Key Takeaways
- Research shows that high homocysteine levels can cause excess oxidative stress and endoplasmic reticulum stress.
- Epidemiologic studies show that high homocysteine levels are strongly linked to an increased relative risk of cardiovascular diseases.
- Homocysteine is an intermediate produced in the methionine cycle and can be remethylated to methionine or converted to cysteine.
- Genetic variants in several pathways interact with what you eat (or don’t eat) to increase homocysteine levels.
Homocysteine
In our ongoing exploration of heart health through genetics, today we will dive into the world of homocysteine – a sulfur-containing amino acid that plays a pivotal role in your cardiovascular well-being.
The Role of Homocysteine in Heart Health
While high homocysteine does not cause a large absolute risk increase for heart disease, this is one biomarker that has fairly straightforward solutions when incorporating genetics.
The Methionine Connection
To understand homocysteine's significance, let's first explore methionine, an essential amino acid derived from protein-rich foods. Methionine serves as the cellular source of methyl groups, crucial in various cellular reactions. In the methionine cycle, methionine is converted to SAM-e (S-adenosyl-methionine), which can transfer methyl groups for critical cellular reactions. Once SAM-e loses a methyl group, it becomes SAH (S-adenosyl-homocysteine), which, in turn, hydrolyzes to form homocysteine.
Methyl Groups:
Methyl groups are vital in various cellular functions, such as converting serotonin to melatonin, producing creatine and phosphatidylcholine, synthesizing neurotransmitters, gene silencing, and detoxifying certain toxins. When these pathways face disruptions, homocysteine levels can surge, leading to adverse long-term health effects.
Balancing Act: Homocysteine Regulation
Your cells maintain relatively constant homocysteine levels through continuous cycles. These intricate mechanisms involve the conversion of homocysteine back to methionine or its transformation into other pathways.
High Homocysteine: Is it really a problem?
Epidemiological studies have linked elevated homocysteine levels to an increased risk of blood clots, heart attacks, and strokes. However, researchers have questioned whether high homocysteine causes these conditions or merely serves as a marker of underlying cellular pathway alterations.
Recent research sheds light on how and why elevated homocysteine levels can harm the cardiovascular system and overall health.
Post-Translational Protein Modifications:
Studies reveal that homocysteine can bind to proteins after their synthesis through post-translational protein modification. This process involves altering the structure and function of proteins, potentially affecting proteins relevant to cardiovascular and neurodegenerative diseases.
Oxidative Stress and ER Stress:
High homocysteine levels correlate with increased oxidative stress and endoplasmic reticulum (ER) stress. ER stress can lead to cell death if the unfolded protein response pathway is overwhelmed. High homocysteine levels can trigger ER stress and activate this pathway, potentially contributing to cell death.
Mendelian randomization studies indicate a causal relationship between high homocysteine and several chronic diseases, including cardiovascular disease.
Defining High Homocysteine
While the normal range for homocysteine levels varies slightly, hyperhomocysteinemia, or high homocysteine, is generally defined as levels exceeding 15 μmol/L. However, the optimal range remains less clear and may vary among individuals. A simple blood test can tell you your homocysteine levels.
Table 1: My Genetic Variants
| Gene | RS ID | Your Genotype | Effect Allele | Effect Allele Frequency | Notes About Effect Allele |
|---|---|---|---|---|---|
| MTHFR | rs1801133 | AA | A | 0.33 | MTHFR C677T, higher homocysteine levels, especially if folate is lacking |
| NOX4 | rs11018628 | C | 0.06 | decreased homocysteine, decreased stroke risk | |
| MTR | rs1805087 | AG | G | 0.19 | increased risk of cognitive impairment due to higher homocysteine |
| MTR | rs2275565 | GT | T | 0.22 | associated with higher homocysteine levels |
| MTRR | rs1801394 | GG | G | 0.5 | somewhat increased homocysteine levels, especially if riboflavin is low |
| CBS | rs5742905 | AA | G | 0.005 | risk of increased homocysteine, responsive to vitamin B6 |
| PEMT | rs7946 | TT | T | 0.68 | TT: homocysteine increases with low folate diet |
| BHMT | rs3733890 | AG | A | 0.3 | reduced conversion of choline to betaine |
If you have the MTHFR variant (first one) and high homocysteine, then folate is likely to be important in reducing homocysteine levels. You could add more folate-rich foods to your diet, or supplement with a low dose of methylfolate if you don’t get the 400 mcg of folate recommended in the RDA.
The MTR and MTRR variants are related to vitamin B12. Consider whether you should add supplemental B12, especially if you are older or eating a primarily vegetarian diet.
If you have the CBS variant highlighted, additional vitamin B6 may help to reduce homocysteine.
The BHMT and PEMT variants are related to choline. Increasing your intake of choline-rich foods may also help with reducing homocysteine.
As always, talk with your doctor or healthcare provider if you have any questions about supplements or interactions with medications.