Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans

Ted R Mikuls, Tricia D LeVan, Karen A Gould, Fang Yu, Geoffrey Milton Thiele, Kimberly K. Bynote, Doyt Conn, Beth L. Jonas, Leigh F. Callahan, Edwin Smith, Richard Brasington, Larry W. Moreland, Richard Reynolds, Angelo Gaffo, S. Louis Bridges

Research output: Contribution to journalArticle

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Abstract

Objective To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P additive = 0.000003) and rs1208 (P additive = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.

Original languageEnglish (US)
Pages (from-to)655-664
Number of pages10
JournalArthritis and rheumatism
Volume64
Issue number3
DOIs
StatePublished - Mar 1 2012

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African Americans
Rheumatoid Arthritis
Smoking
Genes
Single Nucleotide Polymorphism
Epoxide Hydrolases
Enzymes
Genotype
Pharmaceutical Preparations
Risk Adjustment
Glutathione Transferase
Arthritis
Logistic Models
Alleles
Antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans. / Mikuls, Ted R; LeVan, Tricia D; Gould, Karen A; Yu, Fang; Thiele, Geoffrey Milton; Bynote, Kimberly K.; Conn, Doyt; Jonas, Beth L.; Callahan, Leigh F.; Smith, Edwin; Brasington, Richard; Moreland, Larry W.; Reynolds, Richard; Gaffo, Angelo; Bridges, S. Louis.

In: Arthritis and rheumatism, Vol. 64, No. 3, 01.03.2012, p. 655-664.

Research output: Contribution to journalArticle

Mikuls, TR, LeVan, TD, Gould, KA, Yu, F, Thiele, GM, Bynote, KK, Conn, D, Jonas, BL, Callahan, LF, Smith, E, Brasington, R, Moreland, LW, Reynolds, R, Gaffo, A & Bridges, SL 2012, 'Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans', Arthritis and rheumatism, vol. 64, no. 3, pp. 655-664. https://doi.org/10.1002/art.33408
Mikuls, Ted R ; LeVan, Tricia D ; Gould, Karen A ; Yu, Fang ; Thiele, Geoffrey Milton ; Bynote, Kimberly K. ; Conn, Doyt ; Jonas, Beth L. ; Callahan, Leigh F. ; Smith, Edwin ; Brasington, Richard ; Moreland, Larry W. ; Reynolds, Richard ; Gaffo, Angelo ; Bridges, S. Louis. / Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans. In: Arthritis and rheumatism. 2012 ; Vol. 64, No. 3. pp. 655-664.
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abstract = "Objective To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P additive = 0.000003) and rs1208 (P additive = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.",
author = "Mikuls, {Ted R} and LeVan, {Tricia D} and Gould, {Karen A} and Fang Yu and Thiele, {Geoffrey Milton} and Bynote, {Kimberly K.} and Doyt Conn and Jonas, {Beth L.} and Callahan, {Leigh F.} and Edwin Smith and Richard Brasington and Moreland, {Larry W.} and Richard Reynolds and Angelo Gaffo and Bridges, {S. Louis}",
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T1 - Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans

AU - Mikuls, Ted R

AU - LeVan, Tricia D

AU - Gould, Karen A

AU - Yu, Fang

AU - Thiele, Geoffrey Milton

AU - Bynote, Kimberly K.

AU - Conn, Doyt

AU - Jonas, Beth L.

AU - Callahan, Leigh F.

AU - Smith, Edwin

AU - Brasington, Richard

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AU - Gaffo, Angelo

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N2 - Objective To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P additive = 0.000003) and rs1208 (P additive = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.

AB - Objective To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P additive = 0.000003) and rs1208 (P additive = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.

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