EPHX1 Y113H - GET-Evidence

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Curation:
Currentness:

EPHX1 Y113H

(EPHX1 Tyr113His)


Short summary

This gene is involved in response to oxidative stress, and the 113H variant is associated with lower enzyme activity, apparently through disruption of protein stability rather than enzymatic function of the protein itself. Several studies have attempted to link this variant to cancer, lung disease, and other associations, but it is unclear which of these are results reproducible and validated.

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr1:226019633: 25.7% (2760/10758) in EVS
  • C @ chr1:224086255: 29.7% (38/128) in GET-Evidence
  • Frequency shown in summary reports: 25.7% (2760/10758)

Publications
 

Hassett C, Aicher L, Sidhu JS, Omiecinski CJ. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet. 1994 Mar;3(3):421-8. Erratum in: Hum Mol Genet 1994 Jul;3(7):1214. PubMed PMID: 7516776.

This paper identifies polymorphisms in the EPHX1 gene and explores how they affect gene function. The authors looked at COS-1 cells transfected with recombinant plasmids and report that the 113H variant version of the enzyme produces less enzyme than 113Y.

They report that the 113His cells had much less enzyme activity (but similar RNA levels) (61% of the 113Y variant), but that when normalized to protein quantity the enzyme activities are the same (there is 56% protein — normalized to this, enzyme activity is 110%). The authors conclude that this data suggests the residue change does not affect catalytic function, but may affect protein stability (or it may affect translation efficiency).

Smith CA, Harrison DJ. Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet. 1997 Aug 30;350(9078):630-3. PubMed PMID: 9288046.

Exploring how variants in this gene, which is involved in oxidative stress, might be associated with lung diseases, the authors examined several different patient cohorts (all white): 57 patients with chronic asthma, 68 with chronic obstructive pulmonary disease (COPD) associated with cigarette smoking, 144 lung cancer samples (94 with mild to moderate emphysema, 50 with no evidence of emphysema). These were compared to 203 control samples with no known history of lung disease. They examined two mutations in these samples: Tyr113His and His139Arg.

For this variant in the controls: YY: 91, YH: 99, HH: 13. In COPD, YY: 27, YH: 28, HH: 13. In emphysema, YY: 23, YH: 45, HH: 26. According to the authors, the HH genotypes are significantly different for COPD and emphysema with p-values of < 0.01 and < 0.0001 respectively.

The numbers for the controls deviate somewhat from Hardy-Weinberg equilibrium in the opposite direction (with an allele frequency of 9.5%, 19 out of 203 would be expected to be HH), exaggerating the significance of the number of HH homozygotes in disease groups. If the number of homozygotes in the controls had instead been 19, the number of homozygotes in the COPD group would be barely significant (p = 0.05). Although the numbers for the emphysema group still seem strong, it is unclear how well this group (based on tissue section diagnosis) relates to clinical symptoms of emphysema.

Koyama H, Geddes DM. Genes, oxidative stress, and the risk of chronic obstructive pulmonary disease. Thorax. 1998 Aug;53 Suppl 2:S10-4. Review. PubMed PMID: 10193341; PubMed Central PMCID: PMC1765894.

These authors review the findings on Smith & Harrison. They note that the study starts by looking at lung cancer samples and yet ends up reporting an association with emphysema — this emphysema diagnosed based on tissue sections, rather than clinical presentation. This seems to indicate a change of direction during the course of the study as the authors failed to find an association for lung cancer but instead found these promising results when data was re-examined for emphysema.

Koyama and Geddes note that the study population Smith and Harrison used was small and that the findings could be due to chance, and that it needs to be confirmed in some follow up study populations.

Yim JJ, Park GY, Lee CT, Kim YW, Han SK, Shim YS, Yoo CG. Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T1. Thorax. 2000 Feb;55(2):121-5. PubMed PMID: 10639528; PubMed Central PMCID: PMC1745681.

Comparing the genotypes of EPHX1, GSTM1, and GSTT1 in 83 patients with COPD and 76 healthy smoking control subjects, the authors report finding no differences in the frequency of the polymorphisms (including the Y113H polymorphism) between COPD patients and healthy smokers.

Nakajima Y, Saito Y, Shiseki K, Fukushima-Uesaka H, Hasegawa R, Ozawa S, Sugai K, Katoh M, Saitoh O, Ohnuma T, Kawai M, Ohtsuki T, Suzuki C, Minami N, Kimura H, Goto Y, Kamatani N, Kaniwa N, Sawada J. Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients. Eur J Clin Pharmacol. 2005 Mar;61(1):25-34. Epub 2005 Feb 4. PubMed PMID: 15692831.

 

Pautas E, Moreau C, Gouin-Thibault I, Golmard JL, Mahé I, Legendre C, Taillandier-Hériche E, Durand-Gasselin B, Houllier AM, Verrier P, Beaune P, Loriot MA, Siguret V. Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clin Pharmacol Ther. 2010 Jan;87(1):57-64. Epub 2009 Sep 30. PubMed PMID: 19794411.

 

Azzato EM, Chen RA, Wacholder S, Chanock SJ, Klebanoff MA, Caporaso NE. Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations. Pharmacogenet Genomics. 2010 Jan;20(1):58-63. PubMed PMID: 19952982.

 

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het C @ chr1:226019633

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het C @ chr1:226019633

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
hom C @ chr1:226019633

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het C @ chr1:226019633

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het C @ chr1:226019633

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het C @ chr1:226019633

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
hom C @ chr1:226019633

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het C @ chr1:226019633

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr1:226019633

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
hom C @ chr1:226019633

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het C @ chr1:226019633

 

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
hom C @ chr1:226019633

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het C @ chr1:226019633

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het C @ chr1:226019633

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het C @ chr1:226019633

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
hom C @ chr1:226019633

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr1:226019633

 

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het C @ chr1:226019633

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het C @ chr1:226019633

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom C @ chr1:226019633

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het C @ chr1:226019633

 

GS07357 - var-GS07357-1100-36-ASM
het C @ chr1:224086256

 

GS10851 - var-GS10851-1100-36-ASM
het C @ chr1:224086256

 

GS12004 - var-GS12004-1100-36-ASM
het C @ chr1:224086256

 

GS18526 - var-GS18526-1100-36-ASM
het C @ chr1:224086256

 

GS18537 - var-GS18537-1100-36-ASM
het C @ chr1:224086256

 

GS18555 - var-GS18555-1100-36-ASM
het C @ chr1:224086256

 

GS18558 - var-GS18558-1100-36-ASM
het C @ chr1:224086256

 

GS18947 - var-GS18947-1100-36-ASM
het C @ chr1:224086256

 

GS18956 - var-GS18956-1100-36-ASM
het C @ chr1:224086256

 

GS19017 - var-GS19017-1100-36-ASM
het C @ chr1:224086256

 

GS19020 - var-GS19020-1100-36-ASM
het C @ chr1:224086256

 

GS19025 - var-GS19025-1100-36-ASM
het C @ chr1:224086256

 

GS19238 - var-GS19238-1100-36-ASM
het C @ chr1:224086256

 

GS19239 - var-GS19239-1100-36-ASM
het C @ chr1:224086256

 

GS19240 - var-GS19240-1100-36-ASM
hom C @ chr1:224086256

 

GS19648 - var-GS19648-1100-36-ASM
hom C @ chr1:224086256

 

GS19669 - var-GS19669-1100-36-ASM
het C @ chr1:224086256

 

GS19703 - var-GS19703-1100-36-ASM
het C @ chr1:224086256

 

GS19735 - var-GS19735-1100-36-ASM
het C @ chr1:224086256

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr1:224086256

 

Other external references
 

    dbSNP
  • rs1051740
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Craniofacial Abnormalities]
    [phenytoin]
    Risk or phenotype-associated allele: T. Phenotype: In a logistic regression model adjusted for history of phenytoin use during the first trimester and maternal epilepsy, the maternal EPHX1 113 H (rs1051740 T/C) allele was associated with craniofacial abnormalities in the child. Study size: 157 pregnancies. Study population/ethnicity: phenytoin use during the first trimester and maternal epilepsy. metric(s): per rare allele OR: 2.43, 95% confidence interval (CI): 1.16-5.10, P=0.02. Type of association: GN.
    www.ncbi.nlm.nih.gov/pubmed/19952982
  • [Epilepsy]
    [carbamazepine]
    Significantly increased and decreased carbamazepine-10,11-diol/carbamazepine-10,11-epoxide ratios were observed with the block 2 *2 haplotype harboring only 337T>C (Y113H) and the block 3 *2 haplotype harboring 416A>G (H139R), IVS3-114G>C and mostly 1071C>T (N357N). The allele frequency for Y113H (337T>C) was 0.453 in this study of 96 Japanese epileptic patients.
    www.ncbi.nlm.nih.gov/pubmed/15692831
  • [warfarin]
    Risk or phenotype-associated allele: C allele Phenotype: The C allele was not associated with warfarin maintenance dose variability (p = 0.5835). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant Type of association: GN; PK.
    www.ncbi.nlm.nih.gov/pubmed/19794411
    PolyPhen-2
  • Score: 0.997 (probably damaging)
    Web search results (153 hits -- see all)
  • Acute Pancreatitis - Studies from J. Ockenga and colleagues ...
    Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme capable of tobacco ... The researchers concluded: "The EPHX1 Y113H variant is not associated ...
    newsrx.com/library/newsletters/.../1200762.html
  • Pancreasweb
    Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme ... We studied the role of the EPHX1 c.337T>C (p.Y113H) variant, whichleads to altered enzyme activity, in ...
    www.pancreasweb.com/pancreas.asp?ak=Detail&zaehler=5811
  • Variation in genes relevant to aromatic hydrocarbon ...
    CYP1B1 V432L, EPHX1 Y113H, GSTM3 *A/*B (intron. Variation in genes ... V432L, EPHX1 Y113H, GSTM3 *A/*B, and NQO1. P187S (Table 2) were similar to those in other ...
    neuro-oncology.dukejournals.org/.../15228517-2005-003v1.pdf
  • Variation in genes relevant to aromatic hydrocarbon ...
    The EPHX1 variant Y113H has demonstrated increased activity in vitro but not in vivo ... The results for EPHX1 Y113H were suggestive of associations within certain subgroups. ...
    neuro-oncology.dukejournals.org/cgi/content/full/8/2/145
  • Functional analysis of human microsomal epoxide hydrolase ...
    encodes allelic variation at least two amino acid positions, Y113H and H139R. ... tribution of the commonly studied EPHX1 Y113H and. V.P. Hosagrahara et ...
    www.personal.psu.edu/faculty/c/j/cjo10/PDFs/CBI-mEH-2004.pdf
  • Lack of increased genetic damage in 1,3-butadiene-exposed ...
    The polymorphisms of EPHX1, particularly, for EPHX1 Y113H were determined by ... The EPHX1 Y113H polymorphisms had no influence on chromosome damage or HPRT ...
    www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1249498
  • EPHX1 [PharmGKB]
    EPHX1: Y113H; NM_000120.2: c.337T>C; NT_004559.13: g.2221786T>C. Related Drugs: ... EPHX1: H139R; NM_000120.2: c.416A>G; NT_004559.13: g.2228559A>G ...
    www.pharmgkb.org/do/serve?objId=PA27829&objCls=Gene
  • carbamazepine [PharmGKB]
    The allele frequencies for Y113H (337T>C) was 0.453 in this study of 96 Japanese ... EPHX1: Y113H; NM_000120.2: c.337T>C; NT_004559.13: g.2221786T>C ...
    www.pharmgkb.org/do/serve?objId=PA448785

Other in silico analyses
 

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

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