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Interpretive Handbook

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Test 83389 :
N-Acetyltransferase 2 Gene (NAT2), Full Gene Sequence

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Arylamine N-acetyltransferase type 2 (NAT2) is a highly polymorphic phase 2 metabolic enzyme that conjugates hydrazine derivatives and aromatic amine drugs with acetyl-groups. NAT2 also is involved in the acetylation and activation of some procarcinogens.(1)

 

Individuals acetylate drugs at different rates by NAT2, and are described as having slow, intermediate, or fast acetylator phenotypes. A gradient exists in which the prevalence of slow acetylator phenotypes increases with decreasing distance to the equator. Near the equator, up to 80% of individuals may be slow acetylators, while in some more northern countries, as few as 10% of the population may have the slow acetylator phenotype.

 

A number of drugs are metabolized by NAT2 including procainamide, dapsone, nitrazepam, hydralazine, zonisamide, and isoniazid. Isoniazid is used to treat and prevent tuberculosis, and is still used as a primary treatment agent. Adverse reactions with isoniazid, which include nausea, drug-induced hepatitis, peripheral neuropathy, and sideroblastic anemia, are associated more often with a slow NAT2 acetylator phenotype. These individuals may require a lower dose to avoid adverse reactions.

 

The NAT2 gene contains a single intronless exon of 870 base pairs and encodes 290 amino acids. NAT2 is highly polymorphic and contains 16 known single nucleotide polymorphisms (SNPs) and 1 single base pair deletion. These polymorphisms are combined into 36 known haplotype alleles. Each individual haplotype is predictive of either a fast or slow acetylator phenotype. Individuals with 2 fast haplotypes are predicted to be extensive (normal) metabolizers, while those with 1 fast and 1 slow haplotype are intermediate metabolizers, and those with 2 slow haplotypes are poor metabolizers.(2,3) Studies with patients who have different acetylator haplotypes have correlated the ratio of plasma N-acetylisoniazid/isoniazid drug concentrations with haplotypes, with slow and intermediate acetylators having lower ratios than fast acetylators.(4)  

 

NAT2 Allele 

Nucleotide Change

Amino Acid Change

Predicted Acetylator Phenotype

*4

None

None

Fast

*5A

341T->C
481C->T

I114T

Slow

*5B

341T->C
481C->T
803A->G

I114T

K268R

Slow

*5C

341T->C
803A->G

I114T
K268R

Slow

*5D

341T->C

I114T

Slow

*5E

341T->C
590G->A

I114T
R197Q

Slow

*5F

341T->C
481C->T
759C->T
803A->G

I114T

 

K268R

Slow

*5G

282C->T
341T->C
481C->T
803A->G

                                I114T

 

K268R

Slow

*5H

341T->C

481C->T

803A->G

859T->C

I114T

K268R
I287T

Slow

*5I

341T->C

411A->T

481C->T

803A->G

I114T
L137F

K268R

Slow

*5J

282C->T
341T->C
590G->A

 

I114T
R197Q

Slow

*6A

282C->T
590G->A

 

R197Q

Slow

*6B

590G->A

R197Q

Slow

*6C

282C->T
590G->A
803A->G

 

R197Q
K268R

Slow

*6D

111T->C
282C->T
590G->A

 

 

R197Q

Slow

*6E

481C->T
590G->A

 

R197Q

Slow

*7A

857G->A

G286E

Slow

*7B

282C->T
857G->A

 

G286E

Slow

*10

499G->A

E167K

Undetermined

*11A

481C->T

None

Undetermined

*11B

481C->T

859Del

 

S287 Frameshift

Undetermined

*12A

803A->G

K268R

Fast

*12B

282C->T
803A->G

 

K268R

Fast

*12C

481C->T
803A->G

 

K268R

Fast

*12D

364G->A
803A->G

D122N
K268R

Undetermined

*13

282C->T

None

Fast

*14A

191G->A

R64Q

Slow

*14B

191G->A
282C->T

R64Q

Slow

*14C

191G->A
341T->C
481C->T
803A->G

R64Q
I114T

K268R

Slow

*14D

191G->A
282C->T
590G->A

R64Q

R197Q

Slow

*14E

191G->A
803A->G

R64Q
K268R

Slow

*14F

191G->A
341T->C
803A->G

R64Q
I114T
K268R

Slow

*14G

191G->A
282C->T
803A->G

R64Q

K268R

Slow

*17

434A->C

Q145P

Undetermined

*18

845A->C

K282T

Undetermined

*19

190C->T

R64W

Undetermined

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying patients who may require isoniazid dosing adjustments

Interpretation Provides information to assist in interpretation of the test results

The wild-type (normal) genotype for NAT2 is *4. This is the most commonly occurring allele in some, but not all, ethnic groups.(5)

 

Individuals are classified as being slow, intermediate, or fast acetylators depending on their diplotypes. Slow acetylators have 2 slow haplotypes, fast acetylators have 2 fast haplotypes, and intermediate acetylators have 1 of each.

 

Slow acetylators receiving isoniazid therapy should be monitored for signs of toxicity.

 

Dose reductions may be considered for both slow and intermediate acetylators. However, it should be verified that the reduced isoniazid dose produces serum levels within the therapeutic range.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.  

 

NAT2 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient’s NAT2 status.

 

This test sequences the entire NAT2 gene. All variants, including novel variants not listed, should be detected. However, novel variants not described in the literature may be of unknown significance.

 

Mutations in the primer binding regions can affect the testing and, ultimately, the genotyping interpretation made.

 

Drug-drug interactions and drug or metabolite inhibition must be considered when dealing with heterozygous individuals. Drug or metabolite inhibition can reduce residual functional NAT2 catalytic activity. Acetaminophen is a significant inhibitor of NAT2.

 

Patients may develop isoniazid toxicity problems if liver and kidney function are impaired, even in the absence of slow or intermediate acetylator status.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Meyer U: Polymorphism of human acetyltransferases. Environ Health Perspect 1994;102:213-216

2. Sabbagh A, Darlu P: Inferring haplotypes at the NAT2 locus: the computational approach. BMC Genetics 2005;6:30

3. Leff M, Fretland A, Doll M, and Heins D: Novel human N-acetyltransferase 2 alleles that differ in mechanism for slow acetylator phenotype. J Biol Chem 1999;274:34519-34522

4. Chen B, Li J-H, Xu Y-M, et al: The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetylisoniazid in Chinese pulmonary tuberculosis patients. Clin Chim Acta 2006;365:104-108

5. Lin H, Han C, Lin B, Hardy S: Ethnic distribution of slow acetylator mutations in the polymorphic N-acetyltransferase (NAT2) gene. Pharmacogenetics 1994;4:125-134


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