Hyperuricaemia in the Pacific: why the elevated serum urate levels?
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- Gosling, A.L., Matisoo-Smith, E. & Merriman, T.R. Rheumatol Int (2014) 34: 743. doi:10.1007/s00296-013-2922-x
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Pacific Island populations, particularly those of Polynesian descent, have a high prevalence of hyperuricaemia and gout. This is due to an inherently higher urate level among these populations with a demonstrated genetic predisposition. While an excess of urate can cause pathology, urate is also important for human health. It has been implicated as an antioxidant, has a neuroprotective role and is involved in innate immune responses. This paper provides a brief review of urate levels worldwide, with a particular focus on island Southeast Asia and the Pacific. We then present possible evolutionary explanations for the elevated serum urate levels among Pacific populations in the context of the physiological importance of urate and of the settlement history of the region. Finally, we propose that ancestry may play a significant role in hyperuricaemia in these populations and that exposure to malaria prior to population expansion into the wider Pacific may have driven genetic selection for variants contributing to high serum urate.
KeywordsHyperuricaemiaSerum uratePacific IslandersMigrationSelectionMalaria
In humans and the other great apes, urate is the end product of purine catabolism. In most other mammals, it is further degraded into the more soluble allantoin by the enzyme uricase and can thus be easily excreted from the body in urine . Due to a series of mutational silencing events in this gene during hominoid evolution, humans, and their great ape relatives, do not have a functional uricase . This results in urate levels that are much higher in humans (averaging between 4.0 and 6.0 mg/dL) compared to other mammals who generally have a range of 0.5–2.0 mg/dL .
Urate is clinically important because high concentrations in the blood (a condition known as hyperuricaemia; usually defined as >7.0 mg/dL in men and >6.0 mg/dL in women) can result in nucleation, forming crystals of monosodium urate (MSU). These crystals can trigger inflammation , which, depending on the location of the crystal deposition, may result in pathology—gout if in joints and nephrolithiasis if in the kidney. Diseases associated with hyperuricaemia in humans include hypertension, chronic kidney disease and type 2 diabetes . Interestingly, low levels of serum urate have also been found to be associated with diseases of neurological origin, such as Parkinson’s disease , multiple sclerosis [7, 8] and Alzheimer’s disease . Thus, urate is clearly of some biological importance to the physiology of humans—this is supported by the observation that there seem to be multiple pathways resulting in these heightened serum urate levels. Not only is there dysfunction of the uricase gene in humans, but 90 % of the uric acid filtered by the kidneys is resorbed, further raising the levels of circulating urate in the blood . The regulation of urate is complex, with main causal factors of hyperuricaemia being diet and genetic variants of renal urate transporters .
Hyperuricaemia in the Pacific
Examination of these data show that most Pacific Island populations (Polynesians and Micronesians) and their possible ancestral populations (Taiwanese aboriginals) in particular have higher rates of hyperuricaemia, with few other populations showing high mean serum urate levels (in the 6.5 mg/dL + range). Most populations have average serum urate concentrations of between 4 and 6 mg/dL, below the hyperuricaemic threshold. While some of this variation could relate to differences in lifestyles, subsistence and environment, ancestry is also a likely contributing factor. Given the varied evolutionary experiences of populations worldwide since the expansions out of Africa, it is feasible that higher serum urate concentrations may have been positively selected under certain environmental conditions, leading to the variability which we see in modern populations globally.
Environment clearly also has an effect on serum urate levels; a number of studies have sampled from both urban and rural cohorts from within the same population, presumably to help understand the effects of urbanised living [16–23]. Higher urate levels were generally observed in those inhabiting an urban environment. For instance, Tongan men from urban areas had mean serum urate levels of 6.5 mg/dL compared with 5.3 mg/dL in those living in rural areas . Similar trends were seen in Papua New Guinea, with an urban Melanesian population living in Port Moresby having mean serum urate levels of 6.2 ± 1.3 mg/dL, compared to 4.2 ± 1.3 mg/dL in a rural cohort . In general, living in an urban environment exacerbates the tendency towards elevated serum urate levels, concomitant with the increased consumption of foodstuffs (such as sugar-sweetened beverages and alcohol) that increase urate [24–26]. However, the fact that even those living rurally and with more traditional lifestyles in Polynesia have high rates of hyperuricaemia, compared to other populations worldwide, suggests a genetic predisposition.
Hyperuricaemia may be an Austronesian phenomenon
Polynesian and Micronesian peoples speak languages belonging to the Austronesian language family. Austronesian languages are thought to have originated in Island Southeast Asia (ISEA), perhaps Taiwan, around 5,000 years ago before being dispersed throughout ISEA, Oceania and beyond . Non-Pacific Austronesian-speaking populations also have elevated heightened serum urate levels. Taiwanese aborigines have particularly high serum urate concentrations [28, 29], while Filipinos also seem to have elevated serum urate levels . The Merina population in the Highlands of Madagascar, who have also been ancestrally linked to an Austronesian expansion out of ISEA , have likewise been observed to have high rates of gout and hyperuricaemia . Similarly, the Seychellois, who likely have an ancestral genetic contribution from Austronesian-speaking colonists  exhibit elevated serum urate concentrations .
Mitochondrial DNA analyses indicate that Polynesian and many other Austronesian-speaking populations have a significant genetic contribution from Southeast Asia , where mean SU levels range from 5.5 to 6.5 mg/dL (Appended data). Y-chromosome STR analyses of Polynesians show that there is also a significant ancestral contribution from ancient Melanesian or Near Oceanic, non-Austronesian-speaking populations . Figure 2 shows that the hyperuricaemic phenotype does not seem to be present in many Melanesian populations on the mainland of New Guinea and in the Solomon Islands, where sampled populations show mean SU concentrations ranging from 4.2 to 6.2 mg/dL, compared with Polynesians whose mean SU range from 5.3 to 7.1 mg/dL. Near Oceanic populations are not genetically homogenous , so these data should not be taken to be representative of all populations living in this area. However, the raised urate levels as seen in other Austronesian-speaking populations predominate over the lower serum urate concentrations in non-Austronesian speakers. This suggests that there may have been some form of selection to a more hyperuricaemic phenotype in Austronesian populations.
Possible explanations for heightened serum urate in Pacific Islanders
Modern epidemiology has demonstrated that raised serum urate levels have a multifactorial aetiology, with both environmental and genetic factors contributing. Lifestyle, diet in particular, is known to heavily influence the concentration of SU—more specifically the consumption of purine and fructose-rich foods [24–26]. The last five decades in particular have seen radical changes in dietary habits in the Pacific. This is most evident in urban settings, but these changes are also occurring in many rural communities. There is now a reliance on the importation of foreign foodstuffs, because population sizes have reached points where the islands are now no longer self-sustainable . Exacerbating this shift in subsistence practices is the decreasing popularity of traditional production practices and diets [37, 38]. Many of the imported foods are high in fat and sugar, leading to the coining of terms such as “dietary colonisation”, “Coca-colonisation” and “dietary genocide” .
Many theorists writing on the topic have attributed the high rates of hyperuricaemia (and indeed, gout) in the Pacific to this change away from traditional diets and lifestyles, stating that prior to the twentieth century gout was unknown [39–43]. However, recent skeletal evidence of gout from prehistoric archaeological sites in New Zealand [44, 45], Hawaii , Vanuatu  and Micronesia [47, 48], in addition to the nineteenth century reporting and diagnosis of gout , suggest that hyperuricaemia and gout in Pacific Island populations may not be as modern a phenomenon as previously supposed.
Traditional Pacific diets are thought to have been to be relatively healthy, with subsistence dominated by the horticultural production of starchy food crops, including various combinations of taro, yams, breadfruit and kumara, among other domesticated plants [36, 37, 50]. The starchy staple was generally served accompanied with a lesser quantity of some form of protein, often fish or shellfish. It should be noted that seafood consumption has been associated with the development of gout . Given the perception of the healthy prehistoric Pacific diet, with few obvious dietary urate-raising factors, other factors, such as a genetic predisposition to elevated serum urate, are likely to have played a role in prehistoric Pacific hyperuricaemia. Genes encoding proteins involved in renal and gut excretion of uric acid have a strong effect on serum urate levels, though genes involved in glycolysis are also associated . There have been several studies carried out on Māori and Pacific Island people living in New Zealand, which have found that at least some of these genetic variants contribute to the risk of gout [52–54].
Collectively, the evidence suggests an inherent biological (genetic) predisposition to hyperuricaemia in Polynesians. How might this have occurred? There are a number of processes by which genetic variants contributing to heightened serum urate concentrations may have increased in frequency at the population level, including ancestry, random genetic drift and natural selection. The circumstances under which these may have operated will be discussed below.
Colonisation processes and Oceanic voyaging: bottleneck effects?
Pacific populations, at least in part, are descended from peoples associated with the archaeologically defined Lapita cultural complex. The Lapita culture first appeared in the Bismarck Archipelago approximately 3,350 years ago, and people carrying this culture rapidly sailed eastwards colonising the Reef Santa Cruz (Southeast Solomon Islands), Vanuatu and New Caledonia within a few 100 years. Lapita expansion stopped at the edge of Polynesian Triangle, in Tonga, which was settled by 2,830–2,846 years before present (BP), and Samoa, settled at a similar time . The most recent dates for settlement of East Polynesia suggest that around 1,200–1,500 years later, further migrations were undertaken from Samoa into Central and East Polynesia, the Marquesas and the Cook and Society Islands, and even later into the more remote islands, with settlement of Rapa Nui at 800 BP, Hawaii between 800 and 1,200 BP, and Aotearoa New Zealand around 700 BP .
The settlement of Polynesia, and hence modern Polynesians, is thus the end product of a voyaging process, which occurred over many thousands of years. Often founder effects are employed to explain an apparent lack of genetic variation in Polynesian populations and the apparent dissimilarity phenotypically between Polynesia and Melanesia —though continuous contact and voyaging would have nullified these effects. The basis of the underlying idea of limited genetic diversity in the Pacific resulting from founder effects lies in the observation that on average, 94 % of the mitochondrial variation in Polynesian populations is derived from East Asian haplogroups specifically those derived from the B4a1a1 haplotype . However, to suggest that these founder effects have led to the chance emergence of a hyperuricaemic phenotype in Polynesians is simplistic and unlikely. Also, when the data from the wider region are reviewed, the Polynesian serum urate levels are not out of context (Fig. 2) because the phenotype seems to be present in other populations in the homeland region, Taiwanese aboriginals, for instance, who were unlikely to have had the same demographic founder alterations resulting from serial migration.
Another mechanism by which genetic variants contributing to elevated serum urate may have come to prominence is natural selection. In order to assess the possibility of selection for heightened serum urate concentrations, it is necessary to discuss the different biological roles of urate in humans. What follows is a brief description of these roles and how these may have provided a selective advantage to those with hyperuricaemia.
Antioxidant effect of urate
Urate can function as an antioxidant [59, 60]. Antioxidants are very important, as radical oxygen species can cause irreversible oxidative damage to cellular organelles and DNA, which can impair the function of the individual and result in death. Urate accounts for up to 60 % of total plasma antioxidant activity . This may help protect endothelial function, and combat oxidative stress associated with ageing . It has also been implicated as being neuro-protective. Unusually low SU levels have been associated with diseases such as multiple sclerosis [7, 8], Parkinson’s disease  and Alzheimer’s disease . The brain is particularly vulnerable to oxidative damage because of its high metabolic rate and the high lipid content of brain tissue . The antioxidant activity of urate seems an unlikely selective force specifically in the Pacific, as there is no reason to believe that people dwelling in the Pacific, or more precisely Polynesia, should face any more oxidative stress than any other island dwelling population. In addition, most of the diseases associated with low SU levels have impacts in post-reproductive periods of the lifecycle.
There is a strong association between hyperuricaemia, hypertension and cardiovascular risk [62–64], which has led to the hypothesis that in the course of human evolution, urate may have played an important role in maintaining blood pressure in conditions of low salt ingestion . Through an animal experimental model, Watanabe et al.  found that urate helps maintain blood pressure both acutely, by stimulating the renin angiotensin system and chronically, by inducing salt sensitivity.
There is evidence to suggest that during the Miocene epoch, which is when the series of mutations leading to the inactivation of the uricase gene in Hominids are thought to have occurred, salt consumption among our pre-human ancestors was considerably lower than in modern-day societies . In this situation, the increase in blood pressure associated with raised serum urate levels was advantageous . However, again, with the ready availability of salt in Pacific Island environments, this seems an unlikely evolutionary force in the Pacific.
Uric acid as a physiological alarm
Johnson et al.  have proposed that under conditions of environmental stress and starvation, urate may have had a beneficial effect as a physiological alarm. Studies have shown an increase in urate concentration under conditions of fasting  or starvation , may have a number of beneficial effects, including increasing locomotor activity necessary for foraging, stimulating hypertriglyceridaemia, fatty liver and weight gain to help re-establish fat stores, and to increase salt sensitivity to help protect against dehydration . They further suggest that the development of insulin resistance, which is also associated with many metabolic diseases, could also be beneficial, by reducing glucose uptake into skeletal muscle and adipose tissue, thus preserving glucose for utilisation by the brain where glucose uptake is insulin independent.
This potential role of urate has more credibility as a possible selective force in Pacific Island peoples. Island environments, such as those we see in the Pacific, are vulnerable to catastrophic events such as cyclones and tsunami, which are capable of wiping out not only food supplies but also sources of fresh, potable water on islands, causing periods of famine. It is possible that such events in the past have caused some selection for those with apparently enhanced genetic fitness. These sorts of catastrophic events can also result in population bottlenecking events, thus changing allele frequency. The widespread nature of the hyperuricaemic phenotype in Austronesian-speaking populations across Oceania and beyond, however, does suggest that any population bottlenecking to cause a hyperuricaemic phenotype would have had to occur early on prior to population expansion into ISEA and the Pacific for all of the descendant populations to be affected or else to have happened numerous times across the Pacific.
Urate as an adjuvant
Urate plays a significant role in immune regulation . When crystallised, it has been found to activate innate host defence mechanisms in multiple ways and triggers a robust inflammatory response [5, 70]. For this reason, crystallised urate (monosodium urate; MSU) is considered to be an important natural endogenous adjuvant and has been employed in vaccinations to help stimulate a host response against antigens, which may otherwise be considered innocuous. Not only can monosodium urate crystals stimulate phagocytes and monocytes, but they can activate the NLRP3 inflammasome; both the classical and alternative complement pathways interact with antibodies, as well as a number of other immune pathways . Absence of urate inhibits the immune response associated with clearing debris from damaged cells.
Infectious disease is one of the strongest forces of selection . The genes associated with immunity are under selective pressure as contact with an infectious agent requires an appropriate immune response. It is possible that urate-raising genetic variants may be selected for by infectious disease.
There are a number of events in the history and prehistory of the Pacific which may have resulted in the selection of genetic variants, which could contribute to the inherently high mean urate levels throughout the region. Discussed below are two possible periods of selection for genetic variants contributing to inherently high serum urate levels, one deep in prehistory with the exposure of ancestral Polynesian populations to malaria prior to their arrival in the malaria-free islands of Polynesia, and the more recent exposure of these populations to novel diseases post-European contact.
Malaria as a means of selection
Malaria is possibly the most serious infectious disease currently known to humankind, killing on the order of 2 million people annually . Malaria is not a new immunological challenge: humans and malaria-causing Plasmodium species parasites have had a long evolutionary host–parasite relationship . Malaria is known to have influenced the human genome, with disorders such as sickle cell anaemia, alpha- and beta-thalassaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency and band 6 ovalocytosis having been attributed to malarial selective forces . It is possible that the inherent hyperuricaemia seen in Polynesian populations is another such adaptation.
Urate plays an important role in the innate immune response and has been found to induce host inflammatory responses in malaria [76–78]. The urate is released with the lysis of erythrocytes during the cyclical blood stage of malarial infection. It is during this time that the host immune system finally detects the presence of the parasite. Since an early and robust inflammatory response is critical for controlling the infection, inherently high serum urate levels may be advantageous for those living in malarial environments and could have been selected for, as fewer host erythrocytes would need to rupture before the innate immune response countering the malarial parasites was triggered, thus enhancing the rates of host survival.
It is important to note that mean serum urate concentrations reported in populations from coastal Papua New Guinea, where malaria is endemic, are much lower than those observed in Polynesians and, indeed, Micronesians (Fig. 2). For instance, male Papuans living on the Madang Coast (northern mainland Papua New Guinea) have serum urate levels of 4.8 mg/dL , while males from Kalo village in the lowlands (Central Province, Papua New Guinea) were reported to have urate levels of 4.2 mg/dL . Malaria is thought to have been present in coastal regions for a substantial period of time—the early habitation (around 50,000 years ago) of the malaria-free Highland regions of New Guinea  may have been driven by the presence of the malarial parasite in the lowlands. As a result of this long exposure to malaria, a wide array of malaria-associated haemoglobinopathies, including the globin gene variant (α3.7III) seen in Polynesians, are observed in lowland New Guinean populations . Evidence of substantial genetic admixture between the Asian-derived Austronesians and the non-Austronesian original inhabitants of New Guinea is only significant in the Admiralty Islands and the Bismarck Archipelago, to the north of the mainland of New Guinea, particularly the New Ireland Province . To date, there are only published data on the serum urate levels from mainland New Guinea populations. Because of the different genetic background of ancient Near Oceanic- and Asian-derived Austronesian populations, it is conceivable that different adaptive mechanisms developed in response to malaria, explaining the absence of elevated serum urate in these populations.
The introduction of novel diseases and pathogens after European contact had a significant effect on the demographics of many Pacific populations . Prior to the exploration of the Pacific by Europeans, Oceania had long been isolated from most infectious diseases. The small-scale nature of most populations but particularly their isolation protected these islands from influenza, measles, mumps, smallpox, tuberculosis, cholera, plague, typhoid, whooping cough and venereal disease . These diseases were therefore alien to Pacific Islanders, leaving them immunologically naïve, and thus exposure to these diseases had the capacity to cause large-scale loss of life.
While it remains challenging for archaeological and historical demographers to assess the effect of the introduction of Western diseases on these island populations for a number of reasons, in part because of the lack of regular, systematic censuses on many islands and the uncertainty over the initial population sizes , it is clear that introduced diseases did have a major impact. Some islands seem to have been more affected than others, but on some islands where records are available, it is possible to link epidemic outbreaks of diseases such as whooping cough, measles and influenza to visits by certain European ships, and many of these epidemics caused significant mortality . East Polynesia was hit particularly hard—much more so than West Polynesia—particularly during the initial introduction of these diseases, which resulted in losses up to 75 % of the population in some islands . This may go some way to explain some of the genetic differences between East and West Polynesia [53, 84].
Given the role of monosodium urate crystals in enhancing the innate immune response, it is possible that genotypes promoting increased urate levels were positively selected for during these periods of massive depopulation. It is also likely, given the presence of archaeological evidence for gout in samples that are definitely from a pre-European era, that urate-raising variants were already at a higher prevalence prior to the introduction of European infectious diseases.
Raised serum urate levels are seen throughout the Pacific, particularly in Polynesia, Micronesia and among Taiwanese aborigines. Archaeological evidence suggests that this is not a new phenomenon. The multifactorial aetiology of hyperuricaemia indicates that there are likely to be a number of contributing factors, including a genetic contribution. The localised heightened prevalence of hyperuricaemia and gout in Polynesian and Micronesian populations suggests that shared heredity may contribute. However, while potential reasons for this may be proposed, it remains difficult to disentangle how, when and why this hypothesised genetic contribution arose in these populations.
Processes of natural selection may have contributed to the phenotype, which is observed in modern populations—in particular, infectious disease may have played a role in this process of selection; however, random genetic drift cannot be discounted. The colonisation process of the Pacific with serial founder effects, as well as catastrophic events in the fragile island environments, means that there have been ample opportunities for genetic drift. However, at the same time, given the high levels of hyperuricaemia and gout seen in populations who likely share at least some ancestry with the Polynesians and Micronesians, for instance, the Taiwanese aborigines [28, 29, 93], and the Malagasy highlanders , the probability of random genetic drift operating in all of these populations to result in the same phenotype seems unlikely. Multiple processes are likely to have worked in tandem resulting in the genetic predisposition to hyperuricaemia.
Ancestry, itself, is not a trivial consideration. Examination of the available published literature indicates that elevated serum urate may be a trait shared by populations descended from the Austronesian-speaking peoples who departed from Southeast Asia around 8,000 years ago. In the light of the low serum urate levels seen in coastal populations in mainland Papua New Guinea, it would be interesting to investigate the state of serum urate levels among the Lapita-derived, Austronesian-speaking populations living in the Bismarck Archipelago, to the north-east of mainland Papua New Guinea: are they inherently hyperuricaemic like Polynesian and Micronesian populations, or are there lower urate levels similar to the mainland?
There is significant scope for further investigations to determine the reasons for elevated serum urate in populations in the Pacific region. While there have been efforts to understand prehistoric human migration in this region, disease has not been a major focus. The gulf between anthropological studies in the Pacific and genetic disease research has meant that genetic predisposition to conditions like hyperuricaemia has not been examined from an evolutionary perspective. Further genetic studies in Pacific populations are warranted and could assist in testing hypotheses, for example, the application of tools for detecting selection to the genomic sequence of genes involved in the regulation of urate.