Beyond SNPs: Laboratory methylation biomarkers with Dr. David Quig, PhD

Functional Assessment and Clinical Consequences of Aberrant Methionine Metabolism

Focus on SAM and Foe SAH

Functional assessment of methionine metabolism, often referred to as “methylation”, is pivotal towards optimal health and disease prevention in patients of all ages. The essential amino acid methionine and its downstream metabolites have indispensable roles in detoxification, gene expression, neurotransmitter metabolism, immune and mitochondrial functions, and the modulation of oxidative stress and inflammation. Methionine metabolism entails three primary steps starting with essential methylation of DNA, proteins, neurotransmitters, phospholipids and many other small molecules. Methylation is followed by transsulfuration (formation of cysteine, taurine, essential sulfate ions and ultimately glutathione), and re-methylation of homocysteine back to methionine (transmethylation). Conditions associated with untreated aberrant methionine metabolism include, but are not limited to, excessive oxidative stress, compromised endogenous detoxification (arsenic and other xenobiotic toxic elements and chemicals), non-alcoholic fatty liver disease, immune dysregulation/autoimmunity, compromised DNA synthesis and repair (mutagenesis), neurodegenerative diseases, developmental delay, abnormal neurotransmitter metabolism and psychiatric disorders, diminished functioning of mucosal barriers (food sensitivities, IBS, asthma), and increased risk for cardiovascular disease, congenital heart disease, birth defects and Down’s syndrome.

Multiple factors adversely affect methionine metabolism and methylation

Recent research regarding single nucleotide polymorphisms (SNPs) has resulted in hyper-focus on a specific SNP- MTHFR. It is important to note that SNPs (1) do not cause disease, (2) multiple SNPs in a single gene increase the odds for abnormal phenotypic expression, (3) SNPs in multiple genes that encode for enzymes in a common metabolic pathway may be necessary to affect systems/health outcomes (gene-gene interactions), and (4) toxicants can exacerbate potentially minor effects of SNPs. Epigenetic factors such as environmental toxicants and nutritional insufficiencies have been demonstrated to have significant impacts on methionine metabolism independent of specific SNPs. Therefore an integrated metabolic profile reflecting the influences of genetic and epigenetic factors on methionine metabolism has been developed and is available to clinicians. The Plasma Methylation Profile test facilitates identification of specific “bottlenecks” in methionine metabolism and permits targeted intervention for the individual patient. A key feature of the test is the relative abundance of the methyl donor S-adenosylmethionine (SAM) and the potent inhibitor of methylation S-adenosylhomocysteine (SAH). The SAM: SAH ratio is often referred to as the methylation index.

What can be learned from the Plasma Methylation Profile?

Fifty percent of dietary methionine is converted to SAM primarily in the liver by methionine adenosyltransferase (MAT). MAT requires magnesium and can be inhibited by oxidative stress, lipopolysaccharide (LPS) and carbon tetrachloride. A low level of SAM by comparison to methionine is indicative of MAT malfunction. Poor conversion of methionine to SAM can limit methylation. After methyl group donation SAM becomes SAH. A high level of SAH, which can inhibit about 200 methyltransferase enzymes, can result from elevated levels of homocysteine or adenosine. A SAM: SAH ratio less than four is considered indicative of hypomethylation. Elevated SAH (nM), which is not measured at conventional labs, appears to be a better predictor of risk of cardiovascular disease than the much more abundant homocysteine (µM).

Homocysteine can accumulate to elevated levels if the transsulfuration pathway is impaired as a result of insufficient B-6 or poor function of the enzyme cystathionine-β-synthase (CBS); in which case cystathionine and possibly cysteine would be low. The bottleneck accumulation of homocysteine could also be high if it is not efficiently re-methylated to methionine (transmethylation). That can occur as a result of insufficient 5-MTHF, B-12, zinc, B-6, and/or betaine. Furthermore, mercury, lead, and oxidative stress can impair the downstream enzyme methionine synthase (MTR) that requires adequate B-12 with the cobalt moiety in the reduced form. Otherwise simple supplementation with folates can cause a folate trap without resolving, or even be exacerbating, the problem. Since the test requires analysis of an overnight fasted plasma specimen, the level of methionine may be low with compromised transmethylation- recall that methionine is in fact methylated homocysteine.

This brief overview of the functional assessment of methionine metabolism and methylation is not intended to be a comprehensive treatise or interpretation guide, but rather it is provided to draw awareness to a test that goes far beyond SNP testing and draws in important epigenetic factors. Genetic testing of several relevant genes may be helpful after performing the functional assessment, or such SNP analysis may indicate a need to evaluate the patient’s actual phenotypic expression. For a comprehensive resource /interpretive guide with extensive illustrations and references for this test go to www.doctorsdata.com under the category of Environmental Exposures and Detoxification.