lifestyle vs genes in who has strokes


Details:
--genetic data was imputed from the UK Biobank, including 306,473 men and women, aged 40-73 years, from 2006-10, but excluding those not white British, and people who are related (second degree or greater)
--in these people they evaluated 90 single nucleotide polymorphisms (SNPs) that had previously been found to be associated with stroke, at p<1×10−5
--healthy lifestyle was determined by four factors: non-smoker (no current smoking), healthy diet (at least 2 of: increased consumption of fruit, veges and fish, and decreased processed meat and red meats), BMI <30 kg/m2, and regular physical exercise (150 minutes of moderate intensity activity or 75 minutes of vigorous physical activity).

Results:
--2077 incident strokes occurred in the median follow-up 7.1 years (2,138,443 person-years): 1541 ischemic strokes, 287 intracerebral hemorrhages, and 249 subarachnoid hemorrhages
--genetic risk score was significantly associated with systolic BP (p=1.5x10-15), diastolic BP (p=1.1x10-7), use of lipid lowering agents (p=7.5x10-13), and diabetes (p=7.6x10-4), but not with BMI
--incident stroke was 35% higher among those in the top third polygenic score vs the bottom third, HR 1.35 (1.21 - 1.50), p=3.9x10-8
--healthier lifestyle (0 or 1 healthy lifestyle factors) vs those with 3 or 4 of those factors had a 66% increased risk of stroke, HR 1.66 (1.45 = 1.89), p=1.19x10-13
--the combination of a high genetic risk and unfavorable  lifestyle increased the risk of stroke more than 2-fold, HR 2.30 (1.84-2.87), p=3.3x10-13
--the association of stroke with lifestyle was independent of genetic risk strata
--of the healthy lifestyle factors, smoking was by far the most important one associated with stroke risk:
    --those with low genetic risk: HR 2.35 (1.84-3.01), p=7.3x10-12
    --those with moderate genetic risk: HR 2.81 (2.27-3.48), p<2x10-16
    --those with high genetic risk: HR 1.87 (1.48-2.37), p=1.5x10-07

Commentary:
--this study found that there was a gradient for stroke both by lifestyle measures and genetic predisposition. And, that even those at the highest genetic risk category seemed to do much better if they had healthier lifestyles
--other studies noting the importance of the environment in those genetically predisposed to disease:
    --see http://gmodestmedblogs.blogspot.com/2018/01/dietary-effect-strong-when-high-genetic.html , a study finding that those with high genetic risk scores for developing obesity actually responded better to dietary interventions than those at lower genetic risk
    --see http://gmodestmedblogs.blogspot.com/2016/11/lifestyle-changes-and-genetic-risk-for.html , combining genetic data from 3 prospective trials found that those at the highest genetic risk for coronary artery disease had the greatest benefit from lifestyle changes
--the mechanism of the interaction between genes and the environment is unclear, though I suspect multi-fold. For example, epigenetics may play an intermediary role, whereby the environmental stimuli (diet, exercise....) might lead to biochemical changes (eg, dna methylation), modifying the expression of some genes (eg turning some off)
--it should be noted that the role of risk factors in stroke do vary between men women: women have higher prevalence of hypertension, men have more prevalent heart disease, diabetes and unhealthy lifestyle behaviors (smoking, obesity, alcohol use)
--there were other clear limitations to this study: they only assessed some of the important lifestyle issues, these were assessed only at baseline, and they were mostly binary (and for smoking, there was only "current smoker", so a 5-pack per day smoker for 20 years who happened to quit 2 weeks ago rated better lifestyle than the person smoking 1 cigarette a day for the past 6 months); stress, sleep, details of physical activity, alcohol and drug use, etc were not assessed; and there was no differentiation between the types of strokes, which might differ depending on different genetics or lifestyle issues; and, the analysis was homogenously of white people of European descent
--and, this was an observational study. people with different genetic backgrounds were not randomized to different lifestyle interventions to see how many strokes they had over 5-10 years or more.  it is possible that there is confounding. did those with more genetic risk choose different lifestyles? or perhaps different intensities of lifestyles that were not assessed in the binary approach above?

So, this article adds to several recent ones as noted above, all finding that genes are not determinant in some of our most prevalent diseases. in these cases there seemed to be an interaction between the individual person (and their inherited genes) with the environment in determining disease. And in some cases, the lifestyle/environmental issues were in fact more determinant than the genetic ones

the bottom clinical line to me: sometimes we see patients who adopt an overly fatalistic view: stroke (or heart disease, or obesity) runs strongly in their family, so their demise is inevitable. And no use going through the often difficult lifestyle changes of maintaining a healthy weight, eating well, exercising, not smoking….  These studies provide an important talking point with patients: genetics are not determinant (in most cases, and especially in some of these very prevalent chronic illnesses), and this point can help empower patients to help sustain a healthier lifestyle.

geoff

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