Rs3892097

The normal (or wild type) form of this SNP is a (G). The (A) form disrupts proper mRNA formation, resulting in a nonfunctional CYP2D6 protein. The associated allele is also known as CYP2D6*4. The CYP2D6*4 allele is the most common nonfunctioning variant of CYP2D6.

If two copies of this (or similar) changes are inherited, poor metabolism ('PM') of debrisoquine is observed. Many other drugs are typically first metabolized by CYP2D6 including dextromorphan, sparteine, metoprolol, nortriptyline and many other antidepressants and codeine. Of course, sometimes the active form of a drug is the one post-CYP2D6 metabolism; an example of this is tamoxifen, where the active form (endoxifen) is formed primarily via CYP2D6 metabolism; less functioning CYP2D6 can mean less benefit from taking the drug.

The CYP2D6*4 allele (i.e. rs3892097(A)) has been postulated by researchers over the years to have many potential consequences, both positive and negative.

On the positive side: this allele may reduce the risk of certain cancers, such as bladder and lung, and it may correlate with somwhat less severe neurodegeneration in Alzheimer's.

On the other hand, at least two studies [PMID 14991823, PMID 15174030] have concluded that the risk of developing Parkinson's disease upon exposure to pesticides is increased from 3 to 8 fold among carriers of CYP2D6*4 alleles. The risk to CYP2D6*4 carriers appears proportional to the degree of pesticide exposure, with no additional risk of developing Parkinson's seen for CYP2D6*4 carriers with no pesticide exposure, and the highest increased risk of developing Parkinson's seen for CYP2D6*4 carriers with frequent exposure to pesticides.

Patients prescribed tricyclic antidepressants (TCA) who are homozygous for the CYP2D6*4 allele metabolize these drugs more slowly, which puts them at higher risk for adverse side effects. A study of ~1100 Dutch patients reports: (1) 6 fold more side effects upon switching antidepressants for CYP2D6*4 homozygotes, but not for heterozygotes, and (2) that the effective and maintenance doses of antidepressants for CYP2D6*4 homozygotes are lower than for patients with one or more higher metabolizing CYP2D6 alleles.

rs3892097(A;A) patients taking a beta blocker drug such as metoprolol are at ~4x increased risk for bradycardia, based on a study of 1,533 patients in the Rotterdam Study. These CYP2D6 *4/*4 homozygotes have the 'poor metabolizer' (PM) phenotypes, and had adjusted heart rates that were 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (p < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio of 3.86, CI: 1.68-8.86, p = 0.0014).