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.

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.

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.

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.

Does vitamin D supplementation in infancy reduce the risk of pre-eclampsia?

Vitamin D has been suggested to affect the balance between T helper (Th1) and (Th2) type cytokines by favouring Th2 domination. We investigated the association between infant vitamin D supplementation and later pre-eclampsia, a disorder suggested to be dominated by Th1 response. We used data on 2969 women born in the Northern Finland Birth Cohort 1966 of whom 68 (2.3%) had pre-eclampsia in their first pregnancy. Risk of pre-eclampsia was halved (OR 0.49, 95% confidence interval (CI) 0.26-0.92) in participants who had received vitamin D supplementation regularly during the first year of life and this association was not affected by adjustment for own birth order, birth weight, gestational age, social class in 1966 and hospitalizations or pregnancy-induced hypertension of their mothers. Together with earlier observations on a reduced risk of type 1 diabetes after vitamin D supplementation, these data suggest that vitamin D intake in infancy may affect long-term programming of the immune response pattern.

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.

Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood diabetes in Finland study group.

The evidence for the putative role of cow's milk in the development of type 1 diabetes is controversial. We studied infant feeding patterns and childhood diet by structured questionnaire (n = 725) and HLA-DQB1 genotype by a polymerase chain reaction-based method (n = 556) in siblings of affected children and followed them for clinical type 1 diabetes. In a nested case-control design in a population who had both dietary and genetic data available, we selected as cases those siblings who progressed to clinical diabetes during the follow-up period (n = 33). For each case, we chose as matched control subjects siblings who fulfilled the following criteria: same sex, age within 1 year, not from the same family, the start of the follow-up within 6 months of that of the respective case, and being at risk for type 1 diabetes at the time the case presented with that disease (n = 254). The median follow-up time was 9.7 years (range 0.2-11.3). Early age at introduction of cow's milk supplements was not significantly associated with progression to clinical type 1 diabetes (relative risk adjusted for matching factors, maternal education, maternal and child's ages, childhood milk consumption, and genetic susceptibility markers was 1.60 [95% CI 0.5-5.1]). The estimated relative risk of childhood milk consumption for progression to type 1 diabetes was 5.37 (1.6-18.4) when adjusted for the matching and aforementioned sociodemographic factors, age at introduction of supplementary milk feeding, as well as for genetic susceptibility markers. In conclusion, our results provide support for the hypothesis that high consumption of cow's milk during childhood can be diabetogenic in siblings of children with type 1 diabetes. However, further studies are needed to assess the possible interaction between genetic disease susceptibility and dietary exposures in the development of this disease.

Infant feeding patterns in the Finnish type I diabetes prediction and prevention nutrition study cohort.

OBJECTIVE: To investigate infant feeding patterns during the first 2 y and their relation to sociodemographic factors. DESIGN: A population-based cohort study. SETTING: Oulu and Tampere University Hospital district areas 1996-1999, Finland. SUBJECTS AND METHODS: All newborn infants (n=675) with increased genetic risk for type I diabetes were invited to the study in 1996-1997. Of these, 429 (64%) completed the dietary follow-up form by the time they reached 2 y of age. RESULTS: The median duration of exclusive breastfeeding (BF) was 1.8 months (range 0-6 months) and that of total BF 7.0 months (0.3-25 months). Among the infants 20% were exclusively breastfed at least 4 months (recommendation 4-6 months). Infants were introduced to infant formula at the median age of 1.8 months (range 0-25 months) and other supplementary foods at the median age of 3.5 months (1-6 months). Infant's ponderal index at birth was inversely associated with the duration of total BF. The age of introduction of supplementary foods correlated positively with the duration of total BF. Longer parental education and increased maternal age were associated with a longer duration of BF and older age at introduction of supplementary foods. Infant formula and other supplementary foods were added earlier to the diet of the boys than that of the girls. CONCLUSION: Duration of breastfeeding in Finland is shorter than recommended. Compliance with the current recommendations on the timing of introduction of first supplementary food and dairy products is relatively poor. The diet during infancy seems to be conspicuously influenced by the duration of parental education, maternal age and the sex of the infant.

Obesity, increased linear growth, and risk of type 1 diabetes in children.

OBJECTIVE: The purpose of the present study was to evaluate the effect of obesity and linear growth on the risk of developing type 1 diabetes in children. RESEARCH DESIGN AND METHODS: The study population consists of all diabetic children <15 years of age diagnosed from September 1986 to April 1989 in Finland and their birth date- and sex-matched population-based control subjects. Growth data were obtained from well-baby clinics and school health care units for 586 diabetic and 571 control subjects, resulting in a total of 18,823 paired weight-height observations. RESULTS: Both boys and girls who developed type 1 diabetes were heavier and taller throughout childhood than control children. A 10% unit increment in relative weight was associated with a 50-60% increase in the risk of type 1 diabetes before 3 years of age and a 20-40% increase from 3 to 10 years of age. The increase in risk of type 1 diabetes for 1 SD score increment in relative height was 20-30%. Obesity (relative weight > 120%) after 3 years of age was associated with a more than twofold risk of developing type 1 diabetes. CONCLUSIONS: The present observation that obesity and rapid linear growth are risk factors for type 1 diabetes in children indicates that the increase in the prevalence of obesity and secular growth that has occurred in most industrialized countries over the last decades may be involved in the increase in type 1 diabetes incidence simultaneously observed in many countries.

Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group.

OBJECTIVE: To evaluate whether the increased risk of type 1 diabetes conferred by an early introduction of cow's milk supplements can be mediated by accelerated growth in formula-fed infants. RESEARCH DESIGN AND METHODS: All children < or = 14 years of age who were diagnosed with type 1 diabetes from September 1986 to April 1989 were invited to participate in the study. Birth date- and sex-matched control children were randomly selected from the Finnish Population Registry. At least three weight measurements from the first year of life were obtained for 435 full-term diabetic subjects and 386 control subjects from well-baby clinics and school health care units. RESULTS: Increase in body weight was greater in the diabetic girls than in the control girls, and the difference increased from 111 g (95% CI 0-218, P = 0.04) at 1 month of age to 286 g (95% CI 123-450, P = 0.0006) at 7 months. For boys, the difference in weight between the diabetic subjects and the control subjects remained stable during infancy (difference 95 g, 95% CI-2-205, P = 0.09). Increased weight was associated on average with a 1.5-fold risk of type 1 diabetes. Early introduction of formula feeding (< 3 vs. > or = 3 months) was also associated with an increased risk of type 1 diabetes after adjustment for the individual weight gain curve (adjusted odds ratio 1.53, 95% CI 1.1-2.2). No evidence for interaction was observed. CONCLUSIONS: These observations indicate that an early exposure to cow's milk formula-feeding and rapid growth in infancy are independent risk factors of childhood type 1 diabetes.

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.