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Vitamin Absorption and Metabolism
Folate Cycle and Related Pathways
Methylation Cycle
Transulfuration Pathway
Glutathione Synthesis
Tetrahydrobiopterin
Neurotransmitter Pathways
Histamine Metabolism
Nitric Oxide Production
Coenzyme A Synthesis
Oxalate Production and Metabolism

 

Gene Name (Function)

Significant SNPs (Major Allele>Minor Allele)

VITAMIN ABSORPTION AND METABOLISM
       Vitamin B6 Serum Levels (normal serum levels about 5 - 24 ng/ml, ref)
1 NBPF3 and 5-prime end of ALPL gene (alkaline phosphatase, liver/bone/kidney: clears Vit B6 from bloodstream. Higher activity variants lead to lower levels of Vit B6, while loss of function mutations lead to accumulations of phospho compounds including Vit B6)

rs4654748(C>T)--[C/C - 2.90 ng/mL lower Vit B6 blood levels], [C/T - 1.45 ng/mL lower B6 blood level - "C" confers increased alkaline phosphatase activity and more efficient clearing of B6**] (ref) meta-analysis ref (freq of ancestral "C"= 59%; minor allele is "T", freq = 41% ref )
rs1256335 (A>G)-[A/A had higher B6 than carriers of "G" allele,
ref] (freq "G" = 16% ref) **But would only appear to be of significance at low B6 levels already. See normal serum B6 levels above.

 
       Vitamin B12 Serum Levels - (normal levels about 200 – 800 pg/ml, ref) Dietary B12 is transported in the digestive system via the use of three protein transporters that bind the micronutrient in a sequential fashion, following the order haptocorrin (HC), intrinsic factor (IF), and transcobalamin (TC) ref. B12 plays important roles in two essential reactions, one mitochondrial, the other cytoplasmic. In the mitochondria, vitamin B12 (5-deoxyadenosylcobalamin) is required for methylmalonyl CoA mutase to catalyze conversion of methylmalonyl CoA to succinyl CoA, which is critical for odd-chain fatty acid oxidation and ketogenic amino acid catabolism. In the cytoplasm, vitamin B12 (methylcobalamin) is used in the conversion of homocysteine to methionine of critical importance in generation of SAMe, a near universal methyl source for hundreds of methylation reactions.
2 2a – FUT2 (interferes with B12 absorption, while reduced activity increases B12 absorption) rs602662(G/A)--[The "A" allele is associated with 44.2 pg/ml higher B12 blood concentrations ref, freq "A"= 34%] ref
rs601338 (G>A)--[A/A -"non-secretor" phenotype, also gives higher levels of B12, and genetic immunity to Norwalk norovirus, a common cause of infectious viral gastroenteritis ref]
rs492602(A>G )--[G/G associated with higher B12 levels ref]
 
2b –TCN1 (binding protein that protects B12 from stomach acid) rs526934 (A>G)--["A" allele associated with 27.62 pg higher B12 blood concentrations ref](freq of "A" = 79%, ref)  

2c –TCN2 (Acts as primary transport protein for Vitamin B12-- holotranscobalamin "holo-TC" the only fraction of dietary vitamin B12 that is bioavailable for systemic distribution is in the form of holo-TC. Holo-TC represents 6–20% of the total vitamin B12 present in serum and has been used as a marker of B12 sufficiency ref)

"serum vitamin B12 does not reflect cellular, genetic, and pharmacological disturbances that lead to functional vitamin B12 deficiency" ref Holo-TC, MMA, and total homocysteine (tHcy) are probably better.

rs1801198 (C>G) G/G [known as 776C>G, "Transcobalamin 776C>G polymorphism is associated with peripheral neuropathy in elderly with high folate intake" ref. "Conclusion: The TCN2 776C→G polymorphism is associated with increased odds of peripheral neuropathy in the elderly, even with normal vitamin B-12 status, especially if their folate intake is >2 times the Recommended Dietary Allowance.[>800mcg/day]" "increasing folate status due to folic acid fortification and/or folic acid supplementation has been demonstrated to accelerate and worsen both the metabolic and the clinical consequences of B12 deficiency" ref.
rs # ? 67A>G "Transcobalamin Polymorphism 67A->G, but Not 776C->G, Affects Serum Holotranscobalamin in a Cohort of Healthy Middle-Aged Men and Women"ref "Plasma MMA, tHcy, and Cbl were not affected by either polymorphism. In summary, serum holoTC, but not plasma Cbl, MMA, or tHcy, varied according to TCN2 67A- > G genotypes. It remains to be determined whether this polymorphic effect on serum holoTC alters its diagnostic utility as Cbl status indicator."
rs2267163 (C or T) [aka 31T>C, T/T 2.29 x's greater association with frailty in old age. Greater MMA levels ref
 
2d –CUBN (binds to intrinsic factor-cobalamin)

rs11254363 (A>G) ["A" allele associated with –21.49 pg lower B12.] (Freq of "A" = 79%. ref)
rs1801222 (G,A)

 
       Vitamin D Serum Levels - Collectively, known significant snps only explain about 5% of the variance in circulating 25(OH)D levels; on the other hand, estimated heritability of 25(OH)D levels, from twin and family studies, is 43% to 80%. ref
3 GC (Vit D binding protein) transporter of circulating vitamin D3 metabolites. So far no significant association of Bone Mineral Density with lower activity genotypes ref
(In recent study variants were not found to associate with 25-hydroxyvitamin D concentration in blood.)
rs2282679 (T>G)--[G/T - somewhat lower circulating 25(OH)D levels], [G/G - lower levels]; in summer (freq "G" = 22%;
rs1155563 ( T>C) [C/T and C/C - somewhat lower circulating 25(OH)D levels in summer], (freq "C" = 24% ref)
rs4588 (G>T) [aka THR420LYS; T/T and G/T - had somewhat lower circulating 25(OH)D levels in summer. ref ref (freq "T" = 22%; non-pathogenic ref)
rs7041 (A>C) [aka D432E;ASP416GLU] ref (freq "C"=39%; non-pathogenic ref)
But none of these tag snps were associated with serum conc. of the active form - 1,25(OH)D conc. ref
 
VDR (Vit D nuclear receptor mediates active Vit D - 1,25(OH)2-D) action on cells.
(In recent study variants were not found to associate with 25-hydroxyvitamin D concentration in blood.)
VDR rs1544410 (T>C) [aka BsmI; C/C - lower D levels;]
rs731236(A>G)--[aka TaqI; G allele lowers cancer risk];
rs11574143(C>A) ref
rs10735810 Not given by 23andMe ref
 
CYP27A1 (mitochondrial enzyme that converts Vit D3 to 25(OH)D - the major circulating form of Vit D. (In recent study variants were not found to associate with 25-hydroxyvitamin D concentration in blood.) CYP27A1 [rs2282679 (T>G) 8-10 % lower vit D for T/G, G/G] ref;
and rs12512631 (T>C)
 
CYP27B1 (mitochondrial enzyme in kidney and other tissues that converts 25(OH)D or Calcidiol to the active vit D form-1,25 (OH)2-D or Calcitriol) (In recent study variants were not found to associate with 25-hydroxyvitamin D concentration in blood.) CYP27B1 [rs10500804 (T>G) and
rs12794714 (G>A) associated with lower response to supplementation but not to baseline Vit D levels??]
rs10877012 (T>G) ref
 
CYP2R1, (microsomal, cytoplasmic hydroxylase that converts 25(OH)D to the active Vit D form- 1,25(OH)2-D) (In recent study variants were found to associate with 25-hydroxyvitamin D concentration in blood.) rs12794714 (G>A) lower 25-hydroxyvitamin D (Genetically low vitamin D concentrations and increased mortality..., 2014)
rs10500804 (T>G ) significantly lower Vit D levels ref
rs1993116 (G>A) lower Vit D serum levels. ref
rs2060793 (G>A) ref
rs2282679 (T>G
rs10741657 (not given by 23andMe) ref
 
CYP24A1 (mitochondrial initiates degradation of 1.25-(OH)2-D CYP24A1 rs6013897 (not given by 23andMe) ref  
DHCR7 (7-dehydrocholesterol reductase involved in cholesterol synthesis therefore removing Vit D precursors from circulation), and nearby gene, NADSYN1 (nicotinamide adenine dinucleotide (NAD) synthetase) (In recent study variants were found to associate with 25-hydroxyvitamin D concentration in blood.) NADSYN1 rs7944926 (A>G) ["A" alleles = somewhat lower 25(OH)D3 serum levels ref and serves as a near proxy for DHCR7 rs12785878 (T>G), which is not given by 23andMe] (Freq "A" = 53%) (Genetically low vitamin D concentrations and increased mortality..., 2014)
NADSYN1 rs3829251 (G>A) ref (A/A on average lower 25(OH)D levels ref (freq "A" = 24% ref)
DHCR7 rs1790349 (T>C) ref; (freq of "C" = 22% ref)
 
       Other Vitamins
4 BCMO1 (encodes Beta-carotene 15,15'-monoxygenase, a highly regulated enzyme that catalyzes the first step in conversion of dietary provitamin carotenoids to retinal-active vitamin A) ref -carotene absorption and conversion into retinal is quite variable among individuals. The proportion of low responders to dietary -carotene is as high as 45%. ref (Beta Carotene content can be extremely high in some vegetables, so BCMO1's tight regulation is crucial in preventing vit A toxicity. Even amounts of preformed Vit A as small as twice the current RDA are associated with osteoporosis and hip fracture. Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are nonsensitive indicators in this range of liver vitamin A reserves. ref) rs7501331 (C>T)-[A379V, "T" alleles have 32% lower ability to convert beta-carotene to retinyl esters.]
rs12934922 (A>T)-[R267S, normal conversion except that those carrying a "T" in both this and previous SNP have 69% lower conversion of beta-carotene.] ref
rs6420424 (G>A)-[A/A, 59% decrease in conversion efficiency]
rs11645428 (G>A)-[G/G, 51% decrease in conversion efficiency] (freq of "G" = 81.6% ref)
rs6564851 (T>G)-[G/G, 48% reduction in conversion efficiency.] ref Another study found strong association with higher serum beta-carotene ref
 
5 BTD (Biotinidase regenerates free biotin from biocytin – a normal, covalently bound product of biotin to protein that is generated by the enzymes using biotin as a cofactor. Biotinidase is needed to free up biotin so it can be reused in our body and extracted from our food.) rs13078881(G>C) [aka D444H; Loss of 48% of activity for a "C" allele. The most common deleterious BTD variant but only present in 3.9% of general population. ref 
 
 
DIETARY FOLATE PROCESSING
6

FOLR2 folate hydrolase, intestinal transport of folate

FOLR3

   
SLC19A1 - encodes the reduced folate carrier system (RCF) that transports reduced folates such as methyl-folate and folinic acid across the cell membrane into the cytoplasm.    
FOLH1 (synonymous with GCPII ?- encodes folate hydrolase 1 or folylpoly-gamma-glutamate carboxypeptidase, which digests dietary polyglutamylated folates to monoglutamyl folates at the intestinal brush border. acts on different alternative substrates, neuropeptide N-acetyl-l-aspartyl -l-glutamate and is expressed in a number of tissues such as prostate, central and peripheral nervous system and kidney. Expression in the brain may be involved in glutaminate exitotoxicity. (Entrez Gene) rs377746327 (GCPII H475Y) (not in 23andMe) ref
rs588458
rs202700
rs202676
 
GGH (Gamma-glutamyl hydrolase-catalyzes the hydrolysis of folylpoly-gamma-glutamates and antifolylpoly-gamma-glutamates by the removal of gamma-linked polyglutamates and glutamate ref) So far no significant snps that I've found in literature check out ref  
FPGS (    
  PRICKLE2 rs153734 (T/C) Only one report (freq of "C" = 32.9% ref)  
  DHFR - see next entry    
FOLATE CYCLE AND RELATED PATHWAYS
  DHFR (1. Dihydrofolate reductase catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), 2. at a lower rate reduces folic acid (FA) to DHF, 3. regenerates Tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS) (NOS3), from its oxidized form, dihydrobiopterin (BH2).) OMIM ref rs1643649 (T>C) increased susceptibility to spina bifida ref
rs70991108 (not given by 23andMe but indicates presence of deletion variant) There's a common 19-base pair deletion (del/del around 20% of study participants in ref. below.) In those supplementing with more than 500 ug/day, the prevalence of high levels of unmetabolized circulating folic acid was 47% of del/del homozygotes versus high circulating folic acid in around 20 to 24% of del/WT and WT/WT homozygous. At folic acid intakes under 250 ug/d, del/del had 13% lower RBC folate versus del/WT and WT/WT. Between 250 and 500 ug/day no difference in red cell folate for del/del and WT/WT. ref (recommendation: supplement with methylfolate or folinic acid in case the common deletion allele is present)
rs121913223 (A>T) Homozygote: Megaloblastic anemia due to DHFR deficiency. (not given by 23 and Me). ref
 
 

MTHFD1(methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase)

 

rs2236225 (G>A) A/A–Thermolabile variant, 25% reduced activity in cultured cells ref; Abruption of placenta 3x's more likely ref; and 1.5 x's increase risk of neural tube defects. ref And rs1076991 (C>T) reduces promoter activity and influences embryonic activity combined with above snp ref

 
 

MTHFD1L, mitochondrial

MTHFD2

MTHFD2L

   
  SHMT2 - mitochondrial rs34095989 (  
  GLDC - mitochondrial    
  GCSH - mitochondrial    
  AMT - mitochondrial    
  DLD - mitochondrial    
       
  ALDH1L1    
  SHMT1    
  TYMS (Thymidylate synthase uses the 5,10-methylenetetrahydrofolate (methylene-THF) as a cofactor to maintain the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair) TYMS also competes with MTHFR for the folate required for remethylation of homocysteine to methionine. There's a 3'UTR deletion polymorphism that decreases thymidylate synthesis, significantly increases RBC folate and decreases homocysteine in the del/del homozygote vs. the insertion homozygote (ins/ins) or the heterozygote (del/ins) ref Triple-repeat and double-repeat alleles are common in the 5-prime untranslated enhancer region, of which the triple-repeat allele results in greater translational efficiency. ref Neither of these significant polymorphisms can be determined by 23andMe data.

rs1001761 (A>G) [Spina Bifida odds ratio =2.4];
rs502396 (C or T)[S.B odds ratio=2.1]
rs2847149 (A>G)[S.B odds ratio=2.2] ref
rs2853533 (G>C)[Colorectal Cancer risk odds ratio=1.38] ref

 

 
  MTHFR (Methylenetetrahydrofolate reductase – Rate limiting step of folate cycle. Produces 5-methylfolate from methylene-THF. The enzyme requires an FAD cofactor (vit B2) and is inhibited in 3 ways: 1) by dihydrofolate (DHF) and less so by its polyglutamate analogues ref [Conceivably, too much Folic Acid supplementation may lead to higher levels of DHF thus inhibiting activity of MTHFR, but would only happen with wild type DHFR - 50% of population have low activity DHFR, folinic acid and methy-THF wouldn't have this negative effect on MTHFR activity]; 2) by S-adenosylmethionine (SAMe) – [in the presence of higher levels of SAMe there is less need for MTHFR to make more 5-Methyl-THF, which combines with homocysteine to go to Methionine and SAMe ref]; and 3) by phosphorylation – which decreases MTHFR activity and makes it more sensitive to inhibition by SAMe. ref)

rs1801133 (C>T) (aka C677T, c.665C→T, and A222V)- [A/A - 30% of enzyme activity in vitro (in the test tube) compared with G/G, but only 18% lower red cell folate in the body; the hetero A/G enzyme has 65% of activity, and 10% lower red cell folate levels (30% as formylfolates, while wild type has 100% methyfolates). Homocysteine levels are higher for A/A when dietary folate is low or riboflavin is low ref. A/A variant with lower folate dietary intake and lower plasma folate concentrations had lower methylation levels (including lower genomic methylation levels ref) than all other groups ref ; higher folate levels ref, and the FAD cofactor (Vit B2) helps stabilize this thermolabile enzyme variant.] In most studies, MTHFR C677TT aka A/A is associated with moderately reduced colorectal cancer risk. 677TT subjects who had higher folate levels (or a “high-methyl diet”) had the lowest cancer risk. Low dietary folate or alcohol consumption have significantly higher cancer risk. ref.]
How much folate to supplement to lower serum homocysteine? After folic acid supplement to 400 micrograms, TT homozygotes were still slightly higher than CC subjects but not by much, 9.5 vs 8.1 µmol/L. On the low folate exclusion diet TT homozygotes were 14.5 vs. CC homozygotes at 8.9 µmol/L. ref

rs1801131 (T>G) (aka A1298C, E429A and c.1286AC)- [G/G - enzyme activity in vitro is 60% of normal activity, T/G - 80% of normal activity ref, but people with G/G or T/G did not have higher serum homocysteine ref, ref. No association with stomach cancer resulted for MTHFR 1298 G/G, but 1.52x's increased risk for A677C-A/A ref

In compound heterozygotes (C677T on one chromosome, A1298C on the other) there appears to be an interaction between the 2 polymorphism that reduces by 50-60% in vitro enzyme activity, and raises plasma HCY and decreases plasma folate to yield similar features to homozygotes for C677T. Odds ratio of 2.04 times increased risk for Neural Tube Defects. ref. Compound homozygotes are very rarely seen. ref

rs2274976 (C>T) (aka R594Q) this snp and most other lower frequency snps that are clustered at the N-terminal, catalytic half of MTHFR are remediated by higher folate levels. ref

 
  MTR - see entry below in Methylation Cycle    
  MTRR - see entry below in Methylation Cycle

 

 
METHYLATION CYCLE
  MTR (Methionine Synthase – B12 dependent – synthesis of methionine by transferring a methyl group to homocysteine. ref rs1805087 (A>G), [aka A2756G, G/G – Associated with aberrant methylation, ref, The 2756G allele was associated with risk of Down syndrome ref; may or may not be associated with spina bifida.ref  
  MTRR (Methionine synthase reductase – regenerates reduced cobalamine (B12) in inactive Methionine Synthase (MTR) via reductive methylation by SAMe. ref rs1801394 (A>G), [aka c.2756AG and A66G, G/G –no risk, or at most 1.9 times risk compared to A/A for colorectal cancer ref. 2.6 times increased risk of spina bifida in one study and only when B12 levels were low in another, but no effect on heart defects. Other snps, rs10380(C>T) T may have elevated spina bifida risks ref. With antidepressant use, G/G 3.2 times less likely to be in remission from depression than T/T ref.  
  BHMT (betaine homocysteine methyltransferase)    
  BHMT (2 betaine homocysteine methyltransferase-2)    
       
  MAT1A (methionine adenosyltransferase I, alpha – Encodes a a liver-specific enzyme that catalyzes the formation of adenosylmethionine (SAMe) from methionine and ATP. ref There are rare mutations that abolish or greatly reduce MAT1A activity and cause hyper-methioninemia (often with neurological problems) but without elevated homocysteine ref rs3851059 (G>A) -[aka D18777A; homozygous A/A had 4.3 times greater risk of stroke vs. A/G and G/G] ref
rs9471976 (G>T) [decreased transcriptional activity (by how much? –not given in abstract)]
rs11752813 (C>G) [also decreased transcriptional activity, not given by 23andMe] ref
 
  MAT2A (methionine adenosyltransferase I, alpha –encodes enzyme that catalyzes formation of SAMe in organs and tissues outside the liver. C32>T, A11V – Of the 2 polymorphs that changed amino acid sequence only this one significantly reduced activity by reducing translation. (no rs number)
A613>G, I205V - no change in enzyme activity ref
 
  MAT2B (encodes a MAT2A regulatory protein that stabilizes and impedes degradation ref C781>T, P261S ; C872>T, T291I, only 2 polymorphisms discovered that change amino acid sequence, and neither appeared to affect enzyme activity ref
 
  DNMT    
  GNMT (glycine N-methyltransferase – the major hepatic SAMe using enzyme in the liver.    
 

AHCY

   
       
  CHDH (Choline dehydrogenase-irreversible oxidation of choline to form betaine. Forming betaine removes choline from other essential functions in signally and structural integrity of cell membranes rs9001 (T>G) ["G" allele had protective effect on susceptibility to choline deficiency]; ref  
  PEMT (phosphatidylethanolamine N-methyltransferase, forms phosphatidylcholine on way to choline, part of endogenous biosynthesis of choline. rs7946 (C>T) [30% decrease in PRMT activity and increased risk of nonalcoholic fatty liver disease ref],  
 
TRANSULFURATION PATHWAY
  CBS (Cystathionine beta synthase, catalyzes homocysteine to cystathionine, and is the first, rate-limiting and irreversible step in the transulfuration pathway leading to cysteine.
    CBS activity is enhanced by SAMe ref. SAMe allosterically activates CBS by increasing the turnover rate. Low concentrations of SAMe result in low CBS activity therefore funneling homocysteine into the methylation cycle toward SAMe formation. HIgh SAMe concentrations funnel homocysteine into the transsulfuration pathway toward cysteine.
    CBS contains a heme cofactor that modulates CBS activity depending on form of iron within the heme. The redox state of the heme iron, either Fe2+ or Fe3+, is dependent on pH. Under low pH, Fe2+ is oxidized to Fe3+, which doubles enzyme activity. Binding of carbon monoxide (CO) or nitric oxide (NO2) to Fe2+ inhibites CBS activity. ref

Interesting Article: Cystathionine beta synthase modulates senescence of human endothelial cells
rs5742905 (A>G)[homocystinuria, B6-responsive, rare]
rs121964962 (C>T) homocystinuria, B6-nonresponsive, rare,     not given by 23andMe];
rs4920037 (G>A)[A/A may be 25% more at risk in arsenic     exposure ref]
rs5742905 (A>G)[aka c.833T>C and p.1278T, G/G Most common cause of mild homocystinuria that is responsive to pyridoxine-B6 supplementation ref. Increased suscep. to spina bifida ref]

rs234706 (G>A), aka CBS c.699C>T, CBS 1985T; up-regulation variants that non-significantly (3% ref) lower homocysteine (Hcy) not rated as pathogenic ref; also a 68 bp insertion (CBS 844ins68) in 7.5% of Europeans abolishes effect of MTHFR C677T homozygote on raising Hcy, and maintains normal hcy. ref lowers homocysteine about 5% ref
 
  CTH (cystathionine gamma-lyase, catalyzes synthesis of cysteine from cystathionine - derived from methionine) rs1021737 (G>T) [T/T total plasma homocysteine elevated ref] rs28941785 (C>T) [T/T cystathioninuria, rare, not given by 23andMe]  
 
GLUTATHIONE SYNTHESIS
  GCLC (Gamma-glutamylcysteine synthetase, rate-limiting and the first enzyme in glutathione biosynthesis) rs121907946 (T>A) [A/A is pathogenic, hemolytic anemia, autosomal recessive inheritance ref] - not given by 23andMe  
  GSS (Glutathione Synthetase, produces reduced glutathione from glycine and gamma-glutamylcysteine) rs28936396 (G>A) [A/A is pathogenic, Glutathione synthetase deficiency ref]
rs28938472 (T>C) [C/C - hemolytic anemia ref]
 
  Glutathione S-transferases (GSTs) - A huge complex family of enzymes that catalyze conjugation of reduced glutathione via a sulfhydryl group to a variety of substrates. Functions to solubilize, detoxify foreign compounds (carcinogens, pollutants, drugs); degrade peroxide; reduce vit. C etc; There are 3 superfamilies: cytosolic, microsomal membrane and mitochondrial ref. The soluble GSTs are divided into 13 main classes including alpha, mu, pi, and theta
  GSTP1 (Glutathione S-transferase Pi-1, most common GST expressed outside the liver) rs1695 (A>G) A/A, A/G increase in IL-6 (inflammatory interleukin) when supplementing with Vitamin E, while GG saw decrease ref; contradictory studies on asthma ref; A allele associated with asthma ref  
       
       
       
  GSR (Glutathione Reductase) Mutations cause low glutathione and hemolytic anemia, autosomal recessive inheritance.  
 
TETRAHYDROBIOPTERIN (BH4) Tetrahydrobiopterin is an essential cofactor for several enzymes including nitric oxide synthases, and three aromatic amino acid monooxygenases: Phenylalanine Hydroxylase, the rate limiting enzyme in degrading Phe to tyrosine (encoded by PAH, the classical PKU gene); Tryptophan Hydroxylase, the rate limiting enzyme producing 5-HT on way to Serotonin (encoded by TPH1 gene); and Tyrosine Hydroxylases, the rate-limiting enzyme that produces L-Dopa on way to Dopamine (encoded by TH gene) ref    Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitter precursors (L-dopa/CarbiDOPA and 5-hydroxytryptophan- 5-HTP), and supplements of folinic acid in DHPR deficiency? (ref). Sulfa drugs inhibit BH4 production by binding and inhibition of sepiapterin reductase. This may account for some nervous system side effects of sulfa drug therapy, particularly high dose. ref
 

GCH1  [Rate limiting step for de novo Tetrahydrobiopterine synthesis (BH4); BH4 regulates endothelial nitric oxide synthase (eNOS); GCH1 activity is regulated by GCHFR – GTP-cyclohydrolase I feedback gene that normally inhibits, but presence of phenylalanine stimulates.]

Haplotype: rs10483639(C)-rs3783641(A)-rs8007267(T) associated with lower levels of tetrahydrobiopterin. Homozygous has about 80% reduced BH4 levels ref. and Heterozygous, about 60% reduced (my interpretation - see graph.) However, these reductions in BH4 are not enough to yield pathogenic phenotypes - dystonia caused by decreased levels of dopamine, which requires BH4 for synthesis; and BH4-deficient hyperphenylalaninemia (a type of PKU, but not the more common classical form with defective PAH, phenylalanine hydroxylase) ref  
  PTS    
  SPR    
  DHPR (Sometimes DHFR can substitute)    
NEUROTRANSMITTER PATHWAYS
  TH (Tyrosine hydroxylase catalyzes the first rate-limiting step in biosynthesis of the catecholamines (dopamine, noradrenaline and adrenaline). It converts L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), using oxygen (O2), iron (Fe2+) and co-factor, BH4.
Short-term regulation of TH:
1-end product inhibition by catecholamines, and
2- phosphorylation of Ser residues (Ser(19), Ser(31), and especially Ser(40) of hTH1) in the N-terminus relieves the catecholamine-mediated inhibition. ref
Long-term regulation:
1- TH protein synthesis.
2- Nicotine, histamine, angiotensin II and pituitary adenylate cyclase activating polypeptide (PACAP) ref, induce long term activation of TH by sustained phosphorylation of TH at Ser40. ref
Four isoforms of human TH (hTH1-hTH4) are produced from a single gene by alternative mRNA splicing in the N-terminal region. ref

tetranucleotide repeats of (TCAT) occur in 5 to 11 head-to-tail copies, the two most common versions, (TCAT)6 and (TCAT)10i, predicted heritable autonomic traits in twin pairs. ref
and seemed to be cardioprotective, while (TCAT)7 was associated with higher resting systolic blood pressure. (TCA)10 was over-represented in hypertensive subjects, and (TCAT)9 was increased in normal blood pressure subjects, and was associated with higher norepinephrine levels. See background info in this ref.

Common allelic variations (esp C-824T and A-581G) within the promotor region of the TH locus exert a heritable effect on autonomic control of the circulation; changes in catecholamine secretion and blood pressure response to environmental stress. ref

rs10770141 C>T [aka C-824T; A/A greater activity than G/G, A/G was intermediate] ref; "T" alleles augmented nicotine and PACAP increase in TH enzyme activity, associated with increased catecholamine production, increased blood pressure in response to stress and extreme blood pressure values in the population ref, ref , ref]

rs10770140 A>G [aka A-581G; Greater activity of G allele in basal state and during nicotine stimulation than the A allele ref, ref, ref] not given by 23andMe.

 
  DDC    
  DBH    
  PNMT (phenylethanolamine N-methyltransferase, rate-limiting enzyme for epinephrine synthesis. It methylates norepinephrine/noradrenaline to epinephrine/adrenaline using SAMe cofactor. PNMT activity increases in response to both glucocorticoid exposure and neuronal stimulation.ref By suppressing glucocorticoid secretion, pituitary failure compromises epinephrine synthesis and decreases the rate at which epinephrine is secreted; in contrast, prolonged chronic stress can enhance epinephrine synthesis and secretion within the adrenal, the brain, or both organs.ref rs876493 (G>A) [aka G–161A in promotor region, G allele associated with Acute Kidney Injury, O.R(odds ration)=2.19, Urine adrenaline associated with increased shock and mortality, but lowest in A/A carriers] ref
rs5638 (A>G) [aka A+1543G. For AKI, each A allele associated with lower mortality - O.R=.63, G allele associated with oliguria- OR=3.35] ref
 
  MAO A and B (MonoAmine Oxidase types A and B – both genes closely linked in opposite orientation on the X chromosome and expressed in the outer mitochondrial membrane. They oxidatively deaminate neurotransmitters and dietary amines releasing hydrogen peroxide and ammonia. MAOA prefers norepinephrine, serotonin, and dopamine as substrates. MAOB prefers phenylethylamine. Low levels of MAO activity and mutations in the MAOA gene have been associated with violent, criminal, or impulsive behavior (Chen et al., 2004). A repeat polymorphism in the promoter of the MAOA gene influences MAO A enzyme activity. Longer alleles with more repeats – 3.5R, 4R and 5R – resulted in more MAO activity than the shorter 3R allele. Longer alleles were significantly more common in a sample of German and Italian women with panic disorder. ref (Makes sense since monoamine oxidase A inhibitors are effective, though hazardous, treatments for panic disorders.)

MAO A, rs6323 (T>G) [R297R; "G" allele and G/G have the highest activity and are associated with anger-related traits in suicidal men and women. rs909525; rs2064070 associated with anger-related traits in suicidal men, ref rs1137070
 
  MAO B    
 

COMT (Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters: dopamine, epinephrine, and norepinephrine )

[Note: Selection for low activity COMT haplotypes (associated with high pain, anxiety, and stress response) may be driven by a gain of cognitive function related to higher dopamine and norepinephrine levels. ...higher levels of catecholamines [are] associated with increased cognitive function advantageous for memory and attention tasks. Thus, both high and low activity haplotypes, each with opposing advantages and disadvantages, may be maintained in the population due to balancing selection, ref.]

Connection with high homocysteine: Elevated Homocysteine (Hcy) leads to increased S-Adenosyl-Homocysteine (SAH aka AdoHcy) which binds with high affinity to catalytic region of most SAMe-dependent methyltransferases and strongly inhibits them. COMT is one of those. Lower COMT activity increases endogenous catecholoamines (noradrenaline and adrenaline) which stress the body esp. the cardiovascular system ref ref

Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia. ref

rs4680 (G>A) - [Val158Met - G/G high, G/A intermediate, A/A low activity; thermolabile A = 3 fold reduction in activity ref. but "A" alleles delay onset of Parkinson's Disease ref and associated with better reading ability ref G and A alleles approx. equal frequencies in pop. ref interaction of V158M with other snps determines functional outcomes ref

rs6269 (A>G) [G/G = Low COMT Activity, High Pain Sensitivity; G/A= Average Pain Sensitivity]
rs4633 (C>T) [C/C = Lower COMT; C/T = intermediate]

Using 3 snps: rs4633 (C>T) *rs4818 (C>G) rs4680 (G>A) to construct the following Haplotypes:
[C,G,G = High COMT activity = LPS (Low Pain Sensitivity [P.S])
T,C,A = 3.5 fold reduction in COMT = APS (Average P.S.)
C,C,G = > 20 fold reduction in COMT = HPS (High P.S.)= 2.3 times greater risk for chronic musculoskeletal pain conditions] ref   (*not given by 23 and Me)

Adding one more snp to preceding, the following haplotype gives 58 fold reduced COMT activity:
rs6269(A), rs4633(C), rs4818(C) and rs4680(G*) ref. *Wild Type in haplotype was lowest, not minor G allele, thus the importance of looking at haplotypes, and not snps in isolation.

rs165688(G)-rs737865(G)-rs165599(G) very significant association with schizophrenia ref (having all A alleles is protective) and associated with lower expression of COMT mRNA ref
 
  TPH1 (Peripheral form of Tryptophan hydroxylase, which catalyzes the rate-limiting step in serotonin (5-hydroxytryptamine) biosynthesis using tetrahydrobiopterin (BH4) and dioxygen co-substrates and produces 5-HTP, which besides being the precursor for serotonin (5-HT), has it's own functions (ref) TPH activity is dependent on cytosolic concentration of co-substrate BH4. (ref) (ref)    
  TPH2 (Tryptophan hydroxylase 2 is neuron specific and expressed predominantly in serotonergic neurons of the raphe nuclei and in the peripheral myenteric neurons in the gut. Human TPH1 and TPH2 display 72% sequence homology)    
  DDC    
  MAO A and B  
 
HISTAMINE METABOLISM
  HDC (Encodes Histamine decarboxylase, the Vitamin B6 dependant enzyme that catalyzes CO2 removal from the amino acid, histadine to produce histamine.)
rs2073440 (T>G) [G,G has 3% greater incidence of allergy, both allergic rhinitis and asthma. ref
 
  AOC1 (Amine Oxidase, copper containing 1; aka ABP1 and DAO [There is another gene named DAO, D-amino-acid oxidase, which is unrelated] AOC1 is an extracellular enzyme that breaks down histamine and other amines mainly in the gut. The reaction is an oxidative deamination that uses oxygen and releases hydrogen peroxide and ammonia, both toxic byproducts.)

rs10156191 (C>T) [T/T homozygotes shows less DAO mRNA expression in blood mononuclear cells; causes impaired metabolism of circulating histamine associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response. See "The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs" by Agundez et al, 2012;
rs2052129 (G>T) [T allele shows lower promoter activity. Homozygous T/T, shows less DAO mRNA expression in blood mononuclear cells];
rs1049742 (C>T) This and previous 2 snps lower DAO activity but not enough to fully cause HIT (histamine intolerance) ref

 
  HNMT (histamine N-methyl-transferase) Intracellular histamine inactivation by methylation of the imidazole ring. Inhibitors are reaction products: N-methylhistamine, S-adenosyl-l-homocysteine rs1801105*, minor allele codes for an enzyme with reduced thermal stability and decreased HNMT activity. *Not given by 23andMe. No other snps with frequencies over 0.01 described for this gene as of 2009 ref  
  ADH    
  MAO-B    
NITRIC OXIDE PRODUCTION
  NOS2 (nitric oxide synthase-inducible) rs2297518 (G>A) A associated with recurrent apthous stomatitis ref but not Behcet's disease ref  
UREA CYCLE
  ARG1    
  ASL    
  ASS    
  OTC - mitochondrial    
 

CPS1 - mitochondrial

   
       
COENZYME A SYNTHESIS
  PANK 1 (Pantothenate Kinase 1 - Step one in five steps to biosynthesis of Coenzyme A. ; ATP + (R)-pantothenate = ADP + (R)-4'-phosphopantothenate. Step one of five. Regulated by feedback inhibition by CoA and its thioesters. Strongly inhibited by acetyl-Co. Four isoforms.)    
OXALATE PRODUCTION AND METABOLISM
  AGXT 1 (Encodes alanine-glyoxylate aminotransferase, a liver peroxisomal enzyme which catalyzes conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium salts in kidney and other organs - the cause of Primary Hyperoxaluria Type 1 ref)    
  AGXT 2 ()    
  GRHPR (Encodes glyoxylate reductase/hydroxypyruvate reductase. Expressed primarily in liver with smaller amounts in kidneys. Helps prevent the buildup of potentially harmful glyoxylate by converting it to glycolate. Can also convert hydroxypyruvate to D-glycerate. Mutations of GRHPR produce excess of glyoxylate, which is metabolized by alternative pathway to oxalate - the cause of Primary Hyperoxaluria Type 2)    
  HOGA1 (Encodes liver and to lesser extent kidney mitochondrial 4-hydroxyl-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. Mutations are found in patients with Primary Hyperoxalurea type 3.)
   
  AGXT 1 ()    

***Notes: High Homocysteine – Because the hydrolysis of S-Adenosyl-Homocysteine (SAH) is reversible, elevated levels of Homocysteine (Hcy) lead to elevated levels of SAH. SAH is a strong feed-back inhibitor of many of the over fifty SAMe-dependent methyltransferases. ref

OMIM: Online Mendelian Inheritance in Man (Institute of Genetic Medicine, John's Hopkins, National Human Genome Research Institute)

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