SNPs Potentially related to CIS

I have found experimentally that I seem to be sensitive to cholinesterase inhibitors (CIS) at levels typically encountered in the food supply unless actively avoided.  I found that 23andMe could test for some of the single nucleotide polymorphisms (SNPs) in genes relevant to CIS.  This is an attempt to try to see if the 23andMe results can shed any light on which potential causes of CIS in my case may or may not be useful to pursue.

The SNPs most likely to be relevant are now reflected on SNPedia at http://www.snpedia.com/index.php/Cholinesterase_Inhibitors and results will appear in future Promethease reports under Topics/Cholinesterase Inhibitors.  Thanks go to Mike Cariaso for making this happen.

The results for the SNPs I had found in the literature on cholinesterase inhibitors, reflected in the first table, were not as dramatic as I had hoped:
  • BCHE = heterozygous for decreased BuChE activity
    I don't have the uncommon version of any of the three BCHE SNPs that I can successfully cross reference between Dr. Soreq's work and the 23andMe results.  I am, however, heterozygous for the "BCHE K variant."  According to omim, this variant decreases BuChE activity by 33%.  Based on this, the versions of BCHE I have are somewhat less effective than most people's as a defense against cholinesterase inhibitors (CIs).  This doesn't seem enough by itself to explain CIS, but it could contribute. 
  • PON1 = heterozygous for decreased catalytic efficiency
    That implies that one copy of my PON1 gene yields PON enzymes which are not as useful as they could be for breaking down certain CI pesticides.  This also doesn't seem enough by itself to explain CIS, but it could contribute.  It's not clear whether or not it helps explain sensitivity to nightshades.  I can't find any evidence that PON is involved in breaking down solanaceous glycoalkaloids (SGA).  On the other hand, I can't find any evidence that anyone has studied the mechanism for breaking down SGA, so PON is as likely as anything else at this point.  Hopefully one day I'll find the answer to this one.
The other polymorphisms Dr. Soreq's group has found to affect CI response are either SNPs which 23andme does not test for, or I can't figure out the mapping, or they are not SNPs (some are deletions or insertions).  Unfortunately I have not yet found another way short of full genome sequencing to check for them.

On the plus side, the 23andme/Promethease results did also turn up some other directions to pursue which I would not have thought of.  These were atypical results for  receptors potentially relevant to neurochemicals affected by CI levels.  They would not affect the breakdown or prevalence of CIs, but they may affect the likelihood of noticing physiological consequences related to CI levels.  These are reflected in the second table.

The third table is a complete shot in the dark.  It explores the question of whether any of the other SNP results 23andme tests for in the BCHE and PON1 genes were particularly atypical, without having any idea of whether or not those changes are relevant to function.

SNPs known to affect genes relevant to CIS


 Paper      Gene Position
 SNP  My Genotype
 Risky type
 Effect of Risky type
  [15] Soreq  BCHE     D70G  Rs1799807  TT (96%)  C/G  Atypical structure of BCHE, does not detoxify CIs or other drugs like anesthetics; Enzymatic activity 30% lower than wild type (Soreq); Homozygous carriers of this polymorphism display extreme
anxiety after exposure to anti-AChEs (Soreq)
 Soreq (Google Book)
 BCHE     243  Rs28933389  GG  A/T?  Related to FLUORIDE 1 (SNPedia); BCHE resistant to inhibition by fluoride (omim BCHE*243M); moderate change in BCHE activity (Soreq)
  Soreq (Google Book)  BCHE  390  Rs28933390  CC  A/T?  Related to FLUORIDE 2 (SNPedia) (omim BCHE*390V); abolishes catalytic activity (Soreq);
 Soreq (Google Book), Wiebusch 1999
 BCHE  539  rs1803274  CT (32%)
 A/T?  "BCHE K variant," reduces BuChE activity by 33%, acts in synergy with APO epsilon-4 SNP as susceptibility risk for alzheimer's disease (omim BCHE*539T)
 [15] Soreq
 PON1  55L/M   rs854560      Reduced PON protein and mRNA levels (Soreq); paired with PON192, contributes to trait anxiety score (Soreq)
 [15] Soreq  PON1     192Q/R  Rs662  CT (39%)  R=C/G  Reduced catalytic efficiency of PON (Soreq); homozygous genotype associated with high trait-anxiety (Soreq); predictive of Alzheimer's disease (Soreq); paired with PON55, contributes to trait-anxiety score (Soreq)
 [15] Soreq PON1 -108C/T rs705379 GG (9%)
  Reduces PON expression 22.4% (Soreq); heterozygous genotype associated with lower trait-anxiety (Soreq)
 [15] Soreq   PON1  -162A/G  Rs705381  TT (?)  ?  Reduces PON expression 2.4% (Soreq)
  [15] Soreq  PON1     -126C/G  
     Does not affect PON expression (Soreq); heterozygous genotype associated with lower trait-anxiety (Soreq); paired with PON-162, contributes to trait-anxiety score (Soreq)
  [15] Soreq ACHE P446    Linkage marker for a deletion in the GRE region of the ACHE promoter which is associated with elevated blood AChE activity and acute CI hypersensitivity.  Deletion is 0.34% in US population, 3.4% in Israelis.  This marker is 12% in HERITAGE subjects.; heterozygous genotype associated with high trait-anxiety (Soreq)
  [19] Shapira ACHE
 H322N    Biochemically neutral linkage marker for a 4-bp deletion abolishing a HNF3 binding site 17kb upstream of the transcription start site for ACHE.  Heterozygous carriers of the deletion overexpress AChE and exhibit acute hypersensitivity to CIs. (Shapira)
   [19] Shapira ACHE T->A -17113
   A  T->A substitution at position -17113 relative to the ACHE transcription start site affecting the GRE (glucocorticoid response element).  Allele frequency of this mutation (A) is 0.006 in 333 individuals tested.  Carriers overexpress AChE and show increased sensitivity to CIs. (Shapira)
   CHAT  promoter  rs733722  CT    Associated with response of AD patients to cholinesterase inhibitors (SNPedia)

Atypical SNPs from 23andMe that might relate to CIS


 SNP     Gene  My Genotype  Risky type
 Effect
 ADRB1 GG (4%)
 G Affects beta 1 adrenergic receptors.  A study found increased social anxiety and decreased extroversion among carriers of G allele.  This potentially indicates that G version causes beta 1 receptors which are more sensitive to epinephrine, resulting in greater physiological response to stressful stimuli.
 rs1051730  (SNPedia)  CHRNA3  AA (18%)
 A/T  Affects nicotinic receptor alpha 3, increases risk of nicotine and alcohol dependence (23andMe); associated with nicotine dependence and lung cancer susceptibility (omim)
 rs16969968 CHRNA5    AA (13%)
 A/T Affects nicotinic receptor alpha 5, increases risk of nicotine dependence (SNPedia)

SNPs 23andMe reports for relevant enzymes, but unknown impact 

Homozygous for uncommon allele marked in red, heterozygous < 25% incidence in yellow.  


 Gene    SNP My Genome
 Uncommon type
                 PON1 rs3735590 GG (96%)
 A/T
  rs854555 AC (32%)
 A/T
  rs3917550 AG (41%)
 A/T
  rs3917548 AA (90%)
 C/G
  rs3917542 CT (29%)
 A/T
  rs2074354 GG (73%)
 A/T
  rs3917498 GT (50%)
 A/T
  rs854561 CC (35%)
 A/T
  rs2272365 AA (58%)
 C/G
  rs2299260 CT (20%)
 A/T
  rs2299261 AG (50%)
 C/G
  rs854568 AG (54%)
 C/G
  rs2299262 CC (35%)
 A/T
  rs854569 GT (27%)
 A/T
  rs2237584 CC (84%)
 A/T
  rs3917478 TT (92%)
 C/G

     BCHE    rs12186091  CC (89%)
 A/T
 
   rs10049010  TT (88%)
 C/G
        rs1803274  CT (31%)  A/T
       rs2668203  AG (35%)
 A/T
       rs2668207  CT (43%)
 C/G
       rs6798514  GG (88%)
 A/T
       rs16849623  GG (91%)  A/T
       rs829508  TT (86%)
 C/G
       rs1355538  AA (15%)
 A/T
       rs1355535  GT (17%)
 A/T
       rs9873779  GG (56%)
 A/T
       rs9823473  GG (90%)
 A/T
       rs16849671  CC (96%)
 A/T
       rs6808121  CC (83%)
 A/T
       rs1464026  CC (88%)
 A/T
       rs16849681  CT (0%)
 A/T
       rs1511982  AA (87%)
 C/G
       rs6790532  GG (77%)  A/T
       rs4518174  CC (87%)  A/T
       rs28933390  CC  
       rs28933389  GG  
       rs1799807
 TT (96%)
 C/G
    rs4680606 TT (63%) 
    rs4680664 GG (61%) A/T
    rs4680665 GG (62%) A/T



Comments