The genetics underlying metabolic signatures in a brown rice diversity panel and their vital role in human nutrition.

Brown rice (Oryza sativa) possesses various nutritionally dense bioactive phytochemicals exhibiting a wide range of antioxidant, anti-cancer, and anti-diabetic properties known to promote various human health benefits. However, despite the wide claims made about the importance of brown rice for human nutrition the underlying metabolic diversity has not been systematically explored. Non-targeted metabolite profiling of developing and mature seeds of a diverse genetic panel of 320 rice cultivars allowed quantification of 117 metabolites. The metabolite genome-wide association study (mGWAS) detected genetic variants influencing diverse metabolic targets in developing and mature seeds. We further interlinked genetic variants on chromosome 7 (6.06-6.43 Mb region) with complex epistatic genetic interactions impacting multi-dimensional nutritional targets, including complex carbohydrate starch quality, the glycemic index, antioxidant catechin, and rice grain color. Through this nutrigenomics approach rare gene bank accessions possessing genetic variants in bHLH and IPT5 genes were identified through haplotype enrichment. These variants were associated with a low glycemic index, higher catechin levels, elevated total flavonoid contents, and heightened antioxidant activity in the whole grain with elevated anti-cancer properties being confirmed in cancer cell lines. This multi-disciplinary nutrigenomics approach thus allowed us to discover the genetic basis of human health-conferring diversity in the metabolome of brown rice.

Dietary glycemic index, glycemic load, and lung cancer risk: A case-control study in Los Angeles County.

BACKGROUND: Although there is some evidence of positive associations between both the glycemic index (GI) and glycemic load (GL) with cancer risk, the relationships with lung cancer risk remain largely unexplored. We evaluated the associations between GI and GL with lung cancer. METHODS: The analyses were performed using data from a population-based case-control study recruited between 1999 and 2004 in Los Angeles County. Dietary factors were collected from 593 incident lung cancer cases and 1026 controls using a modified food frequency questionnaire. GI and GL were estimated using a food composition table. Adjusted odds ratios (ORs) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. RESULTS: Dietary GI was positively associated with lung cancer (OR for upper vs. lower tertile = 1.62; 95 % CI: 1.17, 2.25). For histologic subtypes, positive associations were observed between GI and adenocarcinoma (OR for upper vs. lower tertile = 1.82; 95 % CI: 1.22, 2.70) and small cell carcinoma (OR for upper vs. lower tertile = 2.68; 95 % CI: 1.25, 5.74). No clear association between GL and lung cancer was observed. CONCLUSION: These findings suggest that high dietary GI was associated with increased lung cancer risk, and the positive associations were observed for both lung adenocarcinoma and small cell lung carcinoma. Replication in an independent dataset is merited for a broader interpretation of our results.

The physiologic and phenotypic significance of variation in human amylase gene copy number.

Background: Salivary α-amylase gene (AMY1) copy number (CN) correlates with the amount of salivary α-amylase, but beyond this, the physiologic significance is uncertain. Objective: We hypothesized that individuals with higher AMY1 CN would digest starchy foods faster and show higher postprandial responses and lower breath hydrogen excretion compared with those with low CN. Design: Four linked studies were conducted. In Study 1, we genotyped 201 healthy subjects with the use of real-time quantitative polymerase chain reaction and determined glucose tolerance, insulin sensitivity, salivary α-amylase activity, body mass index (BMI), and macronutrient intake. In Study 2, a pool of 114 subjects tested 6 starchy foods, 3 sugary foods, 1 mixed meal, and 2 reference glucose solutions, containing either 50 or 25 g of available carbohydrate. In Study 3, we compared glycemic and insulin responses to starchy foods with responses to glucose in 40 individuals at extremes of high and low CN. In Study 4, we compared breath hydrogen and methane responses over 8 h in 30 individuals at extremes of CN. Results: AMY1 CN correlated positively with salivary α-amylase activity (r = 0.62, P < 0.0001, n = 201) but not with BMI, glucose tolerance, or insulin sensitivity. However, CN was strongly correlated with normalized glycemic responses to all starchy foods (explaining 26-61% of interindividual variation), but not to sucrose or fruit. Individuals in the highest compared with the lowest decile of CN produced modestly higher glycemia (+15%, P = 0.018), but not insulinemia, after consuming 2 starchy foods. Low-CN individuals displayed >6-fold higher breath methane levels in the fasting state and after starch ingestion than high-CN individuals (P = 0.001), whereas hydrogen excretion was similar. Conclusions: Starchy foods are digested faster and produce higher postprandial glycemia in individuals with high AMY1 CN. In contrast, having low CN is associated with colonic methane production. This trial was registered at www.anzctr.org.au as ACTRN12617000670370.

Association of Native American ancestry and common variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO genes with glycemic traits in Colombian population.

Insulin resistance and defects in other related glycemic traits are common findings in the context of Metabolic Syndrome. Although genetic factors are clearly implied in susceptibility, and some gene variants have been identified mainly in populations of European ancestry, little is known about this aspect in admixed populations. The association of insulin resistance, ß-cell function, fasting insulin and glucose levels with 48 gene variants, previously related to metabolic syndrome components, and with the ancestral genetic composition, estimated on 50 ancestry informative markers, was evaluated in 417 individuals from the Colombian admixed population. The Native American genetic ancestry was associated with a low ß-cell function (odds ratio (OR) of 1.73 and 95% confidence interval (95% CI) of 1.07-2.81, p = 0.026). Significant genotypic associations were obtained (q-value < 0.05) for gene variants in ACE (rs4340; OR (95% CI): 2.79 (1.58-4.91), insulin resistance; mean difference (95% CI): 0.273 (0.141; 0.406), fasting insulin), ADIPOR2 (rs11061971; OR (95% CI): 0.14 (0.04-0.48), low ß-cell function), MTNR1B (rs10830963; mean difference (95% CI): 0.032 (0.013; 0.051), fasting glucose) and GCK (rs4607517; mean difference (95% CI): 0.038 (0.020;0.056) and rs1799884; mean difference (95% CI): 0.027 (0.013-0.041), fasting glucose). Also the well-known gene variants rs7903146 in TCF7L2, and rs17817449 in FTO, were nominally associated with hyperglycemia (rs7903146), as well as with higher fasting insulin levels (rs17817449). Our findings indicate that gene variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO, are associated with glycemic traits in the admixed Colombian population, while a higher Native American genetic component is related to lower ß-cell function.

No association detected between seven common variants in the CDKAL1 gene and gestational glycemic traits.

Elevated plasma glucose levels in pregnancy increase adverse pregnancy outcomes. Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) has been shown to be involved in insulin secretion in pancreatic ß cells. In this study, we investigated the impact of genetic variants in CDKAL1 on plasma glucose, insulin values, ß cell function and insulin resistance in the fasted state as well as plasma glucose 1 h after the consumption of a 50-g oral glucose load between 24 and 28 weeks of pregnancy among 929 unrelated pregnant Han Chinese women. Seven common variants previously reported to associate with diabetes were genotyped. Insulin resistance and ß cell function were assessed by homeostasis model assessment. The genetic impacts were analyzed using analysis of variance and analysis of covariance. The results showed that there was no significant association between any of the seven variants and those gestational glycemic traits. Therefore, this study suggests that the seven common variants in CDKAL1 are not significant factors for the variations of several gestational glycemic traits in the Han Chinese population. However, further well-designed studies with larger sample size, more ethnic groups and more CDKAL1 variants are required to validate the association between CDKAL1 and gestational glycemic traits.

Evaluation of the impact of orally administered carbohydrates on postprandial blood glucose levels in different pre-clinical models

ABSTRACT We developed a pre-clinical model in which to evaluate the impact of orally administered carbohydrates on postprandial blood glucose levels. For this purpose, we compared the effects of different carbohydrates with well-established glycemic indexes. We orally administered (gavage) increasing amounts (0.2, 0.4, 0.6, 0.8, and 1.0 g/kg) of sucrose and lactose to rats which had been fasted for 6 h or 15 h, respectively. In part of the experiments we administered frutose (gavagem). Three different models were compared for measuring postprandial blood glucose levels: a) evaluation of interstitial glucose concentrations by using a real time continuous glucose monitoring system; b) evaluation of glucose levels in blood obtained from the rat tail; c) evaluation of serum glucose levels in blood collected after decapitation. Our results showed that blood obtained from the tails of 15-h fasted rats was the best model in which to evaluate the effect of carbohydrates on postprandial blood glucose levels.

Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk.

Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10(-5)). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as "druggable" loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes.

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

Cfh genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice.

PURPOSE: Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major risk factors for AMD. We explored the effects of GI on development of early AMD-like features and changes to central nervous system (CNS) inflammation in Cfh-null mice. METHODS: Aged 11-week-old wild type (WT) C57Bl/6J or Cfh-null mice were group pair-fed high or low GI diets for 33 weeks. At 10 months of age, mice were evaluated for early AMD-like features in the neural retina and RPE by light and electron microscopy. Brains were analyzed for Iba1 macrophage/microglia immunostaining, an indicator of inflammation. RESULTS: The 10-month-old WT mice showed no retinal abnormalities on either diet. The Cfh-null mice, however, showed distinct early AMD-like features in the RPE when fed a low GI diet, including vacuolation, disruption of basal infoldings, and increased basal laminar deposits. The Cfh-null mice also showed thinning of the RPE, hypopigmentation, and increased numbers of Iba1-expressing macrophages in the brain, irrespective of diet. CONCLUSIONS: The presence of early AMD-like features by 10 months of age in Cfh-null mice fed a low GI diet is surprising, given the apparent protection from the development of such features in aged WT mice or humans consuming lower GI diets. Our findings highlight the need to consider gene-diet interactions when developing animal models and therapeutic approaches to treat AMD.

TFAP2B -dietary protein and glycemic index interactions and weight maintenance after weight loss in the DiOGenes trial.

BACKGROUND: TFAP2B rs987237 is associated with obesity and has shown interaction with the dietary fat-to-carbohydrate ratio, which has an effect on weight loss. We investigated interactions between rs987237 and protein-to-carbohydrate ratio or glycemic index (GI) in relation to weight maintenance after weight loss. METHODS: This study included 742 obese individuals from 8 European countries who participated in the Diet, Obesity, and Genes (DiOGenes) trial, lost ≥ 8% of their initial body weight during an 8-week low-calorie diet and were randomized to one of 5 ad libitum diets with a fixed energy percentage from fat: either low-protein/low-GI, low-protein/high-GI, high-protein/low-GI, or high-protein/high-GI diets, or a control diet for a 6-month weight maintenance period. Using linear regression analyses and additive genetic models, we investigated main and dietary interaction effects of TFAP2B rs987237 in relation to weight maintenance. RESULTS: In total, 468 completers of the trial were genotyped for rs987237. High-protein diets were beneficial for weight maintenance in the AA genotype group (67% of participants), but in the AG and GG groups no differences were observed for low- or high-protein diets. On the high-protein diet, carriers of the obesity risk allele (G allele) regained 1.84 kg (95% CI: 0.02; 3.67, p = 0.047) more body weight per risk allele than individuals on a low-protein diet. There was no interaction effect between rs987237 and GI on weight maintenance. CONCLUSION: TFAP2B rs987237 and dietary protein/carbohydrate interacted to modify weight maintenance. Considering the carbohydrate proportion of the diet, the interaction was different from the previously reported rs987237-fat-to-carbohydrate ratio interaction for weight loss. Thus, TFAP2B-macronutrient interactions might diverge depending on the nutritional state.

Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study.

BACKGROUND: Differences in the interindividual response to dietary intervention could be modified by genetic variation in nutrient-sensitive genes. OBJECTIVE: This study examined single nucleotide polymorphisms (SNPs) in presumed nutrient-sensitive candidate genes for obesity and obesity-related diseases for main and dietary interaction effects on weight, waist circumference, and fat mass regain over 6 mo. DESIGN: In total, 742 participants who had lost ≥ 8% of their initial body weight were randomly assigned to follow 1 of 5 different ad libitum diets with different glycemic indexes and contents of dietary protein. The SNP main and SNP-diet interaction effects were analyzed by using linear regression models, corrected for multiple testing by using Bonferroni correction and evaluated by using quantile-quantile (Q-Q) plots. RESULTS: After correction for multiple testing, none of the SNPs were significantly associated with weight, waist circumference, or fat mass regain. Q-Q plots showed that ALOX5AP rs4769873 showed a higher observed than predicted P value for the association with less waist circumference regain over 6 mo (-3.1 cm/allele; 95% CI: -4.6, -1.6; P/Bonferroni-corrected P = 0.000039/0.076), independently of diet. Additional associations were identified by using Q-Q plots for SNPs in ALOX5AP, TNF, and KCNJ11 for main effects; in LPL and TUB for glycemic index interaction effects on waist circumference regain; in GHRL, CCK, MLXIPL, and LEPR on weight; in PPARC1A, PCK2, ALOX5AP, PYY, and ADRB3 on waist circumference; and in PPARD, FABP1, PLAUR, and LPIN1 on fat mass regain for dietary protein interaction. CONCLUSION: The observed effects of SNP-diet interactions on weight, waist, and fat mass regain suggest that genetic variation in nutrient-sensitive genes can modify the response to diet. This trial was registered at clinicaltrials.gov as NCT00390637.

Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps.

BACKGROUND: We and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. RESULTS: Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy ß-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. CONCLUSIONS: These results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.

The effect of protein and glycemic index on children's body composition: the DiOGenes randomized study.

OBJECTIVE: To investigate the effect of protein and glycemic index (GI) on body composition among European children in the randomized, 6-month dietary intervention DiOGenes (diet, obesity, and genes) family-based study. PATIENTS AND METHODS: In the study, 827 children (381 boys and 446 girls), aged 5 to 18 years, completed baseline examinations. Families with parents who lost ≥ 8% of their weight during an 8-week run-in low-calorie diet period were randomly assigned to 1 of 5 ad libitum diets: low protein (LP)/low glycemic index (LGI); LP/high GI (HGI); high protein (HP)/LGI; HP/HGI; and control diet. The target difference was 15 GI U between the LGI/HGI groups and 13 protein percentage points between the LP/HP groups. There were 658 children examined after 4 weeks. Advice on food-choice modification was provided at 6 visits during this period. No advice on weight loss was provided because the focus of the study was the ability of the diets to affect outcomes through appetite regulation. Anthropometric measurements and body composition were assessed at baseline, week 4, and week 26. RESULTS: In the study, 465 children (58.1%) completed all assessments. The achieved differences between the GI and protein groups were 2.3 GI U and 4.9 protein percentage points, respectively. The LP/HGI group increased body fat percentage significantly more than the other groups (P = .040; partial η(2) = 0.039), and the percentage of overweight/obese children in the HP/LGI group decreased significantly during the intervention (P = .031). CONCLUSIONS: Neither GI nor protein had an isolated effect on body composition. However, the LP/HGI combination increased body fat, whereas the HP/LGI combination was protective against obesity in this sample of children.

Is there an association between sweetened beverages and adiposity?

Four mechanisms were reviewed to explain the possible association between sweetened beverages and increased overweight or obesity: excess caloric intake, glycemic index and glycemic load, lack of effect of liquid calories on satiety, and displacement of milk. The findings were inconsistent across studies. The strongest support was for the excess caloric intake hypothesis, but the findings were not conclusive. Assigning possible links between sweetened beverage consumption and adiposity requires research that compares and contrasts specific mechanisms, especially in populations at risk for obesity, while controlling for likely confounding variables.

Evidence for a major gene affecting the transition from normoglycaemia to hyperglycaemia in Psammomys obesus.

We investigated the mode of inheritance of nutritionally induced diabetes in the desert gerbil Psammomys obesus (sand rat), following transfer from low-energy (LE) to high-energy (HE) diet which induces hyperglycaemia. Psammomys selected for high or low blood glucose level were used as two parental lines. A first backcross generation (BC(1)) was formed by crossing F(1) males with females of the diabetes-prone line. The resulting 232 BC(1) progeny were assessed for blood glucose. All progeny were weaned at 3 weeks of age (week 0), and their weekly assessment of blood glucose levels proceeded until week 9 after weaning, with all progeny maintained on HE diet. At weeks 1 to 9 post weaning, a clear bimodal distribution statistically different from unimodal distribution of blood glucose was observed, normoglycaemic and hyperglycaemic at a 1:1 ratio. This ratio is expected at the first backcross generation for traits controlled by a single dominant gene. From week 0 (prior to the transfer to HE diet) till week 8, the hyperglycaemic individuals were significantly heavier (4--17%) than the normoglycaemic ones. The bimodal blood glucose distribution in BC(1) generation, with about equal frequencies in each mode, strongly suggests that a single major gene affects the transition from normo- to hyperglycaemia. The wide range of blood glucose values among the hyperglycaemic individuals (180 to 500 mg/dl) indicates that several genes and environmental factors influence the extent of hyperglycaemia. The diabetes-resistant allele appears to be dominant; the estimate for dominance ratio is 0.97.