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Role of CYP1A1 haplotypes in modulating susceptibility to coronary artery disease

Sana Venkata Vijaya Lakshmi1, Shaik Mohammad Naushad, Kankanala Saumya

  • 1Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad 500082, India.

Indian Journal of Biochemistry & Biophysics
|December 25, 2012
PubMed

Insights

Specific cytochrome P450 1A1 (CYP1A1) haplotypes and the glutathione-S-transferase (GST)T1 null variant are linked to coronary artery disease (CAD) risk. These genetic factors contribute to increased oxidative DNA damage, a key mechanism in CAD development.

Area of Science:

  • Genetics and Molecular Biology
  • Cardiovascular Disease Research
  • Environmental Health

Background:

  • Coronary artery disease (CAD) is a multifactorial condition influenced by genetic predisposition and environmental factors.
  • Cytochrome P450 1A1 (CYP1A1) and glutathione-S-transferase (GST) enzymes play crucial roles in xenobiotic metabolism and detoxification.
  • Genetic variations in these enzyme pathways may impact susceptibility to CAD through altered oxidative stress levels.

Purpose of the Study:

  • To investigate the association between specific CYP1A1 haplotypes and GSTT1/GSTM1 null variants with the risk of developing coronary artery disease (CAD).
  • To explore the relationship between these genetic variants, oxidative DNA damage marker 8-oxo-2'-deoxyguanosine (8-oxodG), and conventional CAD risk factors like smoking.
  • To determine if identified genetic risk factors exhibit a dose-dependent effect on CAD severity, such as percentage of stenosis and number of affected vessels.

Main Methods:

  • A case-control study involving 352 CAD cases and 282 healthy controls.
  • Genotyping of CYP1A1 [ml (T-->C), m2 (A-->G), m4 (C-->A)] haplotypes and GSTT1/GSTM1 null variants using PCR-RFLP and multiplex PCR.
  • Quantification of plasma 8-oxo-2'-deoxyguanosine (8-oxodG) levels via competitive ELISA.

Main Results:

  • Two CYP1A1 haplotypes (CAC and TGC) were independently associated with increased CAD risk, while the TAC haplotype showed a protective effect.
  • The GSTT1 null variant was also independently associated with a significantly higher risk of CAD (OR: 2.53).
  • Smoking interacted synergistically with the CYP1A1 CAC haplotype and GSTT1 null genotype to elevate CAD risk. Elevated 8-oxodG levels were observed in individuals with the CYP1A1 CAC haplotype and GSTT1 null variant, with these variants explaining 36% of the variability in 8-oxodG levels.

Conclusions:

  • Specific CYP1A1 haplotypes (CAC, TGC) and the GSTT1 null variant are significant genetic risk factors for coronary artery disease.
  • The association between these genetic variants and CAD risk is likely mediated by increased oxidative DNA damage.
  • These findings highlight the interplay between genetic susceptibility, environmental factors like smoking, and oxidative stress in the pathogenesis of CAD.

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