Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

Stratified glucose-lowering response to vildagliptin and pioglitazone by obesity and hypertriglyceridemia in a randomized crossover trial.

Background: Understanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose metabolism) is the first step in precision medicine. Aims: We hypothesized that people with type 2 diabetes who generally have high insulin resistance, such as people of Maori/Pacific ethnicity, and those with obesity and/or hypertriglyceridemia (OHTG), would have greater glucose-lowering by pioglitazone (an insulin sensitizer) versus vildagliptin (an insulin secretagogue). Methods: A randomised, open-label, two-period crossover trial was conducted in New Zealand. Adults with type 2 diabetes, HbA1c>58mmol/mol (>7.5%), received 16 weeks of either pioglitazone (30mg) or vildagliptin (50mg) daily, then switched to the other medication over for another 16 weeks of treatment. Differences in HbA1c were tested for interaction with ethnicity or OHTG, controlling for baseline HbA1c using linear mixed models. Secondary outcomes included weight, blood pressure, side-effects and diabetes treatment satisfaction. Results: 346 participants were randomised (55% Maori/Pacific) between February 2019 to March 2020. HbA1c after pioglitazone was lower than after vildagliptin (mean difference -4.9mmol/mol [0.5%]; 95% CI -6.3, -3.5; p<0.0001). Primary intention-to-treat analysis showed no significant interaction effect by Maori/Pacific vs other ethnicity (1.5mmol/mol [0.1%], 95% CI -0.8, 3.7), and per-protocol analysis (-1.2mmol/mol [0.1%], 95% CI -4.1, 1.7). An interaction effect (-4.7mmol/mol [0.5%], 95% CI -8.1, -1.4) was found by OHTG status. Both treatments generated similar treatment satisfaction scores, although there was greater weight gain and greater improvement in lipids and liver enzymes after pioglitazone than vildagliptin. Conclusions: Comparative glucose-lowering by pioglitazone and vildagliptin is not different between Maori/Pacific people compared with other New Zealand ethnic groups. Presence of OHTG predicts greater glucose lowering by pioglitazone than vildagliptin. Clinical trial registration: www.anzctr.org.au, identifier (ACTRN12618001907235).

Aotearoa New Zealand Maori and Pacific Population-amplified Gout Risk Variants: CLNK Is a Separate Risk Gene at the SLC2A9 Locus.

OBJECTIVE: The Maori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations. METHODS: A list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry. RESULTS: We identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (rs1635712 [KIAA0319], ORmeta = 1.28, Pmeta = 0.03; rs16869924 [CLNK], ORmeta = 1.37, Pmeta = 0.002; rs2070025 [fibrinogen A alpha chain (FGA)], ORmeta = 1.34, Pmeta = 0.02). The CLNK variant, within the established SLC2A9 gout locus, was genetically independent of the association signal at SLC2A9. CONCLUSION: We provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.

Associations Between Sugars Intakes and Urinary Sugars Excretion and Carbon Stable Isotope Ratios in Red Blood Cells as Biomarkers of Sugars Intake in a Predominantly Maori Population.

Determining the extent to which added sugars intake contribute to non-communicable disease in various populations is challenging because it is difficult to accurately measure intakes. Biomarkers may provide a reliable and easily measured method of assessing intakes. In a predominantly Maori population we compared various sugars intake estimates derived from a 36 item sugar-specific food frequency questionnaire (FFQ) with biomarkers of sugars intake; urinary sugars excretion in random spot collections (n = 153) and carbon stable isotope ratios (n = 36) in red blood cells (RBCs, δ13CRBC) and in the alanine fraction of the RBCs (δ13Calanine). Estimated 24 h urinary sucrose+fructose excretion was statistically significantly correlated with intakes of total sugars (r = 0.23), sucrose (r = 0.26) and added sugars from sugar-sweetened beverages (SSBs; r = 0.26). δ13Calanine was correlated with added sugars (r = 0.40). In log linear multiple regression models adjusted with HbA1C and eGFR δ13Calanine predicted added sugars intakes (r 2 = 0.29) and estimated 24 h urinary sucrose+fructose excretion predicted intakes of total sugars (r 2 = 0.14), sucrose (r 2 = 0.17), added sugars (r 2 = 0.17) and sugars from SSBs (r 2 = 0.14). These biomarkers have potential for improving assessment of sugars intake in New Zealand populations enabling monitoring of the effectiveness of sugar reduction strategies designed to reduce risk of NCDs. However, further validation is required to confirm these preliminary findings.

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout.

OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

The Maori and Pacific specific CREBRF variant and adult height.

BACKGROUND: The CREBRF missense variant (p.Arg457Gln) is paradoxically associated with lower risk of type 2 diabetes, yet higher body mass index (BMI). Here we sought to determine whether this CREBRF variant might be associated with adult height. METHODS: Linear regression was used to analyse the association of the CREBRF minor (A) allele with height in 2286 Maori and Pacific adults living in Aotearoa/New Zealand. A potential type 2 diabetes index event was corrected to account for a bias that may be the cause of paradoxical association between the CREBRF diabetes-protective allele and higher BMI and height. RESULTS: The CREBRF protective allele was associated with increased adult height (ß = 1.25 cm, P = 3.9 × 10-6), with the effect being more pronounced in males. The lower odds of diabetes remained similar when analyses were adjusted for height (OR = 0.67-0.65). We found no evidence of a diabetes index event bias to explain the paradoxical effect of CREBRF with either BMI or height and diabetes. The orthologous CREBRF p.Arg457Gln variant was created in knock-in mice to independently assess the effect of the variant, and length was found to be greater in male mice at 8 weeks of age. CONCLUSION: These data taken together indicate that CREBRF p.Arg457Gln is associated with taller stature in Maori and Pacific adults.

Genomic medicine must reduce, not compound, health inequities: the case for hauora-enhancing genomic resources for New Zealand.

Precision medicine seeks to draw on data from both individuals and populations across disparate domains to influence and support diagnosis, management and prevention in healthcare at the level of the individual patient and their family/whanau. Central to this initiative is incorporating the effects of the inherent variation that lies within genomes and can influence health outcomes. Identifying and interpreting such variation requires an accurate, valid and representative dataset to firstly define what variants are present and then assess the potential relevance for the health of a person, their family/whanau and the wider community to which they belong. Globally the variation embedded within genomes differs enormously and has been shaped by the size, constitution, historical origins and evolutionary history of their source populations. Maori, and more broadly Pacific peoples, differ substantially in terms of genomic variation compared to the more closely studied European and Asian populations. In the absence of accurate genomic information from Maori and Pacific populations, the precise interpretation of genomic data and the success and benefits of genomic medicine will be disproportionately less for those Maori and Pacific peoples. In this viewpoint article we, as a group of healthcare professionals, researchers and scientists, present a case for assembling genomic resources that catalogue the characteristics of the genomes of New Zealanders, with an emphasis on peoples of Maori and Polynesian ancestry, as a healthcare imperative. In proposing the creation of these resources, we note that their governance and management must be led by iwi and Maori and Pacific representatives. Assembling a genomic resource must be informed by cultural concepts and values most especially understanding that, at a physical and spiritual level, whakapapa is embodied within the DNA of a person. Therefore DNA and genomic data that connects to whakapapa (genealogy) is considered a taonga (something precious and significant), and its storage, utilisation and interpretation is a culturally significant activity. Furthermore, such resources are not proposed to primarily enable comparisons between those with Maori and broader Pacific ancestries and other Aotearoa peoples but to place an understanding of the genetic contributors to their health outcomes in a valid context. Ongoing oversight and governance of such taonga by Maori and Pacific representatives will maximise hauora (health) while also minimising the risk of misuse of this information.

Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Maori and Pacific Men.

OBJECTIVE: There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Maori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout. METHODS: All participants had ≥3 self-reported Maori and/or Pacific grandparents. Among the total sample set of 1,808 participants, 191 hyperuricemic and 202 normouricemic individuals were resequenced over the 4 genes, and the remaining 1,415 individuals were used for replication. Regression analyses were performed, adjusting for age, sex, and Polynesian ancestry. To study the functional effect of nonsynonymous variants of ABCC4, transport assays were performed in Xenopus laevis oocytes. RESULTS: A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. This variant was monomorphic for the urate-lowering allele in Europeans. There was evidence for an association of rs4148500 with gout in the resequenced samples (odds ratio [OR] 1.62 [P = 0.012]) that was replicated (OR 1.25 [P = 0.033]) and restricted to men (OR 1.43 [P = 0.001] versus OR 0.98 [P = 0.89] in women). The gout risk allele was associated with fractional excretion of uric acid in male individuals (ß = -0.570 [P = 0.01]). A rare population-specific allele (P1036L) with predicted strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%. CONCLUSION: An association between ABCC4 and gout and fractional excretion of uric acid is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.

Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares.

BACKGROUND: Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels. METHODS: Two thousand fifty one New Zealanders (of Maori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake. RESULTS: Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20% specifically mentioned tomatoes, the 4(th) most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (ß = 0.66 µmolL(-1) increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: ß = 0.84 µmolL(-1), P = 0.035; women: ß = 0.59 µmolL (-1), P = 0.041). CONCLUSIONS: While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption.

INTRODUCTION: The T allele of a single nucleotide polymorphism (SNP: rs2544390) in lipoprotein receptor-related protein 2 (LRP2) is associated with higher serum urate and risk of gout in Japanese individuals. SNP rs2544390 also interacts with alcohol consumption in determining hyperuricemia in this population. We investigated the association of rs2544390 with gout, and interaction with all types of alcohol consumption in European and New Zealand (NZ) Maori and Pacific subjects, and a Maori study cohort from the East Coast region of NZ's North Island. METHODS: Rs2544390 was genotyped by Taqman®. From NZ a total of 1205 controls and 1431 gout cases clinically ascertained were used. Publicly available genotype and serum urate data were utilized from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS). Alcohol consumption data were obtained by consumption frequency questions in all study cohorts. Multivariate adjusted logistic regression was done using STATA. RESULTS: The T allele of rs2544390 was associated with increased risk of gout in the combined Maori and Pacific Island cohort (OR = 1.20, P = 0.009), and associated with gout in the European subjects, but with a protective effect (OR = 0.79, PUnadjusted = 0.02). Alcohol consumption was positively associated with risk of gout in Maori and Pacific subjects (0.2% increased risk/g/week, P = 0.004). There was a non-additive interaction between any alcohol intake and the risk of gout in the combined Maori and Pacific cohorts (PInteraction = 0.001), where any alcohol intake was associated with a 4.18-fold increased risk in the CC genotype group (P = 6.6x10-5), compared with a 1.14-fold increased risk in the CT/TT genotype group (P = 0.40). These effects were not observed in European subjects. CONCLUSIONS: Association of the T-allele with gout risk in the Maori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals. The non-additive interaction in the Maori and Pacific subjects showed that alcohol consumption over-rides any protective effect conferred by the CC genotype. Further exploration of the mechanism underlying this interaction should generate new understanding of the biological role of alcohol in gout, in addition to strengthening the evidence base for reduction of alcohol consumption in the management of gout.

Two-year results from a community-wide diabetes prevention intervention in a high risk indigenous community: the Ngati and Healthy project.

We describe changes in markers and prevalence of glucose metabolism disorders following a 2-year community-wide intervention aimed at reducing insulin resistance (IR) prevalence in a high risk community. Surveys were undertaken before and 2 years after implementation of a community developed and led diabetes prevention program. Proportions and means were calculated and compared by sex and age groups: 25-49 years and 50+ years. A process evaluation contributed to interpretation of results. Response rates were around 50% and demographic characteristics similar in both surveys. Overall, IR prevalence decreased markedly from 35.5% to 25.4% (p=0.003). Most changes were observed amongst 25-49 years old women for whom there was a significant change in prevalences of IR and glucose metabolism disorders (p=0.015), largely due to reduced IR prevalence (38.2-25.6%). In 2006, 60.3% achieved minimum recommended exercise levels and 65.4% ate wholegrain bread compared with 45.1% (p=0.002) and 42.2% (p=0.044), respectively, in 2003. Participation in a community diabetes prevention intervention appeared to reduce IR prevalence after 2 years in those with the highest level of participation and most marked lifestyle changes.