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NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study.

Matejcic M, Vogelsang M, Wang Y, Iqbal Parker M, Parker IM - BMC Cancer (2015)

Bottom Line: The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58).Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81).In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).

View Article: PubMed Central - PubMed

Affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Observatory, UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa. MTJMAR002@myuct.ac.za.

ABSTRACT

Background: Tobacco smoking and red meat consumption are some of the known risk factors associated with the development of oesophageal cancer. N-acetytransferases (NAT1 and NAT2) play a key role in metabolism of carcinogenic arylamines present in tobacco smoke and overcooked red meat. We hypothesized that NAT1 and NAT2 genetic polymorphisms may influence the risk of oesophageal cancer upon exposure to environmental carcinogens.

Methods: Single nucleotide polymorphisms (SNPs) in the NAT1 and NAT2 genes were investigated by genotyping 732 cases and 768 healthy individuals from two South African populations to deduce the acetylator phenotype (slow, intermediate or rapid) from the combination of the genotyped SNPs.

Results: The 341 CC genotype (rs1801280) was significantly associated with a reduced risk for oesophageal cancer in the Mixed Ancestry population (OR = 0.31; 95% CI 0.11-0.87). The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58). Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81). In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).

Conclusions: Our findings indicate that N-acetylation polymorphisms may modify the association between environmental risk factors and oesophageal cancer risk and that N-acetyltransferases may play a key role in detoxification of carcinogens. Prevention strategies in lifestyle and dietary habits may reduce the incidence of oesophageal cancer in high-risk populations.

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Related in: MedlinePlus

Linkage disequilibrium betweenNAT1andNAT2SNPs in Black and Mixed Ancestry South Africans. Plots show r2 and D’ values for pairwise LD between NAT1 and NAT2 variants in the South African Black and Mixed Ancestry population groups. The left triangle in each plot represents NAT1 SNPs, while the right triangle represents NAT2 SNPs. Colour intensity of squares (black to white) indicates the strength of LD (high to low) by D’, while numbers within squares refer to r2 values for pairwise SNPs. D’ and r2 refer to different statistical methods to measure linkage disequilibrium between alleles; r2 is preferred to predict one allele given the other, whereas D’ is mainly used to assess recombination patterns such as haplotype blocks. Linkage disequilibrium analysis was carried out in control groups by using Haploview [34].
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Fig1: Linkage disequilibrium betweenNAT1andNAT2SNPs in Black and Mixed Ancestry South Africans. Plots show r2 and D’ values for pairwise LD between NAT1 and NAT2 variants in the South African Black and Mixed Ancestry population groups. The left triangle in each plot represents NAT1 SNPs, while the right triangle represents NAT2 SNPs. Colour intensity of squares (black to white) indicates the strength of LD (high to low) by D’, while numbers within squares refer to r2 values for pairwise SNPs. D’ and r2 refer to different statistical methods to measure linkage disequilibrium between alleles; r2 is preferred to predict one allele given the other, whereas D’ is mainly used to assess recombination patterns such as haplotype blocks. Linkage disequilibrium analysis was carried out in control groups by using Haploview [34].

Mentions: The results of the linkage disequilibrium analysis (LD) and Hardy-Weinberg equilibrium tests in the two South African populations showed that the distribution of genotypes for each SNP in the control groups were in Hardy-Weinberg equilibrium (P > 0.05; see Additional file 2). The NAT1 1088T>A and 1095C>A SNPs occurred at high frequency (MAF ≥ 0.401) and were in complete LD in both ethnic groups (DI = 1.0). For the NAT2 SNPs, only 341T>C (NAT2*5) and 590G>A (NAT2*6) were present at relatively high frequencies (MAF ≥ 0.214) and strong LD (DI = 1.0) existed between these two polymorphisms in both population groups. Linkage disequilibrium of 857G>A (NAT2*7) and 191G>A (NAT2*14) with other SNPs was not considered because of the low frequency of these two polymorphic variants in both population groups (MAF ≤ 0.063). No significant LD was observed between SNPs in the NAT1 locus and the two most common SNPs in the NAT2 locus (341T>C and 590G>A) in either ethnic group, thereby forming two main LD blocks, Block 1 (including NAT1 SNPs) and Block 2 (including NAT2 SNPs), as shown in Figure 1.Figure 1


NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study.

Matejcic M, Vogelsang M, Wang Y, Iqbal Parker M, Parker IM - BMC Cancer (2015)

Linkage disequilibrium betweenNAT1andNAT2SNPs in Black and Mixed Ancestry South Africans. Plots show r2 and D’ values for pairwise LD between NAT1 and NAT2 variants in the South African Black and Mixed Ancestry population groups. The left triangle in each plot represents NAT1 SNPs, while the right triangle represents NAT2 SNPs. Colour intensity of squares (black to white) indicates the strength of LD (high to low) by D’, while numbers within squares refer to r2 values for pairwise SNPs. D’ and r2 refer to different statistical methods to measure linkage disequilibrium between alleles; r2 is preferred to predict one allele given the other, whereas D’ is mainly used to assess recombination patterns such as haplotype blocks. Linkage disequilibrium analysis was carried out in control groups by using Haploview [34].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4379954&req=5

Fig1: Linkage disequilibrium betweenNAT1andNAT2SNPs in Black and Mixed Ancestry South Africans. Plots show r2 and D’ values for pairwise LD between NAT1 and NAT2 variants in the South African Black and Mixed Ancestry population groups. The left triangle in each plot represents NAT1 SNPs, while the right triangle represents NAT2 SNPs. Colour intensity of squares (black to white) indicates the strength of LD (high to low) by D’, while numbers within squares refer to r2 values for pairwise SNPs. D’ and r2 refer to different statistical methods to measure linkage disequilibrium between alleles; r2 is preferred to predict one allele given the other, whereas D’ is mainly used to assess recombination patterns such as haplotype blocks. Linkage disequilibrium analysis was carried out in control groups by using Haploview [34].
Mentions: The results of the linkage disequilibrium analysis (LD) and Hardy-Weinberg equilibrium tests in the two South African populations showed that the distribution of genotypes for each SNP in the control groups were in Hardy-Weinberg equilibrium (P > 0.05; see Additional file 2). The NAT1 1088T>A and 1095C>A SNPs occurred at high frequency (MAF ≥ 0.401) and were in complete LD in both ethnic groups (DI = 1.0). For the NAT2 SNPs, only 341T>C (NAT2*5) and 590G>A (NAT2*6) were present at relatively high frequencies (MAF ≥ 0.214) and strong LD (DI = 1.0) existed between these two polymorphisms in both population groups. Linkage disequilibrium of 857G>A (NAT2*7) and 191G>A (NAT2*14) with other SNPs was not considered because of the low frequency of these two polymorphic variants in both population groups (MAF ≤ 0.063). No significant LD was observed between SNPs in the NAT1 locus and the two most common SNPs in the NAT2 locus (341T>C and 590G>A) in either ethnic group, thereby forming two main LD blocks, Block 1 (including NAT1 SNPs) and Block 2 (including NAT2 SNPs), as shown in Figure 1.Figure 1

Bottom Line: The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58).Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81).In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).

View Article: PubMed Central - PubMed

Affiliation: International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Observatory, UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa. MTJMAR002@myuct.ac.za.

ABSTRACT

Background: Tobacco smoking and red meat consumption are some of the known risk factors associated with the development of oesophageal cancer. N-acetytransferases (NAT1 and NAT2) play a key role in metabolism of carcinogenic arylamines present in tobacco smoke and overcooked red meat. We hypothesized that NAT1 and NAT2 genetic polymorphisms may influence the risk of oesophageal cancer upon exposure to environmental carcinogens.

Methods: Single nucleotide polymorphisms (SNPs) in the NAT1 and NAT2 genes were investigated by genotyping 732 cases and 768 healthy individuals from two South African populations to deduce the acetylator phenotype (slow, intermediate or rapid) from the combination of the genotyped SNPs.

Results: The 341 CC genotype (rs1801280) was significantly associated with a reduced risk for oesophageal cancer in the Mixed Ancestry population (OR = 0.31; 95% CI 0.11-0.87). The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58). Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81). In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).

Conclusions: Our findings indicate that N-acetylation polymorphisms may modify the association between environmental risk factors and oesophageal cancer risk and that N-acetyltransferases may play a key role in detoxification of carcinogens. Prevention strategies in lifestyle and dietary habits may reduce the incidence of oesophageal cancer in high-risk populations.

Show MeSH
Related in: MedlinePlus