the genes of Inupiat, Yupik and other northern peoples, with health effects that are potentially dangerous for babies and young children but potentially helpful for adults.
At issue is a gene that produces a key enzyme used in the liver: carnitine palmitoyltransferase 1A, or CPT1A for short.
The enzyme is needed in the process that burns fat for energy within the liver. It allows the body to switch between burning glucose -- the simple sugar broken down from carbohydrates -- and burning body fat. The CPT1A gene in some far-north indigenous people dramatically slows the burning of stored fat, preventing the body from getting the energy it needs to function.
That Arctic variant version of CPT1A is found in Inuit, Inupiat and Yupik populations of Alaska, Canada and Greenland and among some Natives in British Columbia, mostly on Vancouver Island, and the Tsimshian of Southeast Alaska who are related to them. It is not found among Interior Alaska or Canadian Native groups like the Athabascan and Cree, nor is it found among Natives in the Lower 48 states.
It is now confirmed in the indigenous people of northern Siberia as well. A Cambridge University-led study, published in October in the American Journal of Human Genetics, found that 68 percent of test subjects carried the gene. An earlier study by the many of the same researchers, published in May in the journal PLOS ONE, identified the CPT1A gene as one of several carried by indigenous Siberians that appeared to have been shaped by Arctic conditions.
The findings are the first to provide concrete evidence backing up the idea that CPT1A Arctic variant is a product of the Arctic environment and Arctic diet, said David Koeller, a pediatrician and geneticist at Oregon Health and Science University and an expert in CPT1A Arctic variant.
"I always assumed this gene was being selected for, but we had no definite proof," said Koeller, a leading researcher in the subject.
Medical risks for the youngest patients
For babies and young children, undiagnosed CPT1A Arctic variant can mean dire consequences during sickness or other periods when children might go without food. Those who go for long periods without breast milk, formula or other food -- generally six to eight hours -- are at risk for low blood sugar, known as hypoglycemia, and possibly worse.
"If it stays low enough long enough, they can get seizures," said Matt Hirschfeld, director of maternal child health at the Alaska Native Medical Center.
The variant is associated with infant mortality in Alaska, British Columbia and in the Canadian Arctic territory of Nunavut, where infant mortality rates from all causes are three times the Canadian average. Fatal cases seem to involve infants and children who suffer respiratory diseases, which are big chronic problems in rural areas of the far north.
There is also evidence that CPT1A Arctic variant is associated with serious respiratory and ear infections in Alaska, according to a 2013 study led by the Alaska Division of Public Health and co-authored by Koeller. It is not clear, Koeller said, whether the children with the Arctic variant are more vulnerable to acquiring infections in the first place or just more likely to have their infections become serious, and therefore more likely to be treated at a clinic or hospital and to have their cases reported.
The findings result in some explicit medical instruction for parents and caregivers of Native children with the Arctic gene: A sick baby or small child who hasn't eaten -- because of vomiting, prolonged sleep or other effects of illness -- should get glucose fluids through breast milk, formula, drinks like Pedialyte or, if necessary, an intravenous glucose drip, experts say. Caregivers should make sure affected children carrying the gene eat frequently, and they are advised to consult with health providers and state officials once the gene has been identified.
Anecdotal evidence is that some adults have long coped with the effects of this gene, if unknowingly, Hirschfeld said. They may talk about how they make sure to carry along snacks if they are engaged in strenuous activity like hunting, he said. After a few hours of exertion and no eating, as these adults describe it, they get sluggish, sleepy and "real jittery," classic signs of hypoglycemia, Hirschfeld said. "They'd have a candy bar, and they'd snap out of it."
Adults, with their larger bodies, can store more sugar in their blood and livers, and even those with the Arctic variant of the gene are able to fast for longer periods than children, unless they are exercising strenuously, Hirschfeld said.
The most serious problems afflict the youngest children, who can't get their own food when they need it, which is why it's important to detect the condition at birth.
The routine health screenings performed on all newborns in Alaska include tests for CPT1A Arctic variant, among the approximately 50 targeted conditions. Drops of blood are taken from babies' feet and spread on test cards to be analyzed for, among other things, signs of how the CPT1A enzyme is functioning. Analysis is done at the Northwest Regional Newborn Screening Program in Oregon, which handles newborn screenings for Alaska and five other states.
That has been the case for only about a decade. Prior to late 2003, when CPT1A tests became part of routine Alaska infant screening, there were only about 30 or 40 confirmed cases in the world of what was then called "CPT1A deficiency." It affected people outside of Arctic indigenous populations, was considered a random mutation, and resulted in near-total shutdown of the CPT1A function.
Once signs emerged that something similar was affecting Native children, researchers found that the gene was functioning differently, at a low level rather than the near-total shutdown seen elsewhere. This version became known as "CPT1A Arctic variant."
"It's not 'deficiency' anymore because, really, that's the normal gene," said Hirschfeld, who with Koeller and other colleagues, conducted some clinical trials to confirm the characteristics.
From late 2003 to mid-2006, according to the Alaska Division of Public Health's Epidemiology Section, 38 infants were identified through the new screenings as having CPT1A Arctic variant -- roughly equivalent to all the known CPT1A deficiency cases in the world at that time. As of now, about 900 Alaska babies have tested positive for CPT1A Arctic variant, Hirschfeld said.
Screenings used today are imperfect, however, because the test looks for the metabolic effects of the Arctic variant, which are not always apparent. A new type of newborn screening process, developed by Koeller and his colleagues, will look for the associated gene itself, meaning identification of all cases.
That new test is planned for introduction in Alaska next year, though administrative approvals are still pending and funding has yet to be arranged.
Once the new test is in place, expect 700 babies to be diagnosed each year with CPT1A Arctic variant, an estimate based on modeling, Hirschfeld said.
Despite the risks associated with it, experts stress that CPT1A Arctic variant is not a disease or disability, but a natural genetic condition for some people.
"The gene is, in and of itself, fairly neutral. It's a matter of context," Koeller said.
A genetic advantage in a harsh climate?
There are signs that the Arctic variant of the gene can provide health advantages.
The latest Cambridge study hypothesizes that the arctic version CPT1A gene gave a metabolic advantage in the past, when there was strict adherence to the traditional high-fat diet, but that lifestyle changes have created a disadvantage. "The deleterious effect of the mutation might be explained by a change from the traditional diet to a more carbohydrate-based one or by recent cultural shifts and environmental stressors such as fasting and pathogens," Alexia Cardona, a lead author of both Cambridge studies on CPT1A, said in an email.
There are also signs of modern protections against obesity-related ills, at least among people eating a traditional diet.
One study of Yup'ik adults in Western Alaska found relatively low levels of diabetes and metabolic syndrome, even for people with a high level of body fat. That study, published in 2007 and led by Bert Boyer of the Institute of Arctic Biology at the University of Alaska Fairbanks, cited a "traditional diet rich in polyunsaturated fatty acids" as a potential factor.
A more recent study by 10 researchers, including Boyer and others at the Institute of Arctic Biology, cited the Arctic variant of CPT1A as a reason for the "healthy obesity" found among Alaska Yup'ik people. The Arctic variant appeared to be protective regardless of test subjects' body weight, said the study, published in 2012 in the Journal of Lipid Research.
If this genetic trait evolved in tandem with the traditional fat-and-protein Arctic diet, said Koeller, it would be logical to expect it to manage the intake of some occasional carbohydrates.
"It slows down how quickly this enzyme can work, but it also eliminates the ability to shut it off in the presence of carbohydrates," he said. That means someone with the variant can continue to burn fatty foods for fuel, even "If you happen to get a few carbohydrates in your body, like you get a good crop of berries," he said.
But as with other aspects of CPT1A Arctic variant, the role of traditional foods has yet to be tested or fully understood.
Koeller, Hirschfeld and their colleagues envision some long-term studies to understand the health outcomes for children growing to adulthood and the differences, if they exist, between those eating traditional diets and those eating more carbohydrate-heavy Western diets.
The study, in the preliminary planning stages, has a noble objective -- to prevent serious illness and death among babies and young children, Koeller said. "The whole point of our study is so that we can understand it more so we can reduce that," he said.