Polymorphisms of cytochromes P450 and glutathione S-transferases synergistically modulate risk for Parkinson's disease

<p><span><strong>Background</strong>: </span><span>Environmental substances such as p</span><span>esticides </span><span>are well-known in </span><span>link </span><span>with</span><span> PD </span><span>risk</span><span>.</span><span> E</span><span>nzymes </span><span>including </span><span>cytochromes P450 (CYPs)</span><span>,</span><span> esterases </span><span>and </span><span>glutathione S-transferases (GSTs) </span><span>are responsible for the x</span><span>enobiotic </span><span>metabolism and </span><span>may functionally compensate each other </span><span>for subtypes in the same class. W</span><span>e hypothesize that the genetic effects </span><span>of each class </span><span>modulate PD risk stronger in a synergistic way</span> <span>than individually.</span></p> <p><span><strong>Methods</strong>: </span><span>We selected 14 polymorphic loci out of 13 </span><span>enzymes in the classes of</span><span> CYP, esterase, and GST, and recruited a cohort of 1026 PD and control subjects from eastern China. The genotypes were identified using improved multiplex ligation detection reaction, and analyzed using multiple models.</span></p> <p><span><strong>Results</strong>:</span><span> A total of 13 polymorphisms remained after Hardy-Weinberg equilibrium analysis. None of the polymorphisms were independently associated with PD risk after Bonferroni correction either by logistic regression or genetic models. In contrast, interaction analyses detected increased resistance to PD risk in individuals carrying the rs12441817/CC (<em>CYP1A1</em>) and rs2070676/G (<em>CYP2E1</em>) genotypes (P = 0.002, OR = </span><span>0.393</span><span>, 95% CI = </span><span>0.216-0.715)</span><span>,</span><span> or carrying the <em>GSTM1</em>-present, <em>GSTT1</em>-null, rs156697/G (<em>GSTO2</em>) and rs1695/AA (<em>GSTP1</em>) genotypes (<em>P</em> = 0.003, OR = </span><span>0.348</span><span>, 95% CI = </span><span>0.171-0.706</span><span>), but not with genotypes of esterases.</span></p> <p><span><strong>Conclusions</strong>:</span><span> We demonstrate a presence of synergistic but not individual impact on PD susceptibility in polymorphisms of <em>CYPs</em> and <em>GSTs</em>. The results indicate that the genetic interplay leads the way to PD development for xenobiotic metabolizing enzymes.</span></p>