Evidence for a causal association between milk intake and cardiometabolic disease outcomes using a two-sample Mendelian Randomization analysis in up to 1,904,220 individuals

Background: High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence (LCT-13910 C>T, rs4988235) variant as an instrumental variable. Methods: We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits (N=123,665 to 697,307) and extended to cover disease endpoints (N=86,995 to 149,821). Results: In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk (P=7.02x10-14). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) (Pmeta-analysis=4.68x10-12) and lower total cholesterol (TC) (P=2.40x10-36), low-density lipoprotein cholesterol (LDL-C) (P=2.08x10-26) and high-density lipoprotein cholesterol (HDL-C) (P=9.40x10-13). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75-0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97-1.16). Furthermore, the two-sample MR analysis showed a causal association between genetically instrumented milk intake and higher BMI (P=3.60x10-5) and body fat (total body fat, leg fat, arm fat and trunk fat; P<1.37x10-6) and lower LDL-C (P=3.60x10-6), TC (P=1.90x10-6) and HDL-C (P=3.00x10-5). Conclusions: Our large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies

O3‐05‐02: Genetic Risk, Lifestyle And Dementia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152906/1/alzjjalz2019064649.pd

Depression increases the genetic susceptibility to high body mass index: evidence from UK Biobank

Background This study aimed to explore the association between depression and body mass index (BMI), and to investigate whether genetic susceptibility to high BMI is different among individuals with or without depression. Methods We used data on 251,125 individuals of white British ancestry from the UK Biobank. We conducted Mendelian randomization (MR) analysis to test for a causal association between depression and BMI using a major depressive disorder (MDD)‐related genetic risk score (GRSMDD) as an instrument for depression. We also examined whether depression modifies genetic susceptibility to high BMI, by investigating the interaction between depression and the BMI‐related GRSBMI. Results We found observational and genetic evidence for an association between depression and BMI (MR beta: 0.09, 95% confidence interval [CI] 0.04–0.13). Further, the contribution of genetic risk to high BMI was higher among individuals with depression compared to controls. Carrying 10 additional BMI increasing alleles was associated with 0.24 standard deviation (SD; 95%CI 0.23–0.25) higher BMI among depressed individuals compared to 0.20 SD (95%CI 0.19–0.21) higher in controls, which corresponds to 3.4 kg and 2.8 kg extra weight for an individual of average height. Amongst the individual loci, the evidence for interaction was most notable for a variant near MC4R, a gene known to affect both appetite regulation and the hypothalamic‐pituitary adrenal axis (pinteraction = 5.7 × 10−5). Conclusion Genetic predisposition to high BMI was higher among depressed than to nondepressed individuals. This study provides support for a possible role of MC4R in the link between depression and obesity

APOA5 genotype influences the association between 25-hydroxyvitamin D and high density lipoprotein cholesterol.

Circulating levels of 25-hydroxyvitamin D (25OHD) are positively associated with high density lipoprotein (HDL) cholesterol. We sought to replicate a previously reported interaction between APOA5 genotype and vitamin D, and to examine whether HDL-associated genetic loci modify the association between serum 25OHD and HDL cholesterol

Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits

BACKGROUND: Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC. RESULTS: After Bonferroni correction, the joint-likelihood ratio test suggested interactions on serum triglycerides (4 SNP - SNP pairs), LDL cholesterol (2 SNP - SNP pairs) and WHR (1 SNP - SNP pair) in the 1958BC. MDR permutation model testing analysis showed one two-way and one three-way interaction to be statistically significant on serum triglycerides in the 1958BC. In meta-analysis of results from two replication cohorts (NFBC66 and Twins UK, total n = 8,183), none of the interactions remained after correction for multiple testing (Pinteraction >0.17). CONCLUSIONS: Our results did not provide strong evidence for interactions between allelic variations in VDR and RXRG genes on metabolic outcomes; however, further replication studies on large samples are needed to confirm our findings

Original Contribution 25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966

Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m) 2 ) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives ( per 1-unit increase in BMI, mean difference in LTL = −0.4%, 95% confidence interval: −0.6, −0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = −0.3%, 95% confidence interval −0.6, −0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL

25-Hydroxyvitamin D concentration and Leukocyte telomere length in young adults: Findings from the Northern Finland birth cohort 1966

Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)2) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = −0.4%, 95% confidence interval: −0.6, −0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = −0.3%, 95% confidence interval −0.6, −0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL.This work was supported financially by the following institutions: the Academy of Finland (grants 104781, 120315, 129269, 1114194, 24300796, and 12926); University Hospital Oulu and Biocenter Oulu, University of Oulu (grant 75617); the European Commission (grant QLG1-CT-2000- 01643); the National Heart, Lung, and Blood Institute, US National Institutes of Health (grant 5R01HL087679-02); the National Institute of Mental Health, US National Institutes of Health (grant 5R01MH63706:02); the Medical Research Council (grants G0500539, G0600705, G0601653, and K014536); the Wellcome Trust (grant GR069224); and Diabetes UK (grant 08/0003775). J.L.B. was supported by a Wellcome Trust Fellowship grant (WT088431MA). D.M.W., S.S., and M.-R.J. were supported by the European Union’s Horizon 2020 research and innovation program under grant agreement DynaHEALTH (633595)

25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort

BACKGROUND: Vitamin D deficiency has been suggested as a cardiovascular risk factor, but little is known about underlying mechanisms or associations with inflammatory or hemostatic markers. Our aim was to investigate the association between 25-hydroxyvitamin D [25(OH)D, a measure for vitamin D status] concentrations with pre-clinical variations in markers of inflammation and hemostasis. METHODOLOGY/PRINCIPAL FINDINGS: Serum concentrations of 25(OH)D, C-reactive protein (CRP), fibrinogen, D-dimer, tissue plasminogen activator (tPA) antigen, and von Willebrand factor (vWF) were measured in a large population based study of British whites (aged 45 y). Participants for the current investigation were restricted to individuals free of drug treated cardiovascular disease (n = 6538). Adjusted for sex and month, 25(OH)D was inversely associated with all outcomes (p or =75 nmol/l compared to < 25 nmol/l. D-dimer concentrations were lower for participants with 25(OH)D 50-90 nmol/l compared to others (quadratic term p = 0.01). We also examined seasonal variation in hemostatic and inflammatory markers, and evaluated 25(OH)D contribution to the observed patterns using mediation models. TPA concentrations varied by season (p = 0.02), and much of this pattern was related to fluctuations in 25(OH)D concentrations (p < or =0.001). Some evidence of a seasonal variation was observed also for fibrinogen, D-dimer and vWF (p < 0.05 for all), with 25(OH)D mediating some of the pattern for fibrinogen and D-dimer, but not vWF. CONCLUSIONS: Current vitamin D status was associated with tPA concentrations, and to a lesser degree with fibrinogen and D-dimer, suggesting that vitamin D status/intake may be important for maintaining antithrombotic homeostasi