NAT2

From SNPedia

NAT2 is one of only 2 N-acetyltransferase genes in humans; the other, NAT1, shows little variation between individuals, whereas NAT2 is known to have over 23 variants. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. The NAT2 acetylation polymorphism is important because of its primary role in the activation and/or deactivation of many chemicals in the body's environment, including those produced by cigarettes as well as aromatic amine and hydrazine drugs used medicinally. In turn, this can affect an individual's cancer risk.

Individuals can be classified as either rapid, or slow, metabolizers (i.e. detoxifiers). In general, slow metabolizers have higher rates of certain types of cancer and are more susceptible to side effects from chemicals metabolized by NAT2.[PMID 10667461] Drugs reported to be metabolized by NAT2 include isoniazid, sulfadimidine, hydralazine, dapsone, procaine amide, sulfapyridine, nitrazepam and some sulfa drugs. [PMID 3712391]

It takes two slow metabolizer alleles to give rise to a slow metabolizer phenotype, or to put it another way, the rapid metabolizer allele is dominant to the slow metabolizer, and you therefore only need one to be a rapid metabolizer.

Promethease evaluates an individual's NAT2 phenotype based on genosets gs138, gs139 and gs140.

Generally, with respect to NAT2, individuals are therefore classified as rapid metabolizers if they have one or more NAT2*4 alleles, and slow metabolizers only if they carry two slow metabolizer variants. The alleles themselves are effectively haplotypes composed of several NAT2 SNPs, most typically assigned according to the status of the following seven SNPs:

• rs1801279, aka G191A
• rs1041983, aka C282T
• rs1801280, aka T341C
• rs1799929, aka C481T
• rs1799930, aka G590A
• rs1208, aka A803G
• rs1799931, aka G857A

The most common alleles are then defined as follows:

• NAT2*4: considered to be the wild-type allele, and the exemplar rapid metabolizer; consists of the first nucleotide shown in the "aka" (also known as) names listed above for these seven NAT2 SNPs, i.e. an allele in question is NAT2*4 if it is rs1801279(G) and rs1041983(C) and rs1801280(T) and ... etc

Almost all of the remaining common alleles are slow metabolizers, such as:

• NAT2*5A: 341C + 481T, i.e. rs1801280(C) + rs1799929(T)
• NAT2*5B: 341C + 481T + 803G, i.e. rs1801280(C) + rs1799929(T) + rs1208(G)
• NAT2*5C: 341C + 803G, i.e. rs1801280(C) + rs1208(G)
• NAT2*5D: 341C, i.e. rs1801280(C)
• NAT2*5E: 341C + 590A, i.e. rs1801280(C) + rs1799930(A)
• NAT2*5G: 282T + 341C + 481T + 803G, i.e. rs1041983(T) + rs1801280(C) + rs1799929(T) + rs1208(G)
• NAT2*5J: 282T + 341C + 590A, i.e. rs1041983(T) + rs1801280(C) + rs1799930(A)
• NAT2*6A: 282T + 590A, i.e. rs1041983(T) + rs1799930(A)
• NAT2*6B: 590A (only), i.e. no variation compared to NAT2*4 except rs1799930(A)
• NAT2*6C: 282T + 590A + 803G, i.e. rs1041983(T) + rs1799930(A) + rs1208(G)
• NAT2*6E: 481T + 590A, i.e. rs1799929(T) + rs1799930(A)
• NAT2*7A: 857A (only), i.e. rs1799931(A)
• NAT2*7B: 282T + 857A, i.e. rs1041983(T) + rs1799931(A)
• NAT2*14A: 191A, i.e. rs1801279(A)
• NAT2*14B: 191A + 282T, i.e. rs1801279(A) + rs1041983(T)
• NAT2*14C: 191A + 341C + 481T + 803G, i.e. rs1801279(A) + rs1801280(C) + rs1799929(T) + rs1208(G)
• NAT2*14D: 191A + 282T + 590A, i.e. rs1801279(A) + rs1041983(T) + rs1799930(A)
• NAT2*14E: 191A + 803G, i.e. rs1801279(A) + rs1208(G)
• NAT2*14F: 191A + 341C + 803G, i.e. rs1801279(A) + rs1801280(C) + rs1208(G)
• NAT2*14G: 191A + 282T + 803G, i.e. rs1801279(A) + rs1041983(T) + rs1208(G)

However there are also a few rapid (i.e. normal) metabolizer variants as well, such as:

• NAT2*11A: 481T, i.e. rs1799929(T)
• NAT2*12A: 803G, i.e. rs1208(G)
• NAT2*12B: 282T + 803G, i.e. rs1041983(T) + rs1208(G)
• NAT2*12C: 481T + 803G, i.e. rs1799929(T) + rs1208(G)
• NAT2*13: 282T (only), i.e. rs1041983(T)

As mentioned above, individuals running the Promethease program associated with SNPedia are automatically tested for NAT2 genotype via the genosets known as gs138, gs139 and gs140.

Alternatively, NAT2 acetylator phenotype can be inferred from a complex NAT2 genotype (i.e. a combination of SNPs observed in a given individual) using the publicly-accessible web-server NAT2PRED (http://nat2pred.rit.albany.edu). [PMID 19261719]

The proportion of slow and rapid metabolizers is known to differ between different ethnic populations. In general, the slow metabolizer phenotype is most prevalent (>80%) in Northern Africans and Scandinavians, and lowest (5%) in Canadian Eskimos and Japanese. Intermediate frequencies are seen in Chinese populations (around 20% slow metabolizers), whereas 40 - 60% of African-Americans and most non-Scandinavian Caucasians are slow metabolizers.