Kidney function and caffeine clearance - if you know your genotype

February 16th, 2023, 10:57 am

If you know your CYP1A2 rs762551 genotype, then this study released a couple weeks ago is interesting, and you might want to control your caffeine consumption if you don't have the AA genotype. If you don't know your genotype, then this is ignorable (ditto to a lessor extent if you don't have untreated stage 1 hypertention (130-139/80-89 mm Hg), or don't live in Italy).

Note that when they say "cup of coffee" below, they mean an Italian single shot espresso, so about 7g of a beans in a blend that includes some Robusta, giving 100mg of caffeine per cup.

Abstract

Importance Caffeine is detoxified by cytochrome P450 1A2 (CYP1A2), and genetic variation in CYP1A2 impacts the rate of caffeine clearance. Factors that may modify the association between coffee intake and kidney disease remain unclear.

Objective To assess whether CYP1A2 genotype modifies the association between coffee intake and kidney dysfunction.

Design, Setting, and Participants The Hypertension and Ambulatory Recording Venetia Study (HARVEST) was a prospective cohort study of individuals with stage 1 hypertension in Italy; HARVEST began on April 1, 1990, and follow-up is ongoing. The current study used data from April 1, 1990, to June 30, 2006, with follow-up of approximately 10 years. Blood pressure and biochemical data were collected monthly during the first 3 months, then every 6 months thereafter. Data were analyzed from January 2019 to March 2019. Participants were screened and recruited from general practice clinics. The present study included 1180 untreated participants aged 18 to 45 years with stage 1 hypertension; those with nephropathy, diabetes, urinary tract infection, and cardiovascular disease were excluded.

Exposures Coffee intake and CYP1A2 genotype rs762551 were exposures analyzed over a median follow-up of 7.5 (IQR, 3.1-10.9) years.

Main Outcomes and Measures Albuminuria (defined as an albumin level of ≥30 mg/24 h) and hyperfiltration (defined as an estimated glomerular filtration rate of ≥150 mL/min/1.73 m2) were the primary outcomes as indicators of kidney dysfunction.

Results Among 1180 participants, genotyping, lifestyle questionnaires, and urine analysis data were obtained from 604 individuals (438 [72.5%] male) with a mean (SD) age of 33.3 (8.5) years and a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 25.4 (3.4). A total of 158 participants (26.2%) consumed less than 1 cup of coffee per day, 379 (62.7%) consumed 1 to 3 cups per day, and 67 (11.1%) consumed more than 3 cups per day. Genotype frequencies for rs762551 (260 participants [43.1%] with genotype AA, 247 participants [40.8%] with genotype AC, and 97 participants [16.1%] with genotype CC) did not differ between coffee intake categories. The level of risk of developing albuminuria, hyperfiltration, and hypertension, assessed by Cox regression and survival analyses, was not associated with coffee intake in the entire group or among fast metabolizers. The risks of albuminuria (adjusted hazard ratio [aHR], 2.74; 95% CI, 1.63-4.62; P < .001), hyperfiltration (aHR, 2.11; 95% CI, 1.17-3.80; P = .01), and hypertension (aHR, 2.81; 95% CI, 1.51-5.23; P = .001) increased significantly among slow metabolizers who consumed more than 3 cups per day.

Conclusions and Relevance In this study, the risks of albuminuria, hyperfiltration, and hypertension increased with heavy coffee intake only among those with the AC and CC genotypes of CYP1A2 at rs762551 associated with slow caffeine metabolism, suggesting that caffeine may play a role in the development of kidney disease in susceptible individuals.

Full article: https://jamanetwork.com/journals/jamane ... le/2800839

February 17th, 2023, 12:25 pm

From the study, "
Introduction

Preventable kidney disease is one of the leading causes of morbidity and mortality worldwide.1 Factors that may modify the association between coffee consumption and kidney disease remains unclear. Coffee is a major source of caffeine and the most widely consumed caffeinated beverage in the world. Some investigations have suggested that caffeine is associated with impaired kidney function in humans2 and adversely alters kidney tissue in animals and humans by stimulating glomerular remodeling and sclerosis,3,4 worsening hypertension5,6 and proteinuria,7 and accelerating preexisting chronic kidney failure.8 However, other studies have found that caffeine intake can slow the progression of diabetic nephropathy,9 while others have observed a lower risk of developing chronic kidney disease (CKD) with increasing coffee consumption.10"

Bolding of section is mine

February 17th, 2023, 12:26 pm

And yeah, I'm not AA

#4: Post by **SutterMill** » February 17th, 2023, 3:23 pm

LBIespresso wrote:From the study, "
Introduction

Preventable kidney disease is one of the leading causes of morbidity and mortality worldwide.1 Factors that may modify the association between coffee consumption and kidney disease remains unclear. Coffee is a major source of caffeine and the most widely consumed caffeinated beverage in the world. Some investigations have suggested that caffeine is associated with impaired kidney function in humans2 and adversely alters kidney tissue in animals and humans by stimulating glomerular remodeling and sclerosis,3,4 worsening hypertension5,6 and proteinuria,7 and accelerating preexisting chronic kidney failure.8 However, other studies have found that caffeine intake can slow the progression of diabetic nephropathy,9 while others have observed a lower risk of developing chronic kidney disease (CKD) with increasing coffee consumption.10"

I love reading studies. They occasionally take the longest route to say they don't have enough info yet.

Great find Andrew. Now I'm curious to know my type.

February 17th, 2023, 3:51 pm

Credit to Craig for finding the study.

February 17th, 2023, 4:33 pm

LBIespresso wrote:... However, other studies have found that caffeine intake can slow the progression of diabetic nephropathy,9 while others have observed a lower risk of developing chronic kidney disease (CKD) with increasing coffee consumption.10"

Bolding of section is mine

Study 9 is on rats. Study 10 is a meta-analysis and so combines many different studies with different samples/cohorts/populations - for example, this study didn't find any relationship when the genotypes were combined, and that is the result that would have been fed into the meta-analysis - if this study was included in study 10.

It is pretty clear to me that genetics affects how we react to caffeine in coffee, and caffeine generally - although those two may be different. Note that CYP1A2 at rs762551 is not the only marker that affects caffeine clearance/metabolism. An individual can have "slow caffeine metabolism," yet have the AA genotype at rs762551.

23andme uses CYP1A2 rs2472297 and AHR rs4410790 to predict caffeine consumption, and I would not be surprised if caffeine consumption was correlated with caffeine metabolism. (Gross simplification: CYP1A2 tells the body how to "make" the enzyme that breaks down caffeine, and some other things - and AHR "controls" CYP1A2.)

LBIespresso wrote:And yeah, I'm not AA

All I know is my(AA) limit is less than one ounce of (Arabica) coffee per day - currently three 8g single shots - and I have to consume them well before noon if I want to get to sleep at a decent hour. On the plus side, this means I can consume quite expensive coffees. On the minus side, the rest of the day is decaf

.

LBIespresso wrote:Credit to Craig for finding the study.

Credit Google for putting the TV news story in my feed. I didn't link the story before because the news story didn't include the details that I wanted to know (which gene/marker). They did interview the lead researcher of the paper: https://toronto.ctvnews.ca/some-coffee- ... -1.6275374

#7: Post by **LBIespresso** » February 17th, 2023, 6:33 pm

For some reason I am with you on the slower metabolism as anything after 3 pm and it affects my sleep. I use a wearable that tracks several data types, so it is real, not just a feeling. But, I can throw down a lot of coffee before then without getting jittery. But give me an espresso at 4PM and I will not sleep as well. Go figure.

February 17th, 2023, 6:48 pm

SutterMill wrote:I love reading studies. They occasionally take the longest route to say they don't have enough info yet.

That's very common online. AKA clickbait.

Now I'm curious to know my type.

If you get jittery after downing 2 cups of coffee, then it's a rough way to figure out.

#9: Post by **jpender** » February 18th, 2023, 11:12 am

baldheadracing wrote:If you don't know your genotype, then this is ignorable

I'm not sure I understand you. Given that the majority of people don't have the AA genotype wouldn't anyone who drinks more than 21g equivalent of Italian coffee beans each day have reason to be at least a little curious?

And how would one go about finding out what their genotype is? The lead researcher said that it can be determined via a "simple saliva sample genetic test". Can one's GP order such a test (affordably)?

I suspect that I metabolize caffeine efficiently based on how I cope with the drug. But maybe it isn't that simple?

February 18th, 2023, 12:21 pm

Of course one can be curious. However, it is not that simple.

For example, caffeine tolerance can build as you consume more caffeine. I had no coffee or caffeine in January. My first shot of coffee in February was very effective in keeping me up until 3am

... but after a couple weeks I was back up to three shots in the morning, and sleeping normally.

Another example: This study's cohort consists only of mildly hypertensive Italians. However, if you have AC or CC and you're Taiwanese, then you may well be less likely to be hypertensive than AA folks in the first place. https://nutritionandmetabolism.biomedce ... 21-00605-9 ... leading one to wonder, are this study's results applicable to non-hypertensive people? Other populations besides Italians?

For a deep dive, a list of studies using this marker is at: https://www.ncbi.nlm.nih.gov/snp/rs762551#publications

For finding out what your genotype is, I would assume that "Simple saliva sample genetic test" means something like 23andme.com or similar services. As an aside, 23andme's tests have been consistently much less expensive on Black Friday/Cyber Monday; IIRC, I had 60% off. Note that I am not recommending 23andme, just using them as an example. They changed their business model to a subscription model a while ago, and it seems that much of the new stuff is only available with a subscription - but when I signed up, all new stuff was supposed to be included in the premium package that I bought.