Gene alleles Table, n=1, Case studies can be informative about heterogenic conditions.

Down's syndrome and many congenital conditions involve many gene alleles rather than just one main problem gene. That can cause variable needs for the patient's supplements or diet.

Now that I gave you the juicy parts, I will go back to the beginning of Table 9. Genes, actually middle, it includes gene polymorphisms that might be causal in histamine excess, Retinoid Toxicity or schizophrenia. Back to the beginning of my n=1 alleles section…

Gene alleles of the author, (n = 1), from a screening of 30 in common with autism.

Described singly, and then potential phenotypes for the genotype are discussed.

*Yes, the author is writing about herself in third person voice in the phenotype section. It appears she is a textbook example of a genotype that may present with a phenotype of histamine excess. Think of it as a nutrigenomic S.O.A.P.I.E. chart note about a patient, n=1, who is being referred to a cardiologist for further diagnostic evaluation.

• Data source: Blood sample, self-pay screening panel by Holistic Health International, ‘DNA Nutrigenomic Test with Methylation Pathway Analysis.’ (DNA Nutrigenomic Test)

  - The author had four double and seven single alleles/polymorphisms (involving nine genes in total) from the panel of thirty, discussed here singly.

  - The author later had confirming information from a saliva screening with ancestry.com but is not going to mix datasets here.

N = 1, Gene polymorphisms.

Normal Function of the protein, and risks or conditions seen with alleles, and nutrients that may become deficient, less bioactive, or elevated and a risk.

1. BHMT/1, rs585800, Double allele, BHMT/1 (Call – T).

   3 Prime UTR Variant. (rs585800, dbSNP; rs585800, snpedia)

   Betaine-homocysteine methyltransferase (BHMT), Protein Code: GC05P079111. (BHMT, genecards)

2. BHMT/8, rs651852, Single allele, BHMT/8 (Call - Hetero),

   Intron Variant. (rs651852, dbSNP; rs651852, snpedia)

   Yasko material suggested this polymorphism may increase effects of psychological stress on the attention span. (snpedia/Yasko #BHMT-08)

BHMT gene functions include: One-carbon methylation cycle. Zinc ion binding. Phosphorylation, Endocannabinoid metabolism and breakdown. DMG production from betaine and methionine from homocysteine, leaving cysteine for glutathione production.

The BHMT protein is portrayed in Li, F., et al., 2008, Figure 3, with the needed atoms of zinc in place. Figure 1 shows the interconnected pathways of the methylation of homocysteine to methionine and folate to 5-THF. (Li, F., et al., 2008, Figure 1, Figure 3) Methionine and 5-THF are methyl donors and may be needed for DNA methylation in the DNMT pathway of the methylation cycles. (Obeid, 2103, Fig. 1; Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Fig. 1)

Affects zinc ion binding. (Zinc Ion Binding; Ashburner, et al., 2000; GO resource, 2021) (Azimi, et al, 2022)

BHMT enzyme is needed to methylate betaine, Trimethylglycine (TMG), to Dimethylglycine (DMG), and homocysteine to methionine; and phosphorylate endocannabinoids. (BHMT, genecards) Figure 1 by Obeid, 2103, Fig. 1, also shows the interconnected methylation cycles and the genes. The CBS pathway of the one-carbon cycle, if disrupted, would result in less cysteine for glutathione production. (Obeid, 2103, Fig. 1)

The re-methylation cycle also converts cyanocobalamin to an active form which is later used by MTR within the interconnected cycles. (Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Fig. 1)

BHMT dysfunctional polymorphism risks include:

Choline deficiency disease, vascular disease or aneurysm, and hyperhomocysteinemia / homocystinuria (a heart disease risk factor) may be a risk but is not generally seen with BHMT alleles. Spina bifida and neural tube defects may be present. (BHMT, genecards) Choline deficiency may occur, and possibly elevated homocysteine, low DMG, methionine, and cysteine.

Lack of DMG may increase headaches and mental agitation as it acts as an inhibitory neurotransmitter. Lack of methionine and cysteine may reduce glutathione availability.

Lack of choline can increase pain by reducing alpha 7 nAChr activity. (El Nebrisi, et al, 2018)

Endocannabinoid deficiency and imbalance are risks. BHMT enzyme is needed to phosphorylate most endocannabinoids and needed to break down some types. Endocannabinoid deficiency and imbalance occurs with dysfunctional alleles. (Williams, 2011)

3. SHMT/ C1420T, rs1979277, Single allele, SHMT/C1420 (Call – Hetero),

   Missense Variant. (rs1979277, dbSNP) (SHMT-1 gene)

   Serine hydroxy- methyltransferase. Protein Code: GC17M050956,

   (SHMT 1, genecards) *SHMT 2 is the mitochondrial version.

SHMT gene functions include: One-carbon methylation cycle. Zinc ion binding.

BHMT and SHMT affect zinc ion binding and DNA methylation. Figure 1 by Azimi, et al, 2022 depicts the interconnected pathways of the SHMT, MTHFR, MTR, and BHMT genes in the conversion of folate to 5-methyl THF, and of homocysteine to methionine. In each pathway, the removal of the methyl group from betaine uses zinc. (Azimi, et al, 2022, Figure 1)

SHMT affects zinc ion binding. (Zinc Ion Binding; Ashburner, et al., 2000; GO resource, 2021)

SHMT dysfunctional allele risks include: May decrease folate and elevate homocysteine. A human study found elevated homocysteine and reduced folate in red blood cells in participants with the SHMT C1420T polymorphism but it was not found to also be associated with increased risk for NTDs. (Heil, et al., 2001) Reduced risk for breast cancer was found with this allele in a study of solid tumors in an Asian population. (Zhao, T., et al., 2015) Gastric and other cancer has been studied in relation to the SNP. (rs1979277, dbSNP)

4. MTHFR/ C677T, rs1801133, Double allele, MTHFR/C677T (Call – T), Missense Variant. (rs1801133, dbSNP; rs1801133, snpedia)

   Methylene tetrahydrofolate reductase, (MedlinePlus/MTHFR)

MTHFR gene functions include: One-carbon methylation cycle. The MTHFR enzyme is needed to convert 5,10-methylenetetrahydrofolate into the 5-methyltetrahydrofolate form which is needed in the conversion of homocysteine to methionine. (MedlinePlus/MTHFR)

“The … (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis.” (CC-BY the authors: Raghubeer, Matsha, 2021)

MTHFR/C677T polymorphism risks: The C677T allele has been associated with Neural Tube Defects, heart disease and stroke. Risk has varied in studies suggesting other factors are involved in addition to this specific polymorphism. Reduced activity allele; may cause hyperhomocystinemia / homocystinuria; low folate may affect histamine accumulation. (MedlinePlus/MTHFR) The C677T allele is one of the more common causes of elevated homocysteine. Inflammatory conditions are also seen, cancer, diabetes and CVD. (Raghubeer, Matsha, 2021) Deficiency of folate, B6, and B12 would also increase risk of elevated homocysteine.

C677 allele is more temperature sensitive – worse enzyme function at temperatures above normal body temp ~ 37’C/98.6’F. The C677T allele causes the enzyme to not work as well at temperatures above 37’C/98.6’F, 50–60% lower activity and 65% reduced at temperatures above 46’C. (Rozen, 1997, cited by Raghubeer, Matsha, 2021), making exertion or a fever more of a risk of homocysteine buildup and reduced folate availability at a time when extra is needed.

Choline deficiency may be a risk. Choline supplements may also be needed with MTHFR, rs1801133, polymorphism. (Ganz, et al., 2016)

5. MTRR/A66G, rs1801394, Double allele, MTRR/A66G (Call-G),

   Missense Variant. (rs1801394, dbSNP; rs1801394, snpedia)

   5-methyltetrahydrofolate-homocysteine methyltransferase reductase or referred to as methionine synthase reductase. (MedlinePlus/MTRR)

MTRR gene functions include: Methionine/homocysteine portion of the One-Carbon interconnected cycles. (Azimi, et al, 2022, Figure 1)

MTRR/A66G polymorphism risks include:

Homocysteine may be elevated. MTRR reactivates methionine synthase so it can continue to convert homocysteine to methionine. The A66G allele may have increased risk for homocystinuria, Down Syndrome and neural tube defects, however, why NTDs are associated with the polymorphism is unknown. (MedlinePlus/MTRR)MTRR/A66G and MTR/A2756G in combination may increase risk of elevated homocysteine more than either alone. (Laraqui, et al., 2006)

Remethylation of folate and B12 may be reduced. MTRR alleles may affect folate and vitamin B12 methylation. Levels of B12 might be in normal range but dysfunctional due to the lack of methylation. Reduced methyl folate levels may increase histamine accumulation. (mtrra66g.com) Reduced methylated folate level is a cause of neural tube defects. (Obeid, Holzgreve, Pietrzik, 2013)

Choline may be low. Choline supplements may also be needed with MTRR, rs1801394. (Ganz, et al., 2016)

Riboflavin may help. Riboflavin supplementation was found protective against gastric cancer for Korean people with MTRR (rs1532268) alleles. (Lu, Y.T., et al, 2022)

6. MTR/A2756G, rs1805087, Single allele, MTR/A2756G (Call – Hetero),

   Missense Variant. (rs1805087, dbSNP; rs1805087, snpedia)

   Methionine synthase gene. (MedlinePlus/MTR)

Lack of active B12 mimics MTR dysfunction; B12 is a cofactor for the MTR. Inactivation by nitrous oxide or lack of methyl B12 can cause similar symptoms as lack of MTR as it is a cofactor for the enzyme. “[30–32].” (CC-BY the authors Ghergurovich, et al., 20021)

MTR gene functions include: One-carbon methylation cycle.

MTR dysfunctional polymorphism risks include:

Folate is left in an inactive form ~ the phenotype would be equivalent to deficiency but would present with a normal lab test for folate levels. MTR dysfunction reduces folate availability by leaving it in an inactive form – present but not functional. The role of MTR in methionine metabolism seems less critical according to Ghergurovich, et al..

“Moreover, because methylene-THF reduction to 5-methyl-THF is nearly irreversible in cells (due to high cytosolic NADPH/NADP+) [33], MTR dysfunction leads to folate trapping as 5-methyl-THF [20, 30, 34–36]. (CC-BY the authors Ghergurovich, et al., 2021)

B12 may be low. Homocysteine may be elevated. MTR/A2756G may cause up-regulation of the conversion of homocysteine to methionine which would use up stores of methylated B12; cyanocobalamin would be inactive. It is recommended to supplement with methyl folate for balance. (mtra2756g) MTRR/A66G and MTR/A2756G in combination may increase risk of elevated homocysteine more than either alone. (Laraqui, et al., 2006)

Choline supplements may also be needed with MTR, rs1805087 [wild-type (WT)]. (Ganz, et al., 2016)

7. MAO A/ R297R, rs6323, Double allele, MAO A/R297R (Call-T),

   Synonymous Variant. (rs6323, dbSNP)

   Monoamine oxidase A (MAO-A) enzyme. (MedlinePlus/MOA A)

MAO A gene function includes: Enzyme for neurotransmitter inactivation. The MAO-A enzyme breaks down the neurotransmitters: serotonin, epinephrine, norepinephrine, and dopamine; and dietary monamines, such as tyramine in cheese. It is involved in apoptosis during embryo development.  (MedlinePlus/MOA A)

MAO A risks with dysfunctional polymorphisms: Lack of the gene is associated with intellectual limits, difficulty with social interaction, repetitive hand motions, and seizures. Low activity alleles of the MAOA-uVNTR type, are linked to aggression in females and males, especially following early childhood trauma, while high activity alleles are linked to panic disorder in females. Polymorphisms of MAO A are being studied in association with depression, bipolar disorder, alcoholism, drug addiction, and other conditions.  (MedlinePlus/MOA A)

The T allele of R297R mutation is associated with generalized anxiety disorder. (MedlinePlus/MOA A)

8. CBS/A360A, rs1801181, Single allele, CBS/A360A (Call-Hetero),

   Synonymous Variant. (rs1801181, dbSNP)

   Cystathionine beta synthase enzyme. (MedlinePlus/CBS)

   Extra dietary vitamin B6, methionine, and folate may be protective for this allele against risk of Non-Hodgkin lymphoma. (Li, Q., et al., 2013, cited by Gardner, 2022)

CBS gene functions include: transsulfuration cycle of the interconnected one-carbon cycles. (Azimi, et al, 2022, Figure 1)

B6 deficiency may mimic CBS gene dysfunction as it is a cofactor. The CBS enzyme uses vitamin B6 to convert homocysteine and serine into cystathionine which another enzyme converts into cysteine. The pathway is needed for glutathione synthesis and methionine. Homocystinuria may be a risk with dysfunctional CBS.  (MedlinePlus/CBS)

CBS dysfunctional polymorphism risks include: CBS gene dysfunction is the cause of Classical homocystinuria.

Methionine levels may also be elevated when homocysteine is elevated and cysteine is low, in Classical homocysteinuria. The CBS gene dysfunctional allele G1330A, rs28934891, (rs28934891, dbSNP), is one of the high risk polymorphisms associated with reduced CBS activity and an accumulation of homocysteine. (Gardner, 2022) Low methionine is not necessarily a biomarker for homocystinuria. Methionine may be normal or low when MTHFR or cblC are the genes with dysfunctional alleles. (Weber Hoss, Poloni, Blom, Doederlein Schwartz, 2019; Table 2).

Allele phenotype -> ‘Night owls’ ? *Sleep in, stay up late. CBS is involved in circadian regulation and function by binding with CRY1. Together they repress the CLOCK/ BMAL1 complex and shorten the circadian period. (Cal-Kayitmazbatir, et al, 2021)

9. COMT/V158M, rs4680, Single allele, COMT/V158M (Call-hetero),

   Missense Variant. (rs4680, dbSNP)

   Catechol-O-Methyltransferase enzyme. (MedlinePlus/COMT)

   The Val158Met polymorphism (rs4680) effects the activity of the enzyme, and the abundance and stability of the protein. (Tunbridge, et al., 2019)

10. COMT/H62H, rs4633, Single allele, COMT/H62H (Call hetero),

    Synonymous Variant. (rs4633, dbSNP)

    Catechol-O-Methyltransferase enzyme. (MedlinePlus/COMT)

COMT gene functions include: Enzyme for neurotransmitter inactivation. COMT is an enzyme that breaks down neurotransmitters in the brain and promotes balanced prefrontal cortex function. Dysfunction may lead to swings in dopamine levels that can cause mental illness. (MedlinePlus/COMT)

COMT gene polymorphism risks include: Schizophrenia, fibromyalgia, alcohol use disorder or opioid addiction may be at increased risk with a dysfunctional allele. (MedlinePlus/COMT) The COMT SNPs rs4680, rs4633, rs4818, and rs6269 were seen more frequently in patients with fibromyalgia compared to the control group. (Lee, et al., 2018) COMT rs4633 may be involved in increased startle response and was associated with more severe anxiety. (Tomasi, et al., 2020)

‘Feels more pain but has difficulty expressing it’ phenotype? Polymorphism in the COMT gene has been linked to alexithymia, (difficulty expressing emotion), and hypervigilance to pain, which have been observed as comorbid. The Met/Met polymorphism seems to be the more at-risk group for emotion and pain being linked compared to Val/Val or Val/Met. (Ikarashi, et al., 2021)

The rs4680, Val158Met, (Call-hetero) polymorphism is associated with an increased risk for dystonia and Extrapyramidal symptoms with antipsychotic medication use, while the Val/Val and Met/Met seem to have a protective effect. (Nicotera, et al., 2021)

Placebo/Nocebo effect: The ‘believer’ phenotype? Low activity polymorphism of COMT leading to elevated dopamine, has been linked to a greater susceptibility to the placebo/nocebo effect. (Hall, Loscalzo, Kaptchuk, 2015)

11. VDR/Fok-1, rs2228570, Single allele, VDR/Fok-1 (Call-Hetero),

    Initiator Codon Variant. (rs2228570, dbSNP)

    Vitamin D Receptor. (MedlinePlus/VDR)

VDR gene functions include: Vitamin D Receptor - calcium/magnesium metabolism, skeletal and immune functions.

The Bsm1, Apa1 and Taq1 polymorphisms are located near each other at the 3’ end of the VDR gene within the ligand binding domain and are a risk for vitamin D deficiency. They have been more studied than the Fok1 located at the 5’ promoter, DNA binding end of the VDR gene. (Uitterlinden, et al., 2004)

VDR dysfunctional polymorphism risks include: Dysfunctional alleles are associated with risk for Vit D deficiency rickets, alopecia areata, kidney stones, intervertebral disc disease, and leprosy. (MedlinePlus/VDR)

Severe dysfunctional alleles of the VDR are linked to rickets, and less severe variations to osteoarthritis, diabetes, cardiovascular disease, cancer, and tuberculosis. Vitamin D deficiency may be more of a risk with Fok1 than normal function, but the Fok1 1allele was not found more in patients with Type 1 Diabetes than in the control group. (Hamed, Abdel-Aal, Din, Atia, 2013)

Fok1 and Taq1 have been associated with Multiple sclerosis and vitamin D levels were low in the patients with Taq1 polymorphisms but not those with Fok1. (Moosavi, et al., 2021)

~~~

Data source: Blood sample, Holistic Health International, ‘DNA Nutrigenomic Test with Methylation Pathway Analysis.’ (DNA Nutrigenomic Test)

It is not looking very promising for the patient. Fortunately, she likes to read and is willing to try new things.

Stay tuned for the other phenotype sections.

Photo op - another Figure from this very excellent paper: Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID. “Figure 9. Vascular Contributions to Cognitive Impairment and Dementia (VCID), LOAD and FOCM.” (Hayden, Tyagi, 2022)

Why should we care? If we like to think rationally, we should care about our folate remethylation cycles, in our cytoplasm, our mitochondria, and our cell nuclei.

“Figure 9. Vascular Contributions to Cognitive Impairment and Dementia (VCID), LOAD and FOCM. Our current society is aging, especially in the group referred to as the baby boom generation and age-related senescence. The aging society including the baby boomers is at a much higher risk for cerebro-cardiovascular disease and stroke especially with their comorbidities of aging such as hypertension and type 2 diabetes (T2DM). This slide focuses on T2DM, LOAD and age-related senescence that is ongoing as our population ages. This image does not portray inflammation; however, it is strongly related to an excess of RONS generated by aging, T2DM, LOAD. This figure points out the nuclear chromatin condensation of the amoeboid, aberrant and activated microglia cells (aMGC) and senescence, which highlights inflammation and its co-occurrence with oxidative stress via reactive oxygen nitrogen species (RONS). Of great concern is that non-replicative senescence can be induced by a variety of factors, including DNA damage (such as chromatin condensation), inflammation, mitochondrial dysfunction, oxidative stress (RONS) and importantly epigenetic disruption as related to impaired folate one-carbon metabolism (FOCM). The importance of impaired FOCM and each of the above listed factors may contribute to the inflammatory contribution of microglia senescence and nuclear chromatin condensation as depicted from our previous discussions in Section 2, Figure 3 and hence the reason for placing images C and F within this framework as well as illustrating the folate and methionine cycles. Since we have found numerous neurovascular unit remodeling changes in the diabetic db/db models, we suggest that VCID might also be considered microvascular VCID or MVCID. Impairment of the cytosolic, mitochondria and nuclear FOCM appear to be playing a role due to excessive reactive oxygen nitrogen species (RONS). Moreover, since there is obvious ongoing senescence in T2DM and LOAD it seems appropriate to ask the following question. Could improvement of impaired FOCM be a possible therapy for senescence and possibly contribute to a synalytic therapy effect? It seems appropriate to discuss this since the field of synalytic therapies is in an emerging stage of study. AGE/RAGE = advanced glycation end products and their receptor RAGE; aMGC = aberrant-activated microglia cell; aMt = aberrant mitochondria; Chr Cond = chromatin condensation.” (CC-BY the authors Hayden, Tyagi, 2022)

Personally, the author likes to read and that requires cognitive skills.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Incomplete Reference List

(Hayden, Tyagi, 2022) Hayden, M.R., Tyagi, S.C., (2022). Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID. Medicina. 58(1):16. https://doi.org/10.3390/medicina58010016 Available at https://www.mdpi.com/1648-9144/58/1/16 (Accessed: 4 Dec 2022) Figure 1: Folate-Mediated One-Carbon Metabolism (FOCM), Figure 2. Compartmentalization of FOCM. Figure 9. Vascular Contributions to Cognitive Impairment and Dementia (VCID), LOAD and FOCM, https://www.mdpi.com/medicina/medicina-58-00016/article_deploy/html/images/medicina-58-00016-g009.png