Caffeine and My Genetics

Over the years I have noticed that I am more sensitive to caffeine than others. In fact, if I drink coffee in the afternoon, I am likely to have difficulty sleeping. I have always associated this with a reduction in the metabolism of caffeine. Then I got a report from 23andMe that confirmed my conclusion:

Thomas, based on your genetics, you are likely to drink slightly less caffeine than average, if you drink caffeine at all.

Apparently I have a genetic variant¹ near the AHR gene coding for a protein that influences the production of CYP1A2 gene which provides the instructions for an enzyme that metabolizes 95% of caffeine that individuals consume.

What is confusing to me is that the variant detected near the AHR gene is one that is associated with consuming more caffeine. Their scientific study showing the result quoted above, conflicts with their assertion that the variant that I have is associated with the consumption of more caffeine. The former, showing that people with this variant drink less caffeine, makes more sense to my personal experience, that I have an enzyme with lower efficiency at metabolizing caffeine causing me to drink less caffeine.

Apparently there are several SNPs near the AHR gene², and variants at each of these SNPs could have an effect on consumption of caffeine. Cornelis et al.² showed that variants at these SNPs were associated with higher plasma caffeine and lower plasma metabolites of caffeine, suggesting slower caffeine metabolism, as I would predict for my variant near the AHR gene.

I have another phenomenon associated with withdrawal from caffeine consumption: transient depression. This behavioral response to my use of caffeine, or actually termination of its use, has further caused me to avoid drinks that have caffeine. This particular result of withdrawal from caffeine use, may have nothing to do with any of the variants effecting metabolism, or the reduction in metabolism, and the resulting prolonged exposure to caffeine, may interact with the physiological response in my central nervous system that causes this response to caffeine withdrawal.

Interestingly, over time I become tolerant to the effects of caffeine, increasing the amount in order to get the same effect. I also notice that, with time, the caffeine effect wears off more quickly and I end up being depressed later in the day that I drank the coffee, and only drinking more coffee will bring me out of the depression. If I stop drinking caffeinated coffee, my depression starts around the second day, and by four days I’m feeling much better, so the depression takes some time to develop, and it is clearly transient.

I’d welcome thoughts about what might be happening for me.

References

1. The marker tested by 23andMe is rs4410790, and one of my alleles for this gene is the ‘C’ (cytosine) variant, while the other is the more common ‘T’ (thymidine) variant.
2. Cornelis, MC et al. “Genome-wide association study of caffeine matabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior”, Hum Mol Genet. 25(24):5472-5482 (2016).
3. rs4410790 in dbSNP, accessed 4-April-2023.
4. The Coffee and Caffeine Genetics Consortium, et al. “Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption”, Mol Psych 20: 647-656 (2015).