Role of vitamin D and folate towards the genetic potential in early life and adult phenotypes Emeritus Professor Khor Geok Lin Universiti Putra Malaysia Jakarta 13 th November, 2016
The author declares no conflicts of interest with respect to this presentation
Outline of presentation The genetic potential in early life and adult phenotypes : Barker s Fetal Programming Hypothesis / Developmental Origins of Health and Disease (DoHaD) Implications of vitamin D and folate in early life genetics and adult phenotypes : genetics and epigenetics Concluding remarks
It has been >25 years since epidemiologic studies showed a relationship between birth outcomes and subsequent risk of diseases in adulthood, such as type 2 diabetes, cardiovascular disease, and the metabolic syndrome. What happens in the womb lasts a lifetime Weight in infancy and death from ischaemic heart disease. Barker DJ, Winter PD, Osmond C, Margetts B, Simmons SJ Lancet 1989; 2: 577 80. Fetal and infant growth and impaired glucose tolerance at age 64. Hales CN, Barker DJ, Clark PMS, et al. BMJ 1991;303:1019 22
What exactly is the fetal origins of disease hypothesis? Barker s Hypothesis states that susceptibility to coronary heart disease, stroke, type 2 diabetes, hypertension, osteoporosis and certain cancers in adulthood originates in utero as a response to fetal malnutrition.
Adverse intrauterine conditions lead to asymmetric growth restriction Low Birth Weight for Gestational Age Low Weight: Height Ratio (thinness) Lower arm circumference Small abdominal girth Disproportionate reduction of kidney, liver, pancreas, skeletal muscle mass
The thrifty phenotype hypothesis (Hales & Barker, 001;Gluckman & Hanson, 2004). Postnatal Postnatal In a postnatal environment in which nutrients are in short supply this metabolic thrift continues to be a survival trait, but if nutrients are present in excess the thrifty trait will promote the metabolic syndrome.
IRS Prevalence IRS percentage IRS percentage IRS percentage Early Life origins of disease: Evidence from wide range of international studies 16 14 12 10 8 6 4 2 0 Birthweight Tertile and Prevalence of Insulin Resistance Syndrome Prevalence of Insulin Resistance Syndrome 1 2 3 Birthweight tertile Valdez et al, Diabetologia 1992 Birth weight tertile Mexican American Non-hispanic American Birthweight Tertile, Adult BMI and Adult BMI and IRS Insulin Resistance Syndrome 30 25 20 15 10 5 0 1 2 3 Birthweight Tertile Valdez at al, Diabetologia 1994 Birth weight tertile 3 1 2 BMI Tertile BMI tertile (Valdez et al., Diabetologia 1994)
Prevalence of non-insulin dependent diabetes and impaired glucose tolerance in men by their birth weight (N=370) % Fetal and infant growth and impaired glucose tolerance at age 64. Hales CN, et al. BMJ 1991;303:1019-22. 40 35 30 25 20 15 10 5 0 < 5.5 > 9.5 Birth weight ( lbs. )
Relative Risk Age-adjusted Relative Risk of Non- fatal Coronary Heart Disease and Stroke 1.50 Mean ± 95% CL 1.25 1.00 0.75 0.50 5.0 7.5 10.0 Birthweight 121,700 American Nurses, self report study BMJ 315:396,1997
What is the role of socioeconomic status in contributing to the associations observed in all of these studies? Do we have a confounder here?
Covariates of socioeconomic status smoking Income Sub-optimal nutrition Other factors obesity Physical inactivity Prenatal care Intrauterine growth restriction Adulthood chronic diseases
Crude and SES adjusted rate ratios for mortality from ischaemic heart disease by birth weight: Cohort from Uppsala, Sweden. Birth weight (kg) <3.25 3.25-3.7 3.75-4.24 >4.25 P value for trend Crude 1.0 0.8 0.7 0.7 0.001 Adjusted * 1.0 0.9 0.7 0.7 0.01 *adjusted for SES-related factors Leon DA, et al. BMJ 1998;317:241-5.
Older Hypothesis: Genetic Influences Fetal Insulin Hypothesis ( Thrifty genotype hypothesis ) States that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus, and ultimately glucose intolerance, diabetes, and hypertension in adult life. (Neel JV 1962 Am J Hum Genet 14:353-62)
Fetal Insulin Hypothesis ( Thrifty genotype hypothesis ) Maternal glucose concentrations Fetal genetically determined responses Glucose sensing by fetal pancreas Insulin secretion by fetal pancreas Insulin-mediated growth Infant s birth weight
Thrifty phenotype Intrauterine environment Figure 1 Two alternative explanations for small thin babies with insulin resistance Fetal genetics Poor intrauterine nutrition Small thin babies Insulin resistance Gene influencing insulin resistance Thrifty genotype Susceptibility To NIDDM and heart disease (Hattersley & Tooke, 1999)
Thrifty genotypes and thrifty phenotypes: implications of epigenetics
Waddington (1957) introduced epigenetics interpreted as changes in gene function that occur without changes in gene sequence. Epigenetics has been proposed as a potential mechanism for these programmed changes through environmentally induced changes in gene expression. Within tissues and organs that control metabolic homeostasis (eg, hypothalamus, adipose tissue, stomach, skeletal muscle, and heart), a range of phenotypes can be induced by sustained changes in maternal diet via modulation of genes that control DNA methylation and by histone acetylation. (Sebert et al., Am J Clin Nutr 2011. 94: Suppl 1953S-1958S
A series of epigenetic modifications transforms transcriptionally active regions of DNA (top) into inactive compact chromatin (bottom). DNA methylation, executed by methyltransferases, allows recruitment of methyl-binding domain proteins (MBD), which then recruit histone deacetylases & other chromatin modifying enzymes). Transcriptionally active chromatin is associated with acetylated histones, whereas inactive chromatin has methylated DNA and de-acetylated histones. Epigenetic modifications in gene silencing. (Cutfield et al., 2007. Pediatr Res 61: 68R 75R)
Three of epigenetic regulation. Three fundamental mechanisms of epigenetic gene regulation DNA methylation Cytosine DNA methylation Conversion of cytosine bases to 5- methylcytosine is catalysed by DNA methyltransferases. Histone code RNA-based mechanisms 2010 by American Physiological Society Yan MSC et al. J Appl Physiol 2010;109:916-926
The DNA and histone methyltransferases all use co-factor, S- adenosylmethionine (SAM) as the methyl donor. SAM is formed from methyl groups derived from folate metabolism Deficiency or sufficiency of methyl donors can have a permanent effect on gene expression via changes in epigenetic marks. SAM is a major source of substrate for post translational modifications (histones, DNA & RNA methylation
Folate metabolism Folic acid Methionine 1 carbon metabolism Tetrahydrofolate (THF) N5, 10 methylene THF S-adenosyl methionine (SAM) Homocysteine S-adenosyl homocysteine (SAH)
Critical roles of folate in reproductive processes Within the cell, folate coenzymes are required for : biosynthesis of DNA-thymidylate (dtmp), which is a nucleotide that is essential in the early stages of DNA synthesis generation of methionine for both genomic (CpG) and nongenomic methylations purine synthesis and serine glycine interconversions Folate sufficiency is necessary for prevention of neural tube defects, the maintenance of active spermatogenesis, and several developmental and degenerative disorders, including cancers and vascular disease. (Lucock et al., 2014)
What about vitamin D is it implicated in early lifecycle and adult phenotypes?
(UV B 280-320nm) Vitamin D in food The pathway of vitamin D acting on the genome UV-B converts 7- dehydrocholesteol into previtamin D3 in the epidermis of the skin (calcitriol) Calcitriol (1,25(OH) 2 D3) enters cells and activates the vitamin D receptor (VDR) protein to bind to DNA in the nucleus, acting as a regulator for hundreds of genes.
Is Vitamin D Inadequacy in Early Life an Instance of the Barker Hypothesis? Heaney RP. Nutrition Today 2016 51:14-17 In a study of more than 44,000 adult patients with multiple sclerosis from Canada, the United Kingdom, Denmark, & Sweden, the highest risk of MS was observed in individuals born in May, and the lowest risk in individuals born in November. May births would have followed a winter-long, vitamin D deprived pregnancy, whereas November births would have followed a summer-long pregnancy with presumably higher vitamin D status values Figure shows the ratio of observed to expected cases for each of the 12 months of the year from the study
Researchers at the University of Oxford and the Wellcome Trust Centre for Human Genetics have demonstrated that vitamin D has direct influence on over 200 genes, including many implicated in disease. They used a new DNA sequencing technology to map vitamin D receptor binding sites across the genome. The group found more than 2,700 genes to which Vitamin D can bind. But more importantly, they found more than 200 genes that were actively up- or down-regulated by the hormone, including genes linked to MS, Crohn s disease, type I diabetes, rheumatoid arthritis, systemic lupus erythematosus (more commonly known as lupus), and colorectal cancer (Ramagopalan SV et al., Genome Res. 2010 20: 1352-1360).
A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution Ramagopalan SV et al., Genome Res. 2010 20: 1352-1360.
Vitamin D is not really a vitamin but the precursor to the potent steroid hormone, calcitriol, which regulates numerous cellular pathways widespread in the body (Feldman D et al., 2014 Nature Reviews Cancer 14: 342-357) 1,25-dihydroxyvitamin D
The role of vitamin D in reducing cancer risk progression Feldman et al., Nature Reviews Cancer 2014 14: 342-357 Calcitriol (1,25(OH) 2 D3 regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer Avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome
The role of vitamin D in reducing cancer risk progression Feldman et al., Nature Reviews Cancer 2014 14: 342-357
Concluding remarks
Potential consequences Potential of environment-epigenetic consequences of environment-epigenetic interactions for the health of the next and subsequent generations. Interactions for the health of the next and subsequent generations Parental lifestyle Maternal phenotypes Feast / famine Nutrient supplements Substance abuse alcohol, tobacco, drugs Therapeutic substances eg steroids (Mcmillen IC and JS Robinson. 2005) 2005 by American Physiological Society Altered epigenetic regulatory mechanisms Embryonic placental and fetal growth Organogenesis New regulatory set points for organ system function CVD Potential for transgenerational inheritance Interactions with postnatal environment Postnatal consequences T2 diabetes Obesity
http://diparts.co/
World Health Organization 2016
WHO recommendations on antenatal care for a positive pregnancy experience 2016
For pregnant women with documented vitamin D deficiency, vitamin D supplements may be given at the current recommended nutrient intake (RNI) of 200 IU (5 μg) per day. According to the Cochrane review, there are 23 on going or unpublished studies on vitamin D supplementation in pregnancy (76). Evidence from these trials should help to clarify the current uncertainties regarding vitamin D effects, particularly the effect on preterm birth, and any other associated benefits or harms of vitamin D when combined with other vitamins and minerals, particularly calcium.
Vitamin D supplementation for women during pregnancy De-Regil LM et al. Cochrane Database Syst Rev 2016 Jan 14; (1) CD008873. doi: 10.1002/14651858.CD008873.pub3. The evidence on whether vitamin D supplementation should be given as a part of routine antenatal care to all women to improve maternal and infant outcomes remains unclear. While there is some indication that vitamin D supplementation could reduce the risk of pre-eclampsia and increase length and head circumference at birth, further rigorous randomised trials are required to confirm these effects. However, when vitamin D and calcium are combined, the risk of preterm birth is increased. The clinical significance of the increased serum 25-hydroxyvitamin D concentrations is still unclear.
Can we optimise maternal health and nutrition to minimise epigenetic errors? THANK YOU