Association of supplemental calcium and dairy milk intake with all-cause and cause-specific mortality in the UK Biobank: a prospective cohort study.

Excessive Ca intakes have been proposed to associate with vascular calcification and a higher risk of prostate cancer. We investigated the associations of supplemental and dietary Ca intake with mortality using data from 497 828 UK Biobank participants. The average follow-up was 4·2 years and 14 255 participants died, 8297 from cancer, 2959 from CVD and 572 from respiratory disease. The use of Ca supplements and milk consumption were associated with differences in mortality in younger (≤65 years) but not in older participants (>65 years, Pinteraction ≤ 0·04 for all comparisons). Among participants <65 years, there was an inverse association between Ca supplementation (OR 0·91, 95 % CI 0·83, 0·99) and milk consumption (OR 0·93, 95 % CI 0·86, 1·00) with respect to all-cause mortality. In the same age group, milk drinkers had lower odds of cancer mortality (OR 0·89, 95 % CI 0·80, 0·98) but Ca supplement use was associated with increased odds of respiratory mortality (OR 1·69, 95 % CI 1·16, 2·74). All associations in participants aged ≥65 years were null after full adjustment. In sensitivity analyses stratified by hormone replacement therapy, Ca supplement use was associated with decreased odds of cancer mortality in users but increased risk in other women (OR 0·81, 95 % CI 0·69, 0·94 v. OR 1·17, 95 % CI 1·01, 1·35, respectively). To conclude, we saw little evidence for harm with dietary or supplemental Ca. Further studies are required to confirm the proposed interaction with hormone replacement therapy and to exclude reverse causation as a determinant in the association between Ca supplements and increased risk of respiratory diseases.

Health effects associated with serum calcium concentrations: evidence from MR-PheWAS analysis in UK Biobank.

We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to survey health effects associated with high normal serum calcium. We found causal evidence for conditions related to renal function, bone and joint health, and cardiovascular risk. These conditions collectively suggest that tissue calcification may be a key mechanism through which serum calcium influences health. INTRODUCTION: Calcium is essential for the normal functioning of the cardiovascular system, muscles, and nerves. In this MR-PheWAS study, we sought to capture the totality of health effects associated with high normal serum calcium. METHODS: We used data from up to 337,535 UK Biobank participants, and tested for associations between calcium genetic score (calcium-GS) and 925 disease outcomes, with follow-up analyses using complementary MR methods. RESULTS: Calcium-GS was robustly associated with serum calcium concentration (F statistics = 349). After multiple testing correction (P < 1.62E-4), we saw genetic evidence for an association between high serum calcium and urinary calculus (OR per 1 mg/dl 3.5, 95%CI 1.3-9.2), renal colic (9.1, 95%CI 2.5-33.5), and allergy/adverse effect of penicillin (2.2, 95%CI 1.5-3.3). Secondary analyses with independent replication from consortia meta-analyses suggested further effects on myocardial infarction and osteoarthrosis. CONCLUSION: We found causal evidence for effects of high normal serum calcium with conditions related to renal function, bone and joint health, and cardiovascular risk, which may collectively reflect influences on tissue calcification and immune function.

Deaths of children aged under 5 years and related factors in the Islamic Republic of Iran: a populationbased case-control study.

The study was conducted to determine the family, social and economic factors associated with deaths of children aged under 5 years. A registry-based nested case-control study was conducted of the deaths of all children aged under 5 years in Kohgilooyeh and Boyer-Ahmad Province in the Islamic Republic of Iran. For each death, two controls were randomly selected among children of the same age, sex and place of residence (186 cases and 372 controls). Congenital abnormality (37.6%) and preterm birth (29.0%) were the two most frequent causes of death among children aged under 5 years. No vaccine-preventable disease was reported as the cause of death. The strongest associations were found with consanguinity of the parents (OR = 3.92; 95% CI = 2.27-6.85 for being first cousins in comparison with no family relation; P < 0.001) and with domestic violence to the mother during pregnancy (OR = 3.13; 95% CI = 1.60-6.17; P < 0.01). The main causes of death of children aged under 5 years in the Province were congenital abnormality and prematurity.

Deaths of children aged under 5 years and related factors in the Islamic Republic of Iran: a population-based case-control study

The study was conducted to determine the family, social and economic factors associated with deaths of children aged under 5 years. A registry-based nested case-control study was conducted of the deaths of all children aged under 5 years in Kohgilooyeh and Boyer-Ahmad Province in the Islamic Republic of Iran. For each death, two controls were randomly selected among children of the same age, sex and place of residence [186 cases and 372 controls]. Congenital abnormality [37.6%] and preterm birth [29.0%] were the two most frequent causes of death among children aged under 5 years. No vaccine-preventable disease was reported as the cause of death. The strongest associations were found with consanguinity of the parents [OR = 3.92; 95% CI = 2.27-6.85 for being first cousins in comparison with no family relation; P < 0.001] and with domestic violence to the mother during pregnancy [OR = 3.13; 95% CI = 1.60-6.17; P < 0.01]. The main causes of death of children aged under 5 years in the Province were congenital abnormality and prematurity

La présente étude a été menée pour déterminer les facteurs familiaux, sociaux et économiques associés aux décès des enfants de moins de cinq ans. Une étude cas-témoin nichée reposant sur les données de registres a été menée sur les décès de tous les enfants de moins de cinq ans dans la province de Kohgilooyeh et Boyer-Ahmad en République islamique d'Iran. Pour chaque décès, deux témoins étaient sélectionnés de façon aléatoire parmi les enfants du même âge, sexe et lieu de résidence [186 cas et 872 témoins]. Les malformations congénitales?[37,6%] et les naissances prématurées [29,0%] constituaient les deux causes de décès les plus fréquentes parmi les enfants de moins de cinq ans. Aucune maladie à prévention vaccinale n'a été rapportée comme cause de décès. Les associations les plus fortes étaient liées à la consanguinité des parents [OR = 3,92 ; IC à 95% = 2,27-6,85 pour les cousins de premier degré en comparaison avec les sujets n'ayant aucun lien de parenté ; p < 0,001] et à la violence conjugale envers les mères pendant la grossesse [OR = 3,13 ; IC à 95% = 1,60-6,17 ; p < 0,01]. Les principales causes de décès des enfants de moins de cinq ans dans la province étaient les malformations congénitales et la prématurité

Vitamin D fortification and seasonality of birth in type 1 diabetic cases: D-tect study.

Fortification of margarine with vitamin D was mandatory in Denmark during 1961-1985. The aim of the study was to assess whether gestational and early infancy exposure to margarine fortification was associated with seasonality of birth in Danish type 1 diabetes (T1D) patients. The risks of T1D in Danes born during various exposure periods around margarine fortification termination in 1985 were analyzed. As expected, the T1D hazards in males unexposed to margarine fortification and born in spring were higher than in males born in autumn: relevant hazard ratios (95% confidence intervals) in various exposure groups ranged from 1.74 (1.112/2.708) to 37.43 (1.804/776.558). There were no indications of seasonality of birth in males exposed to fortification, nor in both exposed and unexposed females. The study suggests that early life exposure to low-dose vitamin D from fortified food eliminates seasonality of birth in T1D male patients. Further studies are required to investigate the identified gender differences.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

"BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required."

25-hydroxyvitamin D, APOE ɛ4 genotype and cognitive function: findings from the 1958 British birth cohort.

Both high and low vitamin D statuses have been associated with lower memory function. Apolipoprotein E (APOE) ɛ4 alleles have been associated with reduced memory function, and separately with higher vitamin D concentrations. This report aims to examine if the presence of APOE ɛ4 alleles contributes to the relationship between vitamin D and memory function. A total of 4848 (46% female) participants from the 1958 British birth cohort had information on APOE genotypes and completed memory tests at 50 years, where 4644 also had 25-hydroxyvitamin D (25(OH)D) concentrations measured at 45 years. Both low and high 25(OH)D concentrations were associated with lower memory function after adjustment for number of APOE ɛ4 alleles (P curvature=0.02). There was evidence of interaction between APOE ɛ4 and 25(OH)D, suggesting the association between 25(OH)D concentrations and memory function is different for those with two APOE ɛ4 alleles compared with those with zero or one APOE ɛ4 alleles (recessive model P interaction=0.01). Among participants with two APOE ɛ4 alleles, higher 25(OH)D concentrations were associated with higher memory function, whereas in others, memory scores were slightly lower for individuals with higher versus lower concentrations. Further studies are required to replicate these findings.

Interaction between vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D concentrations on metabolic and cardiovascular disease outcomes.

AIM: 25-hydroxyvitamin D (25OHD) concentrations have been shown to be associated with major clinical outcomes, with a suggestion that individual risk may vary according to common genetic differences in the vitamin D receptor (VDR) gene. Hence, we tested for the interactions between two previously studied VDR polymorphisms and 25OHD on metabolic and cardiovascular disease-related outcomes in a large population-based study. METHODS: Interactions between two previously studied VDR polymorphisms (rs7968585 and rs2239179) and 25OHD concentrations on metabolic and cardiovascular disease-related outcomes such as obesity- (body mass index, waist circumference, waist-hip ratio (WHR)), cardiovascular- (systolic and diastolic blood pressure), lipid- (high- and low-density lipoprotein, triglycerides, total cholesterol), inflammatory- (C-reactive protein, fibrinogen, insulin growth factor-1, tissue plasminogen activator) and diabetes- (glycated haemoglobin) related markers were examined in the 1958 British Birth cohort (n up to 5160). Interactions between each SNP and 25OHD concentrations were assessed using linear regression and the likelihood ratio test. RESULTS: After Bonferroni correction, none of the interactions reached statistical significance except for the interaction between the VDR SNP rs2239179 and 25OHD concentrations on waist-hip ratio (WHR) (P=0.03). For every 1nmol/L higher 25OHD concentrations, the association with WHR was stronger among those with two major alleles (-4.0%, P=6.26e(-24)) compared to those with either one or no major alleles (-2.3%, P≤8.201e(-07), for both) of the VDR SNP rs2239179. CONCLUSION: We found no evidence for VDR polymorphisms acting as major modifiers of the association between 25OHD concentrations and cardio-metabolic risk. Interaction between VDR SNP rs2239179 and 25OHD on WHR warrants further confirmation.

Parental obesity and risk factors for cardiovascular disease among their offspring in mid-life: findings from the 1958 British Birth Cohort Study.

BACKGROUND: Few studies have investigated whether parental adiposity is associated with offspring cardiovascular health or the underlying pathways. Studying these associations may help to illuminate the paradox of increasing prevalence of obesity and declining trends in cardiovascular disease (CVD) mortality, which may be partially explained by beneficial adaptations to an obesogenic environment among people exposed to such environments from younger ages. OBJECTIVE: To investigate associations between parental body mass index (BMI) and risk factors for CVD among their offspring in mid-life and to test whether associations of offspring BMI with CVD risk factors were modified by parental BMI. METHODS: Data from parents and offspring in the 1958 British birth cohort were used (N=9328). Parental BMI was assessed when offspring were aged 11 years; offspring BMI, waist circumference and CVD risk factors (lipid levels, blood pressure, glycosylated haemoglobin (HbA1c) and inflammatory and haemostatic markers) were measured at 44-45 years. RESULTS: Higher parental BMI was associated with less favourable levels of offspring risk factors for CVD. Most associations were maintained after adjustment for offspring lifestyle and socioeconomic factors but were largely abolished or reversed after adjustment for offspring adiposity. For some CVD risk factors, there was evidence of effect modification; the association between higher BMI and an adverse lipid profile among offspring was weaker if maternal BMI had been higher. Conversely, offspring BMI was more strongly associated with HbA1c if parental BMI had been higher. CONCLUSIONS: Intergenerational influences may be important in conferring the effect of high BMI on CVD risk among offspring.

Genetic association analysis of vitamin D pathway with obesity traits.

OBJECTIVE: Observational studies have examined the link between vitamin D deficiency and obesity traits. Some studies have reported associations between vitamin D pathway genes such as VDR, GC and CYP27B1 with body mass index (BMI) and waist circumference (WC); however, the findings have been inconsistent. Therefore, we investigated the involvement of vitamin D metabolic pathway genes in obesity-related traits in a large population-based study. METHODS: We undertook a comprehensive analysis between 100 tagging single nucleotide polymorphisms (tagSNPs) in genes encoding for DHCR7, CYP2R1, VDBP, CYP27B1, CYP27A1, CYP24A1, VDR and RXRG, and obesity traits in 5224 participants (aged 45 years) in the 1958 British birth cohort (1958BC). We further extended our analyses to investigate the associations between SNPs and obesity traits using the summary statistics from the GIANT (Genetic Investigation of Anthropometric Traits) consortium (n=123 865). RESULTS: In the 1958BC (n=5224), after Bonferroni correction, none of the tagSNPs were associated with obesity traits except for one tagSNP from CYP24A1 that was associated with waist-hip ratio (WHR) (rs2296239, P=0.001). However, the CYP24A1 SNP was not associated with BMI-adjusted WHR (WHRadj) in the 1958BC (rs2296239, P=1.00) and GIANT results (n=123 865, P=0.18). There was also no evidence for an interaction between the tagSNPs and obesity on BMI, WC, WHR and WHRadj in the 1958BC. In the GIANT consortium, none of the tagSNPs were associated with obesity traits. CONCLUSIONS: Despite a very large study, our findings suggest that the vitamin D pathway genes are unlikely to have a major role in obesity-related traits in the general population.

Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.

UNLABELLED: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. INTRODUCTION: Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. METHODS: To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. RESULTS: Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. CONCLUSION: To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 µg (800 IU), which is best achieved with a supplement.

Evidence for a genetic interaction in allergy-related responsiveness to vitamin D deficiency.

BACKGROUND: The hormonal form of vitamin D affects both adaptive and innate immune functions involved in the development of allergies. Certain genotypes have been seen to alter the association between vitamin D deficiency (VDD) and the risk of food sensitization in children. METHODS: We examined 27 functional single nucleotide polymorphisms (SNPs) in/near selected candidate genes for association with total immunoglobulin E (IgE) and effect modification by 25-hydroxyvitamin D in the 1958 British birth cohort (aged 45 years, n = 4921). A cut-off value of 50 nmol/L was used to define VDD. RESULTS: Four SNPs (in FCER1A, IL13, and CYP24A1) and three SNPs (in IL4 and CYP24A1) were associated with total IgE and specific IgE, respectively, after correction for multiple testing. As in a previous study, MS4A2 (rs512555, P(interaction) = 0.04) and IL4 (rs2243250, P(interaction) = 0.02), and their composite score (P(interaction) = 0.009) modified the association between VDD and allergy-related outcome. Vitamin D deficiency was associated with higher total IgE only in the carriers of the 'C' allele (IL4), which is present in 86% of white Europeans, while only 26% of Chinese and <20% of some African populations are carriers. CONCLUSIONS: Our study on white European adults was consistent with a previous study on children from largely non-white ethnic groups, suggesting that IL4 and MS4A2 genotypes modify the association between VDD and allergy risk. The risk allele in IL4 is present in nearly 90% of white Europeans, while less than a quarter are carriers in some other populations, highlighting the need to consider possible ethnic differences in allergy-related responsiveness to VDD.

Proceedings of the Rank Forum on Vitamin D.

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.

Vitamin D and increasing incidence of type 1 diabetes-evidence for an association?

There has been an important shift in the views about the actions of vitamin D during the past decade. In addition to its well-established role in the regulation of calcium metabolism, vitamin D deficiency has been associated with the risk of several extra-skeletal diseases, including type 1 diabetes among other chronic conditions. It is notable that 1,25(OH)(2)D is known to regulate the expression of over 200 different genes, including the ones related to apoptosis and immune modulation. Increased vitamin D intake is currently considered as one of the most promising candidates for the prevention of type 1 diabetes, and it has been suggested that changes in vitamin D intake during the past decades have contributed to the recent trends in the incidence of the disease. This study reviews the evidence for the role of vitamin D in type 1 diabetes development, demonstrating that support has been obtained from various lines of investigation and that the possible biological mechanisms are plausible. However, much of the evidence has been obtained from animal experiments or observational studies in humans and there is an urgent need for well-designed, randomized, controlled trials to show whether the observed associations are indeed causal.

Serum 25-hydroxyvitamin D and IgE - a significant but nonlinear relationship.

BACKGROUND: Hormonal vitamin D system affects the determination of T-cell responses. It is unknown if there is an association between vitamin D status and allergic conditions. Our aim was to investigate differences in serum IgE concentrations by vitamin D status [measured by 25(OH)D] and by a genetic variation in a key vitamin D activation enzyme (CYP27B1) previously shown to be associated with type 1 diabetes. METHODS: 9377 participants in the 1958 British birth cohort completed a biomedical assessment at 45 years of age ; 7288 eligible participants had data on 25(OH)D and IgE, with 6429 having further information on CYP27B1 genotype ()1260C>A). RESULTS: There was a nonlinear association between 25(OH)D and IgE (P-value for curvature = 0.0001). Compared with the reference group with the lowest IgE concentrations [25(OH)D 100-125 nmol/l], IgE concentrations were 29% higher (95% CI 9-48%) for participants with the 25(OH)D <25 nmol/l, and 56% higher (95% CI 17-95%) for participants with 25(OH)D >135 nmol/l (adjusted for sex, month, smoking, alcohol consumption, time spent outside, geographical location, social class, PC/TV time, physical activity, body mass index and waist circumference). CYP27B1 genotype was associated with both 25(OH)D (difference for A vs. C allele: 1.88%, 95% CI 0.37-3.4%, P = 0.01) and IgE concentrations ()6.59%, )11.6% to )1.42%, P = 0.01). CONCLUSIONS: These data suggest that there may be a threshold effect with both low and high 25(OH)D levels associated with elevated IgE concentrations. The same CYP27B1 allele that is protective of diabetes was associated with increased IgE concentrations.

Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey.

BACKGROUND: Identified aetiological factors for chronic widespread pain (CWP) are largely related to emotional and behavioural factors, but current management leads to modest improvement in symptoms. Vitamin D deficiency has been suggested as a new modifiable risk factor for CWP. OBJECTIVE: To examine the association between vitamin D status (measured by 25-hydroxyvitamin D (25(OH)D)) and CWP in a nationwide population sample of white British adults, accounting for potential mediating and confounding lifestyle factors. METHODS: 9377 participants born 1 week in March 1958, in England, Scotland or Wales and completing a biomedical assessment at age 45; 6824 eligible participants had data on 25(OH)D and completed pain manikins. RESULTS: Prevalence of CWP varied by 25(OH)D concentration in women but not in men, with the lowest prevalence observed for women with 75-99 nmol/l (14.4% for <25 nmol/l, 14.8% for 25-49 nmol/l, 11.6% for 50-74 nmo/l, 8.2% for 75-99 nmol/l and 9.8% for participants with > or =100 nmol/l). There was an interaction between 25(OH)D concentration and gender in relation to CWP (interaction, p = 0.006), which was not fully explained by differences in lifestyle or social factors (adjusted interaction, p = 0.03). For women, the association between 25(OH)D concentration and CWP persisted after full adjustment (odds ratio (OR) for <75 nmol/l vs 75-99 nmol/l 1.57, 95% CI 1.09 to 2.26), while no evidence for an association was apparent in men (OR = 1.03, 95% CI 0.75 to 1.43). CONCLUSION: Current vitamin D status was associated with CWP in women but not in men. Follow-up studies are needed to evaluate whether higher vitamin D intake might have beneficial effects on the risk of CWP.

Vitamin D serum levels and allergic rhinitis.

In addition to its role in the regulation of calcium metabolism, vitamin D has a number of immunological effects. Several studies in children found an effect of oral supplementation on allergic sensitization but so far there are no population-based studies of vitamin D serum levels. We therefore examined 25(OH)-D(3) status in 18,224 adults of the Third National Health and Nutrition Examination Survey. There was no effect on sensitization to a single allergen while the prevalence of allergic rhinitis increased across quartile groups of current vitamin D serum levels. The association could be due to unrecognized confounding, however, could also point towards an altered metabolism or an increased sensitivity to vitamin D in allergic patients.

Diabetes risk in British adults in mid life: a national prevalence study of glycated haemoglobin.

AIMS: Information on the population at risk of developing Type 2 diabetes in the UK is scarce. We used data from the 1958 British birth cohort to estimate geographical and socio-economic variations in HbA(1c) in mid life. METHODS: Participants (n = 7799) born in England, Scotland and Wales and currently living in the UK. Individuals were classified according to the presence of Type 2 diabetes and by thresholds of HbA(1c). HbA(1c)> or = 5.5 was used as an indicator for possible subclinical alterations in glucose metabolism. RESULTS: The majority of the population had HbA(1c) < 5.5% (79.3%); 16.7% had HbA(1c) 5.5-5.9%, 2.0% 6.0-6.9% and 0.6% had HbA(1c)> or = 7.0%. Individuals from manual socio-economic groups and those living in the East of England and Scotland had a higher prevalence of HbA(1c) at or above the upper normal range (5.5%). CONCLUSIONS: Estimates from this nationwide sample suggest that a proportion of Britons are likely to have subclinical alterations in glucose metabolism by their mid 40s, and this proportion is greater in some socio-economic groups and geographical regions than in others.