SEARCH · PubMed Health

Results for “variable methylation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed1996

Arsenic methylation patterns before and after changing from high to lower concentrations of arsenic in drinking water.

Inorganic arsenic (In-As), an occupational and environmental human carcinogen, undergoes biomethylation to monomethylarsonate (MMA) and dimethylarsinate (DMA). It has been proposed that saturation of methylation capacity at high exposure levels may lead to a threshold for the carcinogenicity of In-As. The relative distribution of urinary In-As, MMA, and DMA is used as a measure of human methylation capacity. The most common pathway for elevated environmental exposure to In-As worldwide is through drinking water. We conducted a biomarker study in northern Chile of a population chronically exposed to water naturally contaminated with high arsenic content (600 micrograms/l). In this paper we present the results of a prospective follow-up of 73 exposed individuals, who were provided with water of lower arsenic content (45 micrograms/l) for 2 months. The proportions of In-As, MMA, and DMA in urine were compared before and after intervention, and the effect of other factors on the distribution of arsenic metabolites was also analyzed. The findings of this study indicate that the decrease in arsenic exposure was associated with a small decrease in the percent In-As in urine (from 17.8% to 14.6%) and in the MMA/DMA ratio (from 0.23 to 0.18). Other factors such as smoking, gender, age, years of residence, and ethnicity were associated mainly with changes in the MMA/DMA ratio, with smoking having the strongest effect. Nevertheless, the factors investigated accounted for only about 20% of the large interindividual variability observed. Genetic polymorphisms in As-methylating enzymes and other co-factors are likely to contribute to some of the unexplained variation. The changes observed in the percent In-As and in the MMA/DMA ratio do not support an exposure-based threshold for arsenic methylation in humans.

Adult↗

PubMed1978

Inhibition of morphological transformation induced with N-methyl-N'-nitro-N-nitrosoguanidine in cultures of hamster embryo cells by 5'-bromo-2'-deoxyuridine-photolysis.

The present study was performed in order to determine whether type III transformed foci induced by N-methyl-N'-nitro-N-nitrosoguanidine originate from the small subpopulation of cells stimulated by the carcinogen to enter DNA synthesis. During the last 30 min of variable treatment periods using different doses of N-methyl-N'-nitro-N-nitrosoguanidine, administered alone or in association with the thymidine analogue, 5'-bromo-2'-deoxyuridine (0.98 x 10(-5)M), the density-inhibited monolayers of hamster embryo cells were exposed to fluorescent light and then assayed for abnormal growth patterns by the focus formation method. Mock-irradiated cultures as well as monolayers whose medium lacked N-methyl-N'-nitro-N-nitro-soguanidine, 5'-bromo-2'-deoxyuridine, or both, served as controls. The cytotoxicity of 5'-bromo-2'- deoxyuridine + N-methyl-N'-nitro-N-nitrosoguanidine + photolysis (BMP) protocol on confluent as well as logarithmically growing hamster embryo cells was estimated in single-cell survival experiments. Plating efficiency determinations have demonstrated that, unlike their actively growing counterparts, confluent hamster embryo cell monolayers are extremely resistant to the cytotoxic effects of the BMP protocol. The quantitative transformation assays indicated that: (1) in non-illuminated cultures addition of 5'-bromo-2'-deoxyuridine to carcinogen-containing medium does affect transformation frequency of hamster embryo cells in the sense that the incidence of type III foci did not subside at later intervals during the post-carcinogen administration period as it did in the absence of the analogue; (2) irradiation of N-methyl-N'-nitro-N-nitrosoguanidine and halogenated pyrimidine analogue-treated cultures with fluorescent light practically suppressed transformation; (3) analogue-added and analogue-removed experiments pointed out that the event(s) on which 5'-bromo-2'-deoxyuridine fluorescent light sensitization of morphological transformation largely depends, takes place between 5 and 15 h after N-methyl-N'-nitro-N-nitrosoguanidine administration, i.e., during the period of maximal carcinogen-stimulated DNA synthesis; and (4) neither fluorescent light nor 5'-bromo-2'-deoxyuridine, singly or in combination, were able to transform cultures of hamster embryo cells. These findings are strong indirect arguments for the concept that carcinogen-induced DNA synthesis and the initiation of transformed clones are causally related.

Animals↗

PubMed1992

Abnormalities of insulin-like growth factor (IGF-I and IGF-II) genes in human tumor tissue.

Recent findings have indicated that Insulin-like growth factors (IGF-I and IGF-II) may play a role in neoplasia. Expression of their genes, which are highly complex structures, is tissue-specific and developmentally regulated. The purpose of the present study was to determine whether a relationship exists between tumorigenesis and the structure and expression of IGF genes. The structures of the IGF-I and IGF-II genes were investigated in 40 tumors by Southern blot analysis but no obvious re-arrangements (such as amplification or deletion) were observed in any of the tissues investigated. DNA methylation was also studied, using the enzyme Avall. The extent of DNA methylation of the IGF genes was highly variable in most of the tumors, as was the level of mRNA expression. A relationship could be detected between IGF over-expression and gene demethylation in tumors associated with hypoglycemia and in certain hepatocarcinomas. Loss of heterozygosity has been reported in the 11p15 region of some childhood tumors. The present findings provide further evidence of this loss of heterozygosity for the IGF-II gene and show an imbalance in the leukocyte alleles in several childhood tumors. Likewise, an imbalance in the alleles was noted in several adult tumors, including hepatocarcinomas and breast cancers. This suggests that in certain adult tumors alterations of the IGF-II gene may be associated with tumorigenesis, but in other tumors another mechanism may be involved.

Alleles↗

PubMed1993

Structural characterization and expression analysis of the Neurospora conidiation gene con-6.

The gene con-6 of Neurospora crassa is expressed during the formation of asexual spores (conidia), but it is not expressed in mycelium. con-6 mRNA appears upon induction of conidiation and reaches high levels at the late stages of conidiation, and in mature conidia. The CON6 polypeptide and a CON6-beta-Gal fusion protein were present at high levels only in free conidia. Shortly after spore germination con-6 mRNA disappears and the CON6 polypeptide is degraded. CON6 is a small, hydrophilic polypeptide containing a repeat sequence; it not homologous to any known protein but has features resembling the late embryogenesis abundant proteins of maize. Inactivation of con-6 by the repeat-induced point mutation process had no demonstrable effect on formation or germination of conidia. Upstream sequence comparisons for con-6 and other con genes identified a common potential regulatory sequence, designated CRS-B. DNA mobility shift analyses with cell extracts identified a factor that bound to synthetic DNA fragments containing this sequence. This binding factor was present in mycelium but not in conidiating cultures. Experiments with independent integrated con-6'-'lacZ translational fusions revealed substantial variability of expression among transformants carrying identical fusion constructs: This variability may be due to the differential methylation of transformant DNA noted by others.

Amino Acid Sequence↗

PubMed1977

Non-equilibrium method for the radioimmunoassay of clozapine in the presence of metabolites.

Cross-reactions with metabolites are an ever-recurring problem encountered in the use of radioimmunoassay techniques to determine active compounds in biological material. Metabolites may interfere with the assay of the parent drug to a variable extent. Taking 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine as an example, it was shown that the extent to which the antiserum produced interacts with the parent drug and the metabolites can be estimated by determining the equilibrium constants and the kinetics. In the present case, therefore, it was advantageous to carry out the radioimmunoassay in disequilibrium, i.e. in order to differentiate the metabolites from the parent drug, the sample was incubated with the antiserum for 10 min, after which the labelled antigen was added and the reaction mixture again incubated for a brief, exactly timed interval. It was shown that cross-reactions did not occur in mixtures of clozapine and its N-demethyl and N-oxide metabolites in the propor tions 1:1:2 over a range of concentration of 1.5-48 ng clozapine per 100 microliter human plasma. The equilibrium constants measured with the clozapine goat antiserum were as follows: clozapine 1.2 X 10(8) M-1, the N-demethyl metabolite 4.6 X 10(7) M-1 and the N-oxide metabolite 3.7 X 10(7) M-1 (pH 7.5 and 20 degrees C).

Administration, Oral↗

PubMed1984

Comparison of sigma- and kappa-opiate receptor ligands as excitatory amino acid antagonists.

Using the technique of microelectrophoresis in pentobarbitone-anaesthetized cats and rats, the effects of benzomorphans, with known actions at sigma- and kappa- opioid receptors, were tested on responses of spinal neurones to amino acids and acetylcholine. The racemic mixture and both enantiomers of the sigma opiate receptor agonist, N-allylnormetazocine (SKF 10, 047), and the dissociative anaesthetic, ketamine, reduced or abolished excitation evoked by N-methyl-aspartate (NMA) with only small and variable effects on responses to quisqualate or kainate. (+)-SKF 10, 047 was 1.2 +/- 0.7 times more potent than the (-)-enantiomer in antagonizing NMA. On Renshaw cells, (+)-SKF 10, 047 enhanced responses to acetylcholine whereas the (-) enantiomer produced only a small reduction. The kappa- opiate receptor agonist, ethylketocyclazocine, had no selective effects on responses to amino acids or to acetylcholine. We conclude that actions at sigma- but not kappa-, opiate receptors are responsible for the NMA antagonism observed with benzomorphans.

Acetylcholine↗

PubMed1994

Stereoselective differences in the binding of N-methylated barbiturates to human serum albumin.

The binding to human serum albumin (HSA) of a homologous series of N-methylated chiral barbiturates was studied by means of equilibrium dialysis. The length of the aliphatic side chain at C-5 of the barbiturate ring was variable, and the compounds used were: (+)-(S)- and (-)-(R)-5-methyl-(A), -5-ethyl-(B), -5-propyl-(C) and -5-butyl-(D)-1-methyl-5-phenyl-barbiturate. Binding parameters (numbers of binding classes and of binding sites in each class, affinity constant, total binding constant) were obtained from the Scatchard plot of the percent binding values. For both enantiomers of A and D as well as for (-)-(R)-B 2 classes were obtained; (+)-(S)-B and both enantiomers of C had only 1 class. The total binding constant (K) indicated a more than twofold higher binding of (-)-(R)-B (2.64 x 10(3).mol-1) and C (5.75 x 10(3).mol-1) compared with the corresponding (+)-(S)-enantiomer (1.02 and 2.00 x 10(3).mol-1, respectively); in the case of D the (+)-(S)-enantiomer was preferentially bound (K = 10.14 vs. 5.40 x 10(3).mol-1 for the (-)-(R)-enantiomer). The percent binding values of (+)-(S)-A were higher than those of (-)-(R)-A; however, the K-values of the A-enantiomers were almost identical.

Barbiturates↗

PubMed1985

The effects of some beta lactam antibiotics on (3H)-methyl-yohimbine binding to intact human platelets.

Several antibiotics have been reported to cause a bleeding diathesis in man, characterized by reduced platelet aggregation. We investigated the effects of several of the penicillins and of moxalactam on the binding of (3H)-methyl-yohimbine to intact human platelets. The (3H)-methyl-yohimbine binding met the criteria for interaction at an alpha2 adrenergic binding site and showed low interindividual variability. Penicillin G, ticarcillin, carbenicillin, piperacillin and moxalactam all inhibited (3H)-methyl-yohimbine binding, but at concentrations far in excess of clinically achievable plasma levels. We conclude that these compounds exert their antiplatelet effects by a mechanism other than competitive inhibition of catecholamine binding.

Adrenergic alpha-Antagonists↗

PubMed1997

DNA hypomethylation in breast cancer: an independent parameter of tumor progression?

The global DNA methylation status was investigated on a series of 59 breast cancers by Southern blotting, using methylation sensitive restriction enzymes. By comparison to control DNA, almost all tumor DNAs were found globally hypomethylated. However, the demethylation was variable from tumor to tumor. Compared to other biological parameters, the methylation did not correlate with chromosome alterations, steroid hormone receptor status, or histopathological grading. Tumors which appeared to be the most evolved for other parameters were only mildly hypomethylated, whereas tumors with strongly hypomethylated DNA corresponded to those with slight alterations of the other parameters. Thus, DNA hypomethylation is a consistent characteristic of breast cancer, but its variations may not correlate with tumor progression of most breast cancers.

Age Factors↗

PubMed1984

Antiadrenergic antihypertensive drugs: their effect on renal function.

Peripheral alpha antagonists not only preserve renal hemodynamics, but decrease RVR and maintain renal perfusion autoregulation in the face of decreased systemic perfusion pressures. On the other hand, central alpha agonists appear to have variable effects. Clonidine preserves RBF and GFR both acutely and chronically, guanabenz decreases RBF acutely but not chronically, and alpha-methyl dopa preserved RBF but decreases GFR. Beta blockers also have variable effects on RBF: the most-often-studied beta blocker, propranolol, has reduced RBF by 10-20% while other commonly used beta blockers, such as nadolol and metoprolol, may preserve RBF. This may reflect propranolol's inability to maintain renal perfusion autoregulation in the face of decreased systemic blood pressure. This failure of propranolol is not completely understood but may be a function of its lack of cardioselectivity or ISA (49). It is also possible that inhibition of renal vasodilators such as the kallikrein-kinin system plays a role (49). Finally, it appears that patients with normal renal vascular tone may be at highest risk to suffer decrements in RBF with beta blockers. Perhaps most importantly, the clinical impact of propranolol's effect on renal function is unclear, since the reductions in GFR have not been sufficient to produce azotemia.

Administration, Oral↗

PubMed1990

The effect of T-DNA copy number, position and methylation on reporter gene expression in tobacco transformants.

Inter-transformant variability in the expression of introduced genes was studied in the R1 and R2 generations of 10 tobacco transformants, produced by Agrobacterium-mediated transformation. In replicated and physiologically equivalent material, tranformants showed considerable variability in the expression of the reporter gene uidA as shown by transcript levels and beta-glucuronidase (GUS) activity. However, homozygous R2 material could be investigated for seven of the transformants and among these, and in one line in which two inserts could segregate independently, this inter-transformant variability was reduced to simple bimodal expression. The two levels of expression for GUS activity in leaves were high or low (approximately 2.5 or 0.3 nmol cm-2 min-1 respectively), with no continuous variation. Transformants in the high group had single T-DNA insertions, while those in the low group had multiple T-DNA insertions, at the same or different loci. Within each group, although T-DNA was apparently integrated at different sites in the plant genome, there was no evidence of position effects. GUS activity levels of the transformants were very similar in the field and in environmentally controlled conditions under high or low light. Plants with multiple insertions and low expression also tended to have increased methylation of the integrated T-DNA.

Bacterial Proteins↗

PubMed1990

Extraction with methyl tert-butyl ether overcomes erratic elution patterns of 6-keto-prostaglandin F1 alpha on high pressure liquid chromatography.

Solvent extraction of 6-keto-PGF1 alpha from aqueous solutions with ethyl acetate was found to result in variable and irreproducible elution patterns, when the extracts were subjected to high pressure liquid chromatography. These problems could not be resolved satisfactorily by using ethyl acetate from different suppliers, nor by changing acids or pH for acidification. After a number of unsuccessful attempts to resolve this problem, we found that variable and irreproducible elution patterns could be avoided by using methyl t-butyl ether as extraction solvent.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Intra- and interindividual variability in systemic exposure in humans to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine, carcinogens present in cooked beef.

During the cooking of beef, the genotoxic heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed. Little is known about the fate of these compounds in humans or the factors affecting it. We have developed assays based on capillary column gas chromatography-negative ion mass spectrometry capable of the simultaneous measurement of MeIQx, DiMeIQx, and PhIP in cooked meat and in human urine using stable isotope labeled analogues. Ten normal, healthy male volunteers were invited to consume a standard cooked meat meal (400-450 g lean beef, cooked as patties on a griddle hotplate) on four separate occasions over a period of 14 months. Following consumption of the test meals, urine was collected from 0 to 8 h, during which time all free amines were excreted and analyzed for MeIQx, DiMeIQx, and PhIP. Subjects ingested 240 +/- 9 (SEM) g cooked meat, which contained 2.2 +/- 0.2 ng MeIQx/g meat, 0.7 +/- 0.1 ng DiMeIQx/g meat, and 16.4 +/- 2.1 ng PhIP/g meat. The variability in relative systemic bioavailability was assessed from the percentage of ingested amine excreted unchanged in the urine. Subjects excreted 2.1 +/- 1.1% of MeIQx and 1.1 +/- 0.5% of PhIP ingested as unchanged amine in the urine. Levels of DiMeIQx in urine, if present, were below the sensitivity of our assay (20 pg/ml) and could not be detected in any of the samples analyzed. Irrespective of dose, urinary excretion of unchanged MeIQx or PhIP (expressed as a percentage of the ingested dose) remained constant for each individual subject. The intraindividual coefficients of variation for MeIQx (28.4%) and PhIP (23.7%) were low and the pooled interday (intrasubject) coefficients of variation for both compounds were only 19 and 3.4%, respectively. In contrast, inter-subject (intraday) variation was greater, with pooled coefficients of variation of 145% for MeIQx and 71% for PhIP. Based on these studies, it should be possible to use the percentage excretion of MeIQx and PhIP to assess the relative bioavailability of these compounds in humans.

Adult↗

PubMed1994

Structure-activity relationships and pH dependence of binding of 8-alkyl-N5-deazapterins to dihydrofolate reductase.

Thermodynamic dissociation constants (Kd) have been determined for two series of 8-alkyl-N5-deazapterins in binary complexes with human and chicken dihydrofolate reductases (DHFRs) and ternary complexes with the enzyme.NADPH complex. For an initial series of 12 compounds with variable 8-alkyl substitutents and pyrazine ring-methyl substitution patterns, Kd values at pH 6.6 were found to range from > 100 to 0.5 microM, with consistent trends depending on the enzyme source, the size of the 8-substituent, and the presence and position of the pyrazine ring-methyl substituent. For most compounds in this first series, Kd values were significantly lower for the ternary complex than for the binary complex with ratios of Kd(binary)/Kd(ternary) ranging from 0.6 to 62, suggesting a degree of cooperativity in binding to the enzyme between ligand and cofactor. This effect was more pronounced for the human enzyme. The structure-activity relationships developed in the first series suggested a number of strategies for developing ligands with greater affinity for DHFR. These were tested with a second series of four compounds. The Kd of 80 nM at pH 6.6 of one of these compounds [5-methyl- 8-isobutyl-N5-deazapterin (15)] in ternary complex with human DHFR is more than 200 times lower than that for the lead compound (8-methyl-N5-deazapterin (1); Kd 21 microM). Studies of binding stoichiometry indicated two binding sites in binary complexes with DHFR for 8-alkyl-N5-deazapterins with smaller 8-substituents. The second site was not found in ternary complexes or for ligands with larger 8-substituents, suggesting that the second ligand molecule in binary complexes is probably binding in the cofactor site and that the larger 8-substituents also bind in this area. A detailed study of the inhibition kinetics for one compound, 6,8-dimethyl-N5-deazapterin (5), showed it to be a competitive inhibitor of the chicken DHFR-catalyzed reduction of 6,8-dimethylpterin suggesting that the 8-alkyl-N5-deazapterins bind in the substrate site of DHFR. The pH dependence of the binding of several ligands in binary and ternary complexes with DHFR was examined by determining their Kd values at a range of pH's. This suggested that binding was predominantly between protonated ligand and deprotonated enzyme, but with variable contributions to binding observed between deprotonated enzyme and neutral ligand, and protonated enzyme and protonated ligand, depending on compound and complex type.

Folic Acid Antagonists↗

PubMed1991

Differential methylation at the 5' and the 3' CCGG sites flanking the X chromosomal hypervariable DXS255 locus.

The degree of methylation at the 5' and 3' CCGG sequences flanking the variable number of tandem repeat (VNTR) region of the DXS255 locus at Xp11.22 was analysed separately in several haematopoietic cell lineages. The 5' CCGG site on active chromosomes was found to be completely methylated in B and T lymphocytes and granulocytes. Methylation of the 5' site on inactive X chromosomes differed between females (0%-60%), but was consistent in different cell lineages obtained from individual females. In contrast, methylation at the 3' CCGG site on active chromosomes was found to vary in B lymphocytes (40%-100%), whereas complete methylation was found in T lymphocytes and granulocytes. The extent of methylation on inactive X chromosomes was found to differ significantly between B lymphocytes (17%), T lymphocytes (54%) and granulocytes (82%). Thus, methylation at the 5' CCGG site seems to be primarily related to the status of X chromosome inactivation, whereas methylation at the 3' CCGG site is mainly subject to cell-lineage-specific influences.

Blotting, Southern↗

PubMed1993

Differential effects of NBQX on the distal and local toxicity of glutamate agonists administered intra-hippocampally.

The ability of the non-NMDA glutamate antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline) to protect the brain against the neuronal death caused by glutamate agonists was examined. Glutamate agonists and NBQX were co-injected into the dorsal region of the rat hippocampus and 4 days later the brain was examined histochemically for the loss of neurons. 95 nmol NBQX prevented the toxicity of glutamate agonists acting on the AMPA receptor (quisqualate and AMPA [L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate]), except for the higher dose of AMPA where toxicity was only partially reduced. This dose of NBQX also prevented about 50% of the toxicity of kainate, but produced a slight increase in the size of the lesions caused by NMDA (N-methyl-D-aspartate). With 190 nmol NBQX, a variable degree of non-specific damage resulted, but was mainly confined to the dentate region. Allowing for this damage, almost complete protection against the toxicity of non-NMDA glutamate agonists was obtained, with a partial protection against NMDA toxicity. Kainate, and a high dose of AMPA (2 nmol), consistently caused neuronal death in other limbic regions of the brain in addition to the hippocampal damage. About 50% of rats treated with 15 nmol quisqualate also showed damage to limbic regions. Both doses of NBQX prevented this distal damage caused by quisqualate, but not that caused by kainate. With AMPA, only the high dose of NBQX blocked the distal toxicity. Diazepam also blocked the distal toxicity of AMPA, but had only a minor effect on the hippocampal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Methyl mercury exposure in northern Quebec. I. Neurologic findings in adults.

Cree Indians of northern Quebec were exposed to methyl mercury through contamination of local fish. The relationship between measures of exposure and neurologic abnormalities was studied in two communities in 1978 by comparing the exposure of 41 "cases" with selected neurologic abnormalities with that of 179 normal "controls." In the community of Mistassini, a significant positive association was found between neurologic abnormalities and methyl mercury exposure; in Great Whale, the association, although also positive, was not statistically significant. However, although allowance was made for confounding variables, it remains possible that the effects are not entirely attributable to methyl mercury. Further, the data do not permit estimation of a threshold level of exposure above which excess neurologic abnormalities might occur, because recent levels of exposure do not reflect those of the past. Whether the abnormalities observed in this study will remain stable, regress, or progress can only be determined by continued surveillance.

Adult↗

PubMed2026

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.

Despite the substantial variability in physical function among older adults, the molecular mechanisms remain poorly characterized, particularly within skeletal muscle. This study aimed to determine the patterns of DNA methylation in skeletal muscle associated with physical function in healthy older adults. We analyzed DNA methylation (EPIC v2 array; 875,554 CpG sites) in skeletal muscle from 92 healthy older adults (median age 74; 62% female). Associations were examined across five phenotypes: Short Physical Performance Battery (SPPB), 6-min walk test (6MWT), handgrip strength, perceived disability (PAT-D), and lifestyle health (modified Life's Essential 8). Linear regression models adjusted for age, sex, race, BMI, and muscle fiber composition. Genomic inflation corrected via the BACON method (FDR < 0.05). Gene set enrichment analysis was performed on suggestive hits (FDR < 0.1). We identified significant differentially methylated probes (DMPs) and regions (DMRs) across all phenotypes: SPPB (70 DMPs, 22 DMRs), 6MWT (16 DMPs, 566 DMRs), handgrip strength (2 DMRs), PAT-D (19 DMPs, 1 DMR), and lifestyle health (2 DMPs). DMRs largely overlapped promoters. Identified genes overlapped known musculoskeletal and neurological GWAS hits, including RUNX2 and FOXL1 (bone mineral density), IGFBP3 (muscle mass), and NEK1 and SHANK1 (neurological function). Enrichment analysis revealed that 6MWT-associated genes relate to nervous and skeletal system development, while handgrip-associated genes involve cytoskeletal dynamics and protein assembly. Epigenetic variation in aging skeletal muscle is associated with physical function. The enrichment of pathways related to nervous and musculoskeletal development suggests specific epigenetic mechanisms underlying functional decline, offering potential targets for intervention in older adults.

DNA methylation↗