Homocysteine

Background

Homocysteine is a naturally occurring amino acid, a building block of proteins, found in the blood. It is an intermediate product in the metabolism of methionine, an essential amino acid obtained from dietary protein. While necessary for various metabolic processes, homocysteine is typically present in the body at very low concentrations due to its rapid conversion into other substances.

Biological Basis

The body metabolizes homocysteine through two primary pathways: remethylation and transsulfuration. In the remethylation pathway, homocysteine is converted back into methionine, a process that relies heavily on folate (vitamin B9) and vitamin B12 as cofactors, with the enzyme methionine synthase playing a key role. Another enzyme, methylenetetrahydrofolate reductase (MTHFR), is critical for producing the active form of folate needed for this pathway. In the transsulfuration pathway, homocysteine is converted into cysteine, a process requiring vitamin B6. Impairments in these metabolic pathways, often due to deficiencies in folate, vitamin B12, or vitamin B6, or genetic variations in enzymes likeMTHFR, can lead to an accumulation of homocysteine in the blood, a condition known as hyperhomocysteinemia.

Clinical Relevance

Elevated levels of homocysteine have been associated with an increased risk of several health conditions. These include cardiovascular diseases, such as coronary artery disease, stroke, and peripheral artery disease, as well as an increased risk of venous thrombosis. High homocysteine levels have also been linked to cognitive impairment, dementia, and certain birth defects, particularly neural tube defects. While homocysteine is considered a biomarker for these conditions, its precise role as a causal factor versus an indicator of underlying metabolic stress is a subject of ongoing research. of homocysteine levels in plasma or serum, often performed after fasting, can provide insight into an individual’s metabolic health and potential risk factors.

Social Importance

The widespread association of elevated homocysteine with various health issues highlights its social importance. Public health initiatives, such as the fortification of grain products with folic acid, have aimed to reduce folate deficiency and, consequently, lower homocysteine levels in the general population, particularly to prevent neural tube defects. For individuals, understanding their homocysteine levels can inform dietary choices and the potential need for vitamin supplementation. Genetic variations affecting homocysteine metabolism, such as common polymorphisms in theMTHFR gene, underscore the role of personalized medicine in assessing individual risk and guiding preventive strategies.

Limitations

Understanding the genetic and environmental factors influencing homocysteine is subject to several methodological and design limitations common in large-scale genetic studies. These limitations, while addressed through rigorous statistical approaches, can impact the generalizability and comprehensive interpretation of findings.

Study Design and Methodological Constraints

While large-scale genetic studies offer significant power, the accurate identification of genetic variants associated with homocysteine relies heavily on robust study designs and rigorous statistical methods. The reliance on genotype imputation, for instance, to infer missing genetic data across diverse marker sets and cohorts, introduces inherent error rates ranging from 1.46% to 2.14% per allele, which, even if small, can collectively impact the precision and confidence of identified associations.^[1]Furthermore, the application of stringent filters for single nucleotide polymorphisms (SNPs), such as requiring presence in multiple cohorts and a minimum participant count, is crucial for robust findings, yet these criteria can sometimes limit the discovery of true associations, particularly for variants with smaller effect sizes or those less common across studies.^[2]

Ancestry-Specific Generalizability and Population Stratification

A significant challenge in understanding the genetic architecture of homocysteine across populations is the disparity in sample sizes, particularly for non-European ancestries. Limited participation from these groups often necessitates the relaxation of stringent quality control filters during meta-analyses, potentially reducing the statistical power to detect associations or affecting the reliability and generalizability of findings in these populations.^[2] Despite comprehensive adjustments for population substructure using principal components and genomic control corrections to minimize spurious associations, the potential for subtle, residual population stratification may persist.^[3] This residual stratification can subtly bias effect estimates and hinder the accurate comparison of genetic effects across diverse ancestral backgrounds.

Phenotypic and Residual Confounding

The precise quantification and appropriate statistical transformation of homocysteine levels are critical, as analytical problems, such as improper trait transformations, can introduce errors and compromise the validity of genetic association analyses.^[2]Moreover, while studies typically adjust for key demographic and cohort-specific confounders like age, sex, and site of recruitment, the complex interplay of unmeasured environmental or lifestyle factors can introduce residual confounding.^[3]Factors such as dietary intake of B vitamins, smoking, or specific medications (e.g., those affecting folate metabolism) may not always be fully captured or adjusted for, potentially obscuring true genetic effects or the intricate nature of gene-environment interactions influencing homocysteine levels.

Variants

Genetic variations play a crucial role in regulating homocysteine levels, a key metabolite in one-carbon metabolism that influences various physiological processes. TheMTHFR gene, encoding methylenetetrahydrofolate reductase, is a central player in this pathway. The rs1801133 (C677T) variant in MTHFR leads to a thermolabile enzyme, with the TT variant alleles resulting in a significant 30% reduction in enzyme activity.^[4]This reduced activity impairs the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for the remethylation of homocysteine to methionine. Consequently, individuals carrying the Val/Val (TT) genotype forrs1801133 typically exhibit a moderate increase of 15–19% in mean plasma homocysteine levels compared to those with the Ala/Ala (GG) genotype.^[4]However, this effect on homocysteine levels can be significantly lessened in individuals with adequate or high folate intake.

Other genes involved in amino acid and one-carbon metabolism pathways also contribute to homocysteine regulation. TheCPS1gene, encoding carbamoyl phosphate synthetase I, is critical for the initial step of the urea cycle in the liver, a process that helps remove excess nitrogen. Variants likers7422339 and rs1047891 in CPS1may influence the efficiency of this pathway, indirectly affecting amino acid balance and potentially homocysteine levels, althoughrs7422339 has not consistently shown genome-wide significance for homocysteine associations in all studies.^[4] Similarly, the CBSgene, which codes for cystathionine beta-synthase, is vital for the transsulfuration pathway, irreversibly converting homocysteine into cystathionine, a precursor to cysteine. Variants such asrs234714 , rs234709 , and rs2851391 in CBScan modulate this critical homocysteine clearance pathway; reducedCBSactivity directly impairs homocysteine removal, potentially leading to its accumulation.^[4]Further influencing homocysteine metabolism are genes likeGNMT, PSPH, and ALDH1L1. The GNMTgene encodes glycine N-methyltransferase, an enzyme that regulates the S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio, a crucial determinant of cellular methylation capacity and homocysteine production. Thers9296404 variant near GNMTcould alter its activity, thereby impacting the balance of methyl groups and homocysteine levels.PSPH, or phosphoserine phosphatase, plays a role in serine biosynthesis, providing a vital one-carbon unit for the folate cycle; thers4948102 variant might affect serine availability and indirectly influence homocysteine remethylation. Meanwhile,ALDH1L1 (aldehyde dehydrogenase 1 family member L1) and its antisense RNA ALDH1L1-AS2, with the variant rs10934753 , are involved in folate catabolism and NADPH production, both essential for maintaining the folate pool and the efficient remethylation of homocysteine.^[4]Plasma homocysteine levels are generally inversely related to plasma levels of folate and vitamin B12, highlighting the interconnectedness of these pathways.^[4]Other genetic variations may exert more indirect influences on homocysteine.NOX4 (NADPH oxidase 4), involved in reactive oxygen species generation, has variants like rs7130284 , rs957140 , and rs187169250 that could affect oxidative stress, which is known to interact with homocysteine metabolism. While specificNOX4variants were not genome-wide significant for homocysteine in all studies, their impact on redox balance can still be relevant.^[4] Genes like CHMP1A, involved in cellular trafficking, with variants rs154657 and rs164746 , or the less characterized C1orf167 and its antisense C1orf167-AS1 with rs12134663 , may affect fundamental cellular processes that, when perturbed, could indirectly contribute to metabolic dysregulation, including altered homocysteine levels. Additionally, theHNF1A-AS1 antisense RNA, with variant rs2251468 , influences the HNF1Atranscription factor, which is crucial for metabolic regulation, thus potentially linking to homocysteine through broader metabolic health.

Key Variants

RS ID	Gene	Related Traits
rs1801133	MTHFR	homocysteine high altitude adaptation folic acid amount age at menopause schizophrenia
rs9296404	RPL24P4 - GNMT	homocysteine
rs154657 rs164746	CHMP1A	homocysteine
rs7422339 rs1047891	CPS1	homocysteine chronic kidney disease, serum creatinine amount circulating fibrinogen levels creatine amount glycine
rs234714 rs234709 rs2851391	CBS	homocysteine
rs12134663	C1orf167-AS1, C1orf167	homocysteine
rs7130284 rs957140 rs187169250	NOX4	homocysteine
rs4948102	PSPH	homocysteine serine glycine
rs2251468	HNF1A-AS1	homocysteine low density lipoprotein cholesterol , free cholesterol:total lipids ratio total cholesterol
rs10934753	ALDH1L1, ALDH1L1-AS2	homocysteine N-acetylglycine glycine glomerular filtration rate serum creatinine amount

Homocysteine and Cardiovascular Disease Risk

Elevated homocysteine levels have a well-established association with an increased risk of cardiovascular diseases. Studies indicate a link between homocysteine and coronary atherosclerosis.^[5]and it has been explored as a candidate genetic risk factor for vascular disease, particularly in the context of genetic variations like theMTHFR C677T polymorphism.^[6]Plasma homocysteine concentration has also been investigated for its role in the risk of first acute coronary events, with research examining its interplay with other therapies such as statins.^[7]Large community-based studies, such as the Framingham cohorts and the Hordaland Homocysteine Study, have extensively characterized the determinants of homocysteine and its associations with various diseases, underscoring its relevance in cardiovascular risk stratification.^[8]These findings highlight the potential prognostic value of homocysteine levels in identifying individuals at higher risk for adverse cardiovascular outcomes.

Homocysteine, Cancer, and Neurological Health

Beyond cardiovascular implications, elevated homocysteine levels and low plasma B-vitamin levels have been associated with an increased risk of certain cancers.^[4] Specifically, research has linked plasma folate consumption and red cell folate levels to the risk of colorectal adenomatous polyps.^[9]and further studies have examined the relationship between folate, methionine, alcohol intake, and the risk of colorectal adenoma.^[10] Meta-analyses have also explored the association between the MTHFRC677T variant and colorectal cancer risk.^[11]as well as folate and the risk of breast cancer.^[12]Furthermore, homocysteine levels are relevant in neurological health, with studies demonstrating associations between folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.^[13] suggesting its potential role in neurodegenerative processes.

Genetic and Nutritional Influences on Homocysteine

The clinical utility of assessing homocysteine levels extends to understanding its underlying determinants, which are crucial for personalized medicine approaches and prevention strategies. Plasma homocysteine levels are inversely related to plasma levels of folate and vitamin B12, indicating that nutritional status significantly impacts homocysteine metabolism.^[4] Genetic factors also play a substantial role, with the MTHFR C677T (rs1801133 ) polymorphism being a well-studied functional variant strongly associated with plasma homocysteine levels.^[4] Individuals carrying specific variants, such as the MTHFR222Val allele, tend to exhibit higher plasma homocysteine levels.^[4] Other genetic loci, including rs12085006 , rs1999594 , and an association on chromosome 9 in the gamma-aminobutyric acid B-type receptor G-protein coupled receptor 51 (GPR51) gene (rs10986018 ), have also been identified as significant predictors of plasma homocysteine, providing further insights into the genetic architecture influencing this metabolite.^[4]Understanding these genetic and nutritional influences aids in identifying high-risk individuals and guiding targeted dietary or supplemental interventions, though the direct clinical benefits of such interventions on disease outcomes are complex and require careful consideration of broader clinical evidence.

Large-Scale Cohort Investigations and Genetic Associations

Extensive population studies have illuminated the genetic and environmental factors influencing plasma homocysteine levels. Large-scale biobank and cohort studies, such as the Framingham Heart Study (FHS) through its SNP Health Association Resource (SHARe) project, have genotyped thousands of participants to identify genetic predictors.^[4] The SHARe project included 9274 Caucasian participants, with 8508 samples demonstrating high call rates, and specifically measured one-carbon metabolites in 1647 Caucasian women and 1458 Caucasian men from the original and offspring cohorts between 1995 and 1998.^[4] Similarly, the Nurses’ Health Study (NHS), initiated with 121,700 US registered nurses, has provided a robust longitudinal framework for examining health-related exposures and genetic markers, with a subset of 1658 women genotyped for genome-wide association studies.^[4]These significant cohorts have been instrumental in genome-wide evaluations, revealing novel genetic associations with plasma homocysteine. A meta-analysis combining data from the NHS CGEMS and FHS SHARe datasets, encompassing 4763 individuals, identified genome-wide significant predictors of homocysteine levels.^[4] This research confirmed the strong association of the well-studied MTHFR C677T polymorphism (rs1801133 ) with plasma homocysteine, demonstrating that participants with the Ala/Ala (G/G) variant typically exhibit lower levels.^[4]Further, other single nucleotide polymorphisms (SNPs) likers12085006 and rs1999594 , located near MTHFR, showed even stronger associations, with specific alleles linked to higher homocysteine concentrations.^[4]

Epidemiological Patterns and Gene-Nutrient Interactions

Epidemiological research has consistently highlighted the inverse relationship between plasma homocysteine and levels of B vitamins, particularly folate and vitamin B12.^[4]Findings from the third National Health and Nutrition Examination Survey (NHANES) DNA Bank in the United States have provided insights into the prevalence and complex interplay of gene-gene and gene-nutrient interactions on serum folate and total homocysteine concentrations.^[14]These studies underscore how nutritional status can modify genetic predispositions, influencing population-level homocysteine patterns.

The impact of nutritional interventions, such as food fortification, on homocysteine levels and genetic effects has been observed across populations. While theMTHFR C677T polymorphism (rs1801133 ) showed strong associations with homocysteine concentrations in studies like InCHIANTI and SardiNIA, its effect was not evident in the Baltimore Longitudinal Study of Aging (BLSA).^[15] This significant heterogeneity, with a chi-squared value of 18.11 and a p-value of 1.2 x 10^-4, is largely attributed to the higher folate status prevalent in the United States due to widespread food fortification, which can compensate for the genetic effect of the 677C/T variant.^[15]

Cross-Population Variances and Methodological Considerations

Cross-population comparisons reveal that while many large-scale genetic studies, including those using the FHS and NHS cohorts, predominantly feature participants of self-reported European ancestry, this demographic focus also highlights the need for broader representation.^[4]The consistency of assay methodologies, such as the use of high-performance liquid chromatography with fluorescence detection for measuring plasma homocysteine in both NHS CGEMS and FHS SHARe studies, is crucial for ensuring comparability and reliability of findings across different cohorts.^[4] However, variations in environmental factors like dietary practices and public health policies, such as folate fortification, can introduce significant heterogeneity in genetic associations observed across different geographical and ethnic populations, necessitating careful interpretation of findings and consideration of population-specific effects.^[15] The methodological rigor of these studies, including large sample sizes and comprehensive genotyping platforms, is vital for robust epidemiological associations. For instance, the Women’s Genome Health Study, with its genome-wide evaluation of 13,974 participants, identified novel associations of genes like CPS1, MUT, NOX4, and DPEP1with plasma homocysteine in a healthy population.^[16]While these large cohorts offer excellent statistical power, the generalizability of findings is often limited by the demographic homogeneity of the study populations, emphasizing the ongoing need for diverse and globally representative cohorts to fully understand the population-level implications of homocysteine measurements.

Frequently Asked Questions About Homocysteine

These questions address the most important and specific aspects of homocysteine based on current genetic research.

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1. Can just eating healthy fix my high homocysteine?

It depends. While a diet rich in folate, vitamin B12, and vitamin B6 is crucial for healthy homocysteine levels, some people have genetic variations that make their bodies less efficient at processing it. In those cases, even a good diet might not be enough, and supplementation could be beneficial.

2. My parents have heart issues; will I too because of homocysteine?

Potentially, yes. High homocysteine levels are associated with an increased risk of cardiovascular diseases, and genetic factors influencing homocysteine can run in families. Knowing your family history and your own homocysteine levels can help you assess your personal risk.

3. Could my memory problems be linked to my homocysteine?

Yes, it’s possible. Elevated homocysteine levels have been linked to cognitive impairment and dementia. While it’s considered a biomarker rather than a definitive cause, it’s a factor your doctor might consider when investigating memory concerns.

4. Is it worth it for me to get my homocysteine checked?

It can be, especially if you have risk factors for heart disease, cognitive issues, or if there’s a family history of these conditions. A homocysteine can provide insight into your metabolic health and help guide preventive strategies, including diet and supplements.

5. Does smoking affect my homocysteine levels?

Yes, lifestyle factors like smoking can indeed influence your homocysteine levels. These factors can introduce confounding effects in studies and may impact your body’s overall metabolic processes, including those that regulate homocysteine.

6. Does my homocysteine naturally go up as I get older?

Age is one of the demographic factors that can influence homocysteine levels, and it’s often accounted for in health studies. It’s a good idea to monitor your metabolic health, including homocysteine, as part of your regular check-ups as you age.

7. If my homocysteine is high, can I lower it?

Often, yes. High homocysteine is frequently linked to deficiencies in B vitamins, particularly folate, vitamin B12, and vitamin B6. Addressing these deficiencies through diet or targeted supplementation can often help bring your levels back into a healthy range.

8. Why do healthy diets affect my homocysteine differently than others?

Your unique genetic makeup plays a significant role. Genetic variations in enzymes involved in homocysteine metabolism, such as one responsible for activating folate, can mean your body processes homocysteine less efficiently than someone else’s, even with a similar diet.

9. Does my family’s background affect my homocysteine risk?

Yes, your ancestry can influence your risk. The prevalence and impact of specific genetic variations that affect homocysteine metabolism can differ across various ethnic backgrounds, which means your family’s heritage might play a role in your individual risk.

10. Is the extra folate in my food enough for me?

For many people, the folic acid fortification in grain products is beneficial and helps keep homocysteine levels healthy. However, if you have certain genetic variations, your body might still struggle to use that folate effectively, and you might need additional intake or specific forms of folate.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Willer CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, 2008.

[2] Noordam R, et al. “Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.” Nat Commun, 2019.

[3] Wu JH, et al. “Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.”Circ Cardiovasc Genet, 2013.

[4] Hazra, A. “Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway.” Hum Mol Genet, 2009.

[5] Mayer, E.L., D.W. Jacobsen, and K. Robinson. “Homocysteine and coronary atherosclerosis.”Journal of the American College of Cardiology, vol. 27, no. 3, 1996, pp. 517-527.

[6] Frosst, P., et al. “A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.”Nature Genetics, vol. 10, no. 1, 1995, pp. 111-113.

[7] Ridker, P.M., et al. “Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events.”Circulation, vol. 105, no. 15, 2002, pp. 1776-1779.

[8] Selhub, Jacob. “The many facets of hyperhomocysteinemia: studies from the Framingham cohorts.” Journal of Nutrition, vol. 136, no. 6, 2006, pp. 1726S-1730S.

[9] Bird, C.L., et al. “Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps.” Cancer Epidemiology, Biomarkers & Prevention, vol. 4, no. 7, 1995, pp. 709-714.

[10] Giovannucci, Edward, et al. “Folate, methionine, and alcohol intake and risk of colorectal adenoma.”Journal of the National Cancer Institute, vol. 85, no. 11, 1993, pp. 875-884.

[11] Hubner, R.A., and R.S. Houlston. “MTHFR C677T and colorectal cancer risk: A meta-analysis of 25 populations.”International Journal of Cancer, vol. 120, no. 5, 2007, pp. 1027-1035.

[12] Larsson, Susanna C., et al. “Folate and risk of breast cancer: a meta-analysis.”Journal of the National Cancer Institute, vol. 99, no. 1, 2007, pp. 64-76.

[13] Clarke, R. “Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.”Archives of Neurology, vol. 55, no. 11, 1998, pp. 1449-1455.

[14] Yang, Q.H., et al. “Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank.”American Journal of Clinical Nutrition, vol. 88, no. 1, 2008, pp. 232–246.

[15] Tanaka, T., et al. “Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations.”Am J Hum Genet, 2009.

[16] Pare, G., et al. “Novel Associations of CPS1, MUT, NOX4 and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study.”Circulation: Cardiovascular Genetics, vol. 2, no. 2, 2009, pp. 142–150.