1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
2Department of Epidemiology and Inhabitants Well being, Albert Einstein School of Drugs, Bronx, NY
3Shanghai Scientific Heart for Endocrine and Metabolic Ailments and Shanghai Institute of Endocrine and Metabolic Ailments, Ruijin Hospital, Shanghai Jiao Tong College College of Drugs, Shanghai, China
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
5Department of Ophthalmology, Harvard Medical College, Massachusetts Eye and Ear Infirmary, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
5Department of Ophthalmology, Harvard Medical College, Massachusetts Eye and Ear Infirmary, Boston, MA
6Division of Gastroenterology, Massachusetts Normal Hospital, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
7Department of Epidemiology, Harvard T.H. Chan College of Public Well being, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
7Department of Epidemiology, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
7Department of Epidemiology, Harvard T.H. Chan College of Public Well being, Boston, MA
8Division of Preventive Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
7Department of Epidemiology, Harvard T.H. Chan College of Public Well being, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
7Department of Epidemiology, Harvard T.H. Chan College of Public Well being, Boston, MA
1Department of Vitamin, Harvard T.H. Chan College of Public Well being, Boston, MA
4Channing Division of Community Drugs, Division of Drugs, Brigham and Girls’s Hospital and Harvard Medical College, Boston, MA
Related Information
Summary
Introduction
DNA methylation is among the main epigenetic occasions that have an effect on gene expression by way of a mechanism that isn’t induced by adjustments within the DNA sequence (1). Rising proof signifies that DNA methylation performs a pivotal position in regulating physique adiposity (2–5). In a current large-scale epigenome-wide affiliation examine, Dick et al. (4) discovered that DNA methylation at HIF3A was related to BMI. Nonetheless, genetic variants on this locus weren’t related to BMI, though they have been related to HIF3A methylation ranges in blood and adipose and pores and skin tissues. The authors recommended that the affiliation between HIF3A methylation and BMI won’t be working by the Mendelian randomization idea (4), however the examine didn’t take into account potential modifying results of environmental elements on the genetic associations. Earlier proof helps the significance of contemplating interactions between genetic and food regimen/way of life elements within the growth of adiposity (6–10).
It has lengthy been acknowledged that DNA methylation ranges are topic to modulation by environmental elements resembling food regimen and way of life. Methylation of DNA is a biochemical course of through which a methyl group is added to DNA nucleotides. A number of B nutritional vitamins, together with folate, riboflavin (B2), pyridoxine (B6), and B12, act as key enzyme cofactors and play important roles in methyl group metabolism and DNA methylation specifically (11,12). Earlier research have related B-vitamin consumption with adiposity in people (13,14). Subsequently, we hypothesized that B nutritional vitamins modify the relation between the methylation-associated genetic variants at HIF3A and BMI. To check this speculation, we examined interactions between consumption of B nutritional vitamins and DNA methylation variants on the HIF3A locus in relation to BMI and 10-year adjustments in BMI in two potential cohorts: the Nurses’ Well being Examine (NHS) and the Well being Professionals Observe-Up Examine (HPFS).
Analysis Design and Strategies
Outcomes – “b vitamin methylation”
Dialogue
In two giant potential cohorts of U.S. ladies and men, we discovered vital interactions of DNA methylation variant HIF3A rs3826795 with complete or supplemental vitamin B2, vitamin B12, and folate consumption on 10-year adjustments in BMI. A genetic affiliation with a smaller enhance in BMI was noticed within the subgroup with decrease consumption of vitamin B2, vitamin B12, and folate, whereas the affiliation with a larger enhance in BMI was noticed within the subgroup with larger consumption of vitamin B2, vitamin B12, and folate. The findings assist the speculation that DNA methylation might causally have an effect on physique adiposity. Nonetheless, we didn’t measure DNA methylation on the HIF3A locus; with such knowledge, we’d have carried out Mendelian randomization evaluation to supply stronger proof to assist or dispute causality, though outcomes from genetic associations may additionally present proof for a possible causal relation between the genetic variants–related publicity and outcomes, as recommended in earlier research (32).
Rising proof signifies that epigenetic elements contribute to the event of weight problems (2–5). DNA methylation, the key epigenetic regulator in mammalian cells, has been related to BMI or different indices of weight problems (33–35). A current large-scale epigenome-wide examine demonstrated that elevated DNA methylation on the HIF3A locus in blood cells and adipose tissue was related to elevated BMI in adults of European origin (4). However, genetic variants within the HIF3A locus, which has been related to DNA methylation, weren’t associated to BMI in the entire examine inhabitants (4). These findings are according to the present outcomes that DNA methylation variants weren’t related to measures of adiposity within the NHS and HPFS. Taken collectively, these knowledge seem to assist the earlier postulation that the affiliation between HIF3A methylation and BMI could also be not causal (4). Nonetheless, our additional subgroup analyses accounting for B-vitamin consumption refute such a conclusion.
Within the present examine, we discovered that DNA methylation variant HIF3A rs3826795 was considerably related to BMI adjustments amongst members with both excessive or low intakes of vitamin B2, vitamin B12, and folate. Though we didn’t conduct a Mendelian randomization evaluation owing to lack of DNA methylation knowledge, the outcomes not less than partly assist a possible causal relation between HIF3A methylation and adiposity in line with Mendelian randomization idea (36). In response to the speculation, the associations between the genetic variants, which act as a proxy of DNA methylation ranges (4), and adiposity are freed from threat for reverse causation and fewer more likely to be affected by confounding, subsequently offering proof for causality (37,38). The present findings present constant proof from two cohorts displaying strong associations between the DNA methylation variants and BMI adjustments. Of be aware, the methylation variant exhibited reverse results on weight change in response to high and low B-vitamin intakes. These findings are consistent with the speculation of differential susceptibility (39,40), which means that vulnerability genes might perform like plasticity genes; thus, genetic threat is both attenuated by a good atmosphere or amplified by an opposed atmosphere (39,40). The present outcomes spotlight the significance in contemplating impact modifications by environmental elements when assessing genetic associations.
The mechanism for the noticed interactions between B nutritional vitamins and DNA methylation variant in relation to BMI adjustments stays unknown. Nonetheless, the current findings are biologically believable as a result of B nutritional vitamins play an vital position in DNA methylation. Vitamin B2, vitamin B12, and folate are effectively established as the key determinants of one-carbon metabolism through which a methyl group donor is shaped (41). Within the DNA methylation course of, a methyl group is added to the cytosine or adenine DNA nucleotide that usually happens in a CpG dinucleotide context. Animal research have proven that maternal methyl dietary supplements (e.g., folic acid, vitamin B12) enhance offspring DNA methylation (42,43). A randomized trial demonstrated that folic acid supplementation will increase DNA methylation in leukocytes and colonic mucosa (44). As well as, earlier research have proven that the interplay of dietary folate and vitamin B12 with a genetic variant would possibly modulate gene expression by way of DNA methylation (45). DNA methylation adjustments attributable to folate and vitamin B12 can have downstream results by altering gene expression (46) and might modulate illness threat related to genetic variants (47). The present findings underscore the necessity to assess the impact of DNA methylation on HIF3A perform in experimental research and the impact of food regimen on epigenetic adjustments within the HIF3A genomic area by way of in vivo research.
Within the present examine, we individually analyzed B-vitamin consumption from supplemental and meals sources and noticed stronger interactions on BMI adjustments for B nutritional vitamins from dietary supplements. The variations in these findings for B nutritional vitamins from meals sources in contrast with supplemental sources might be defined by variations within the bioavailability of those nutritional vitamins (48). This can be most pertinent for folate and vitamin B12, that are extra bioavailable in supplemental types (43). A considerable physique of proof exhibits that the bioavailability of folic acid (each from dietary supplements and from fortified meals), which is largely ruled by the extent of intestinal absorption, is sort of all the time considerably larger than the web bioavailability of naturally occurring dietary folate from meals sources (49). As well as, vitamin B12 deficiency is widespread amongst individuals with a low consumption of animal meals sources and amongst aged individuals owing to malabsorption of B12 from meals (50). Vitamin B12 or folate complement customers have larger plasma values of those vitamins (51). Subsequently, it’s not stunning that stronger interactions for B nutritional vitamins from dietary supplements have been noticed within the present examine. In additional analyses, we didn’t discover a vital interplay between B-vitamin–wealthy meals (e.g., fish, poultry, meat, greens, dairy, legumes, complete grains) and methylation variants; the attainable purpose is that the associations/interactions are more likely to be contaminated by many different elements within the meals.
The foremost strengths of the present examine embody constant findings from two well-established potential cohorts, detailed assessments of nutrient and meals intakes and measures of adiposity, and minimal inhabitants stratification. Use of longitudinal knowledge minimized a random measurement error and enhanced the robustness of the findings. Nonetheless, a number of limitations have to be acknowledged. First, dietary B nutritional vitamins and adiposity measures have been self-reported, and errors in these measurement are inevitable; nevertheless, the meals frequency questionnaires (23,24) and adiposity measurement knowledge (27) have been effectively validated. Second, confounding by different unmeasured or unknown elements would possibly exist, though we rigorously adjusted for a number of dietary and way of life elements. Third, just like different genetic research, the present analyses to detect gene-diet interplay might need suffered from a a number of testing burden that might have hampered detection and interpretation (52). Nonetheless, the interactions noticed within the present examine for nutritional vitamins B2 and B12 remained vital at P < 0.006 (0.05/8) after Bonferroni correction for a number of testing. Certainly, Bonferroni correction is often too conservative, and overadjustment for a number of comparisons might enhance the danger for sort II error and scale back energy to detect vital variations (53). Fourth, whether or not the genetic markers are practical variants or just correlated markers is unclear. The 2 methylation variants might tag for a practical epigenetic marker; subsequently, it's not stunning that the 2 SNPs confirmed distinct interactions, which don't indicate interplay on the causal variant (54). Fifth, the members have been middle-aged and older adults of European ancestry recruited within the U.S., and it stays to be examined whether or not the outcomes might be generalized to different demographic or ethnic teams. Lastly, we examined two HIF3A variants independently related to methylation at a particular CpG website inside intron 1 of HIF3A, however we didn't discover any interplay for rs8102595. Our earlier examine might present a attainable purpose (8). Not all SNPs are delicate to environmental modifications, and the present examine of 32 BMI variants confirmed numerous interactions with fried meals consumption in relation to adiposity. Additional research are required to research the differential interactions of those variants on the affiliation of DNA methylation with adiposity. In conclusion, the information present constant proof from two cohorts {that a} DNA methylation variant interacts with complete or supplemental B nutritional vitamins in relation to 10-year BMI adjustments. These outcomes, which have to be replicated, assist a possible causal relation between DNA methylation and adiposity. As well as, these findings emphasize the significance of contemplating gene-environment interactions in assessing genetic associations.
Supplementary Materials