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Cited by 1,460Genetic Associations and EpidemiologyNutrition, Genetics, and DiseaseCardiovascular Health and Risk Factors

Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease

Open access
Khera, Amit V., Emdin, Connor A., Drake, Isabel, Natarajan, Pradeep, Bick, Alexander G., Cook, Nancy R., Chasman, Daniel I., Baber, Usman +8 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1605086PMC PMC5338864
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Abstract

BACKGROUND: Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. METHODS: Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. RESULTS: The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category. CONCLUSIONS: Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

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Crossref · 10.1056/nejmoa1605086

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.

    “In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.”
    • Also stated in: § Results · plain
      “Within each subgroup of genetic risk, a significant trend was observed toward decreased coronaryartery calcification among participants who were more adherent to a healthy lifestyle (Fig. 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    Among people at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle, with a hazard ratio of 0.54 (95% CI, 0.47 to 0.63).

    “Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63).”
    • Also stated in: § Results · plain
      “Adherence to a favorable lifestyle, as compared with an unfavorable lifestyle, was associated with a 45% lower relative risk among participants at low genetic risk, a 47% lower relative risk among those at intermediate genetic risk, and a 46% lower relative risk (hazard ratio, 0.54; 95% CI, 0.47 to 0.63) among those at high genetic risk.”
    Quote in the paperSubstantial claim
  • Findingown data

    A favorable lifestyle, defined as at least three of four healthy factors, was associated with a substantially lower risk of coronary events than an unfavorable lifestyle, defined as no or one factor, regardless of genetic risk category.

    “A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category.”
    • Also stated in: § Discussion · plain
      “However, within any genetic risk category, adherence to a healthy lifestyle was associated with a significantly decreased risk of both clinical coronary events and subclinical burden of coronary artery disease.”
    Quote in the paperSubstantial claim
  • Findingown data

    Across three cohorts, people in the top quintile of a polygenic score had a 91% higher relative risk of incident coronary events than those in the bottom quintile, with a hazard ratio of 1.91 (95% CI, 1.75 to 2.09).

    “The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09).”
    • Also stated in: § Results · plain
      “Across all three cohorts, the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk (hazard ratio, 1.91; 95% CI, 1.75 to 2.09).”
    Quote in the paperSubstantial claim
  • Findingown data

    Similar patterns were observed after excluding coronary revascularization from the composite end point.

    “Similar patterns were noted after the exclusion of coronary revascularization from the composite end point (Fig. S4 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    Across four studies with 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease.

    “Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease.”
    • Also stated in: § Discussion · hedged
      “First, our data indicate that inherited DNA variation and lifestyle factors contribute independently to a susceptibility to coronary artery disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the three prospective cohorts, among people at high genetic risk, the standardized 10-year incidence of coronary events was lower with a favorable lifestyle than with an unfavorable lifestyle: 5.1% vs 10.7% in ARIC, 2.0% vs 4.6% in WGHS, and 5.3% vs 8.2% in MDCS.

    “This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS.”
    • Also stated in: § Results · plain
      “Among participants at high genetic risk, the standardized 10-year coronary event rates were 10.7% among those with an unfavorable lifestyle and 5.1% among those with a favorable lifestyle in the ARIC cohort, 4.6% and 2.0%, respectively, in the WGHS cohort, and 8.2% and 5.3% in the MDCS cohort (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Within any genetic risk category, adherence to a healthy lifestyle was associated with a significantly decreased risk of both clinical coronary events and subclinical burden of coronary artery disease.

    “However, within any genetic risk category, adherence to a healthy lifestyle was associated with a significantly decreased risk of both clinical coronary events and subclinical burden of coronary artery disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    High genetic risk was independent of healthy lifestyle behaviors and was associated with an increased risk of coronary events (hazard ratio, 1.91) and a substantially increased burden of coronary-artery calcification.

    “High genetic risk was independent of healthy lifestyle behaviors and was associated with an increased risk (hazard ratio, 1.91) of coronary events and a substantially increased burden of coronary-artery calcification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Participants with an unfavorable lifestyle had higher rates of baseline hypertension and diabetes, a higher body-mass index, and less favorable circulating lipid levels than those with a favorable lifestyle.

    “Participants with an unfavorable lifestyle had higher rates of baseline hypertension and diabetes, a higher body-mass index, and less favorable levels of circulating lipids than did those with a favorable lifestyle (Tables S12, S13, and S14 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Self-reported family history of coronary artery disease was an imperfect surrogate for genotype-defined risk, although its prevalence tended to be higher among people at high genetic risk than among those at low genetic risk.

    “A family history of coronary artery disease was an imperfect surrogate for genotype-defined risk, although the prevalence of such a self-reported family history tended to be higher among participants at high genetic risk than among those at low genetic risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In each prospective cohort, people at high genetic risk had significantly higher risk of coronary events than those at low genetic risk, with adjusted hazard ratios of 1.75 in ARIC, 1.94 in WGHS, and 1.98 in MDCS.

    “A risk gradient was noted across quintiles of genetic risk such that the participants at high genetic risk (i.e., in the top quintile of the polygenic scores) were at significantly higher risk of coronary events than those at low genetic risk (i.e., in the lowest quintile)”
    • Also stated in: § Results · plain
      “with adjusted hazard ratios of 1.75 (95% confidence interval [CI], 1.46 to 2.10) in the ARIC cohort, 1.94 (95% CI, 1.58 to 2.39) in the WGHS cohort, and 1.98 (95% CI, 1.76 to 2.23) in the MDCS cohort”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the BioImage Study, both genetic and lifestyle factors were associated with coronary-artery calcification.

    “A cross-sectional analysis of 4260 of 4301 white participants with available data from the BioImage Study showed that both genetic and lifestyle factors were associated with coronaryartery calcification (stratified according to the baseline characteristics in Tables S16 and S17 in the Supplementary Appendix).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among people at low genetic risk, standardized 10-year coronary event rates were 5.8% for unfavorable lifestyle and 3.1% for favorable in ARIC, 1.8% and 1.2% in WGHS, and 4.7% and 2.6% in MDCS.

    “Among participants at low genetic risk, standardized 10-year coronary event rates were 5.8% among those with an unfavorable lifestyle and 3.1% among those with a favorable lifestyle in the ARIC cohort, 1.8% and 1.2%, respectively, in the WGHS cohort, and 4.7% and 2.6% in the MDCS cohort.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genomewide association analyses since 2007 have identified more than 50 independent loci associated with coronary artery disease risk.

    “Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease.7–15”
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    • cites [14] The CARDIoGRAMplusC4D Consortium, 2013, Nat Genet source

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    • cites [15] source

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  • May combine two claims.

    Premisecitation

    Genetic factors and lifestyle factors both contribute to an individual's risk of coronary artery disease.

    “Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease.”
    • Also stated in: § CONCLUSIONS · plain
      “Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide.1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When aggregated into a polygenic risk score, these risk alleles predict incident coronary events and give a continuous quantitative measure of genetic susceptibility.

    “These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility.16–24”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [16] source

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    • cites [24] Abraham G, Eur Heart J

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    WGHS analyses were adjusted for initial trial randomization to aspirin versus placebo and vitamin E versus placebo.

    “In addition, WGHS analyses were adjusted for initial trial randomization to aspirin versus placebo and vitamin E versus placebo.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The genetic substructure of the population was assessed by calculating the principal components of ancestry.

    “The genetic substructure of the population was assessed by calculating the principal components of ancestry.37”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] source

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  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Primary analyses included adjustment for age, sex, self-reported education level, and the first five principal components of ancestry (unavailable in MDCS).

    “The primary analyses included adjustment for age, sex, self-reported education level, and the first five principal components of ancestry (unavailable in MDCS).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Investigators in each cohort used slightly different methods to assess lifestyle at baseline.

    “Second, investigators in each cohort used slightly different methods to assess lifestyle at baseline.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    End-point adjudication was performed by a committee review of medical records within each cohort.

    “End-point adjudication was performed by a committee review of medical records within each cohort.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    Behavioral changes before or after ascertainment or competing risks of other illnesses may have had an effect on risk estimates.

    “Behavioral changes before or after ascertainment or competing risks of other illnesses may have had an effect on risk estimates.”
    Quote in the paperNot a substantial claim
18 of 18

  • The paper relies on this without support.

    The degree to which a healthy lifestyle can offset elevated genetic risk is not known.

    “The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Existing findings demonstrate a large reduction in prediction utility in non-European populations.

    “Those existing findings indeed demonstrate a large reduction in prediction utility in non-European populations11,”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [11]

    The Results (page unavailable) report similar findings among black and white participants in the ARIC cohort, rather than a large reduction in non-European populations. The Discussion (page unavailable) says the risk score was associated with coronary events among black participants, while cautioning that generalizability needs further testing; it does not report a comparative measure of prediction utility. (LLM, conf=0.79)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • A set of 40 variants predicts TG levels in the population of the European part of Russia.

    “The weighted polygenic risk score (PRS) was calculated using the β-coefficients from the original article, which previously demonstrated significant associations with TG levels (40 variants predicting TG levels [67]) in the population of the European part of Russia.”

    From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [67]

    The Methods (Polygenic Risk Score; page unavailable) describe a score based on up to 50 variants associated with coronary artery disease, not 40 variants predicting triglyceride (TG) levels. The Methods (Study Populations; page unavailable) identify the study cohorts but no population in European Russia. The paper therefore describes a different score and outcome from those attributed to it. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • PRS are many-fold more accurate in European ancestry individuals than in others, and this disparity is the major ethical and scientific challenge surrounding clinical implementation.

    “However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [11]

    The Results (page not provided) note a paucity of well-validated genetic loci in black populations, and the Discussion (page not provided) calls for testing the score in more diverse populations. But the paper reports similar findings among black and white ARIC participants; it does not show that scores are many-fold more accurate in people of European ancestry or identify that disparity as the major ethical and scientific challenge to clinical implementation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The scientific basis of the imbalance in PRS accuracy has been demonstrated theoretically, in simulations, and empirically across many traits and diseases.

    “The scientific basis of this imbalance has been demonstrated theoretically, in simulations, and empirically across many traits and diseases11–22.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [11]

    The Methods (Polygenic Risk Score; page unavailable) describe a score for coronary artery disease, and the Results (page unavailable) report similar findings among Black and white participants in one cohort. Searches for ancestry-related differences in PRS accuracy found no passage demonstrating the claimed scientific basis theoretically, in simulations, or empirically across many traits and diseases. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • High polygenic risk for CAD may be offset by adherence to a healthy lifestyle or cholesterol-lowering statin therapy.

    “For example, we previously showed that a high polygenic risk for CAD may be offset by either of two interventions: adherence to a healthy lifestyle or cholesterol-lowering therapy with statin medications.19–21”

    From Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations (2018) · cites this paper as [19]

Cites

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Research works printed but not linked: 1

  1. Abraham G, Eur Heart J

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Related

Authors
Khera, A. V., Emdin, C. A., Drake, I., Natarajan, P., Bick, A. G., Cook, N. R., Chasman, D. I., Baber, U., Mehran, R., Rader, D. J., Fuster, V., Boerwinkle, E., Melander, O., Orho-Melander, M., Ridker, P. M., & Kathiresan, S.
Affiliations
Broad Institute (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-12-15
Volume
375
Issue
24
Pages
2349-2358
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1605086
PMC
PMC5338864
OpenAlex
W2549881333
Semantic Scholar
6914fe5d2747eff7681845d6f4fa23f8ec76ac8a
Cited by
1,460
References
39
Citations by year
2026: 119 · 2025: 136 · 2024: 164 · 2023: 218 · 2022: 156 · 2021: 142 · 2020: 136 · 2019: 155 · 2018: 122 · 2017: 102 · 2016: 9
FWCI
104.37
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Novo Nordisk Fonden (NNF16OC0021370, NNF13OC0005339, NNF14OC0011049, NNF15OC0016320)
  • National Institutes of Health (KL2TR001100)
  • National Heart, Lung, and Blood Institute (R01HL127564, T32HL007208)
  • National Human Genome Research Institute (UM1HG008895)
  • National Cancer Institute (UM1CA182913)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
Keywords
coronary artery disease, polygenic risk score, genetic risk, healthy lifestyle, lifestyle modification, coronary events, coronary artery calcification, smoking, obesity, physical activity, diet, DNA polymorphism, gene-environment interaction, cardiovascular risk factors, Atherosclerosis Risk in Communities Study, Malmö Diet and Cancer Study
MeSH terms
Healthy Lifestyle, Aged, Coronary Disease, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Patient Compliance, Polymorphism, Genetic, Risk, Cohort Studies, Incidence, Genetic Predisposition to Disease, Multifactorial Inheritance

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