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What if I said that we had a multitude of observational studies, each showing a potential protective effect of alcohol at moderate doses on risk of heart disease and stroke. And that despite our best efforts, elucidating causality was nigh-impossible owing to (i) feasibility,
(ii) funding, (iii) ethics, etc. And that despite some strong efforts, randomized controlled trials had been abandoned due to perceived bias by industry nih.gov/news-events/ne…
And that perhaps the only way to clarify whether the relationship between alcohol & vascular disease is causally protective (at low dose) was through an epidemiological approach called Mendelian randomization
Mendelian randomization uses naturally occurring genetic variants to mimic randomized controlled trials (more info here: bmj.com/content/362/bm…)
Using MR, our best efforts in Europeans suggested that alcohol doesn’t protect from heart disease, but the genetic variant only led to a 17% difference in alcohol intake, which posed a challenge to extrapolate across the distribution of alcohol intake bmj.com/content/349/bm…
But there is a genotype that has a massive effect on alcohol consumption: ALDH2. Notably this variant is monomorphic in Europeans, but polymorphic in East Asians. Thus, we can use this ALDH2 genotype to reliably investigate the causal effect of alcohol on vascular disease
These data tell us a multitude of things: the linear relationship of alcohol with risk factors deleterious for vascular disease, the linear relationship with stroke, with no threshold effect (i.e. no safe or protective effect at any level of consumption). thelancet.com/journals/lance…
But – can we extrapolate these findings to individuals that aren’t East Asians? Absolutely. We have strong evidence that risk factors for vascular disease are generally consistent irrespective of geographical location and ancestry thelancet.com/journals/lance…
So in effect, these data definitively bunk the J-shape hypothesis of alcohol at moderate doses on risk of stroke. Note that @MichaelMarmot wrote about this back in 1991! ncbi.nlm.nih.gov/pmc/articles/P…
