Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR

Int J Epidemiol. 2004 Oct;33(5):971-8. doi: 10.1093/ije/dyh251. Epub 2004 Jul 15.


Background: Impaired metabolism of toxic chemicals is a postulated mechanism underlying multiple chemical sensitivity (MCS). Because genetic variation alters the rate of chemical metabolism, this study was designed to determine if MCS cases differed from controls for genetic polymorphisms in drug-metabolizing enzymes.

Methods: Female Caucasian participants (203 cases and 162 controls) were drawn from a larger case-control study based on a reproducible and validated case definition. Common polymorphisms for CYP2D6, NAT1, NAT2, PON1, and PON2 were genotyped.

Results: Comparing cases and controls, significant differences were found in genotype distributions for CYP2D6 (P = 0.02) and NAT2 (P = 0.03). Compared with the referent homozygous inactive (CYP2D6) or slow (NAT2) metabolizers, the odds for being CYP2D6 homozygous active (OR = 3.36, P = 0.01) and NAT2 rapid (OR = 4.14, P = 0.01) were significantly higher in cases than controls. The odds for being heterozygous for PON1-55 (OR = 2.05, P = 0.04) and PON1-192 (OR = 1.57, P = 0.04) were also significantly higher in cases.

Conclusions: A genetic predisposition for MCS may involve altered biotransformation of environmental chemicals. The CYP2D6 enzyme activates and inactivates toxins; the NAT2 enzyme bioactivates arylamines to protein-binding metabolites. A gene-gene interaction between CYP2D6 and NAT2 suggested that rapid metabolism for both enzymes may confer substantially elevated risk (OR = 18.7, P = 0.002). Our finding parallels others' observation of a link between PON1 heterozygosity and neurological symptoms in Gulf War syndrome. This first demonstration of genetic variation in drug-metabolizing enzymes in association with MCS requires replication. However, it suggests new research directions on genetically variable toxin pathways that might be important in MCS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aryldialkylphosphatase / genetics
  • Case-Control Studies
  • Cytochrome P-450 CYP2D6 / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Inactivation, Metabolic / genetics
  • Middle Aged
  • Multiple Chemical Sensitivity / enzymology*
  • Multiple Chemical Sensitivity / genetics*
  • Polymorphism, Genetic


  • Cytochrome P-450 CYP2D6
  • Aryldialkylphosphatase