Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke
Open accessAbstract
Background and Purpose—: Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms together as an AF genetic risk score (AF-GRS) can improve prediction of one’s risk for AF. Methods—: In 27 471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 single nucleotide polymorphisms that had been previously shown to be associated with AF at genome-wide significance. Results—: During follow-up, 2160 participants experienced a first AF event and 1495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (hazard ratio, 2.00; 95% confidence interval, 1.73–2.31; P =2.7×10 –21 ) and ischemic stroke (hazard ratio, 1.23; 95% confidence interval, 1.04–1.46; P =0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification ( P <0.0001 for both). Conclusions—: An AF-GRS can identify 20% of individuals who are at ≈2-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.
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Written from the paper’s full text.
TL;DR
A 12-SNP atrial fibrillation genetic risk score (AF-GRS) was associated with incident AF and ischemic stroke in a large Swedish prospective cohort. The top AF-GRS quintile had about two-fold higher AF risk and 23% higher ischemic stroke risk than the bottom quintile.
Key findings
- Among 27,471 Malmö Diet and Cancer Study participants, 2,160 had incident AF and 1,495 had incident ischemic stroke over median follow-up of 14.4 and 14.5 years, respectively.
- Top vs bottom AF-GRS quintile: incident AF HR = 2.00 (95% CI 1.73–2.31; P=2.7×10−21); incident ischemic stroke HR = 1.23 (95% CI 1.04–1.46; P=0.015 in Results; abstract reports P=0.02).
- Adding AF-GRS to established AF risk factors modestly improved discrimination (c-statistic 0.735 to 0.738; P<0.0001) and reclassification (continuous NRI = 0.225; 95% CI 0.187–0.323; P<0.0001).
- For likely cardioembolic stroke, top vs bottom AF-GRS quintile HR = 1.81 (95% CI 1.20–2.73; P=0.005; Ptrend=0.009); adding AF-GRS to CHADS2 improved reclassification (continuous NRI = 0.166; 95% CI 0.0175–0.315; P=0.03).
Methods
- Prospective, community-based cohort: Malmö Diet and Cancer Study, participants enrolled 1991–1996; 27,471 included after exclusions for missing/poor DNA, prevalent AF, and loss to follow-up.
- AF-GRS was a weighted sum of 12 SNPs previously associated with AF at genome-wide significance, using published minor-allele risk estimates as weights.
- Cox proportional hazards models adjusted for age, sex, BMI, systolic and diastolic blood pressure, antihypertensive use, current smoking, diabetes, coronary events, and heart failure; outcomes ascertained from Swedish registers, with AF validation reported at 94% and ischemic stroke validated in the Malmö stroke registry.
Limitations
- Stated: the cohort was Swedish middle-aged to elderly individuals, so generalizability to other ethnicities or age groups is uncertain; stroke subtype information was insufficient for validated cardioembolic stroke; the SNP panel focused on AF loci and omitted SNPs for AF risk factors such as blood pressure or BMI; family history of AF was not routinely available; AF incidence may be underestimated because ICD codes came from hospitalized participants and asymptomatic AF is often undiagnosed.
- Evident: this is an observational cohort, so the clinical benefit of targeting diagnostic or therapeutic interventions to high AF-GRS individuals was not tested.
- Evident: AF-GRS weights were derived from external published studies rather than estimated solely within this cohort.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
0 of 21 cited sources checked · 0 supported · 0 flagged
- Findingown data
Participants in the top AF-GRS quintile had a two-fold greater risk of incident AF compared with those in the bottom quintile (HR = 2.00; 95%CI 1.73 to 2.31; P=2.7×10−21).
“Participants in the top AF-GRS quintile were at increased risk for incident AF (HR = 2.00; 95%CI = 1.73 to 2.31; P=2.7×10−21)”
- Also stated in: § A multi-locus AF-GRS and risk for incident AF · plain
“those in the top quintile of AF-GRS had a two-fold greater risk of incident AF compared with those at the bottom quintile (HR = 2.00; 95%CI 1.73 to 2.31, P=2.7×10−21)”
Quote in the paperSubstantial claim - Also stated in: § A multi-locus AF-GRS and risk for incident AF · plain
- Findingown data
The AF-GRS comprising 12 SNPs is associated with incident AF after adjustment for established AF risk factors.
“The AF-GRS was associated with incident AF (Table 3, Ptrend =1.8×10−28) after adjusting for age, sex, BMI, systolic and diastolic blood pressure, use of antihypertensive medication, smoking, diabetes, coronary events, and heart failure”
- Also stated in: § Discussion · plain
“We found that an AF-GRS comprising 12 SNPs was associated with incident AF and ischemic stroke, even after accounting for non-genetic risk factors including age and hypertension.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Participants in the top AF-GRS quintile had about 23% greater risk of ischemic stroke compared with those in the bottom quintile (HR = 1.23; 95%CI 1.04 to 1.46; P=0.015).
“Those in the top quintile of the AF-GRS, had about 23% greater risk of ischemic stroke compared with those in the bottom quintile (HR = 1.23; 95%CI 1.04 to 1.46, P=0.015).”
- Also stated in: § Results · plain
“and ischemic stroke (HR = 1.23; 95%CI = 1.04 to 1.46; P=0.02)”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
The AF-GRS is associated with incident ischemic stroke after adjustment for established AF risk factors.
“The AF-GRS was associated with incident ischemic stroke (Table 3, Ptrend=0.02) after adjusting for age, sex, BMI, systolic and diastolic blood pressure, use of antihypertensive medication, smoking, diabetes, coronary events, and heart failure”
- Also stated in: § Discussion · plain
“We found that an AF-GRS comprising 12 SNPs was associated with incident AF and ischemic stroke, even after accounting for non-genetic risk factors including age and hypertension.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Addition of the AF-GRS to established AF risk factors modestly improved discrimination (c-statistic increased from 0.735 to 0.738; P<0.0001).
“The c-statistic for the established risk factors model was 0.735, and increased to 0.738 (P<0.0001) after the addition of the AF-GRS to the model.”
- Also stated in: § Results · plain
“Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
The association of AF-GRS with overall ischemic stroke was not as strong as that of hypertension.
“an association with overall ischemic stroke that was not as strong as that of hypertension (Supplemental Table IV)”
Quote in the paperNot a substantial claim - Findingown data
The association of AF-GRS with likely cardioembolic stroke remained similar when adjusted for CHADS2 score instead of established risk factors (top vs bottom quintile HR = 1.74; 95%CI 1.15 to 2.62; P=0.009).
“This association remained similar when we adjusted the association of the AF-GRS with likely cardioembolic stroke events for the CHADS2 score instead of established risk factors: for the top vs. bottom quintile, the HR was 1.74 (95%CI 1.15 to 2.62), P=0.009, Ptrend=0.014.”
Quote in the paperNot a substantial claim - Findingown data
In the MDC study population, a model including 10 SNPs provides as much information about genetic risk for AF as a model including all 12 SNPs according to forward and backward model selection algorithms.
“In this study population, a model that includes these 10 SNPs provide as much information about genetic risk for AF as a model that includes all 12 SNPs according to both forward and backward model selection algorithms.”
Quote in the paperNot a substantial claim - Findingown data
Addition of the AF-GRS to established AF risk factors improved reclassification (continuous NRI = 0.225; 95%CI 0.187 to 0.323; P<0.0001).
“we also assessed continuous NRI and found that adding the AFGRS to the established risk factors model improved reclassification (continuous NRI =0.225; (95%CI 0.187 to 0.323, P<0.0001).”
- Also stated in: § Results · plain
“Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
The probability of a first AF event, assessed from the cumulative event rate after 15-year follow-up, increased smoothly with increased AF-GRS.
“The probability of a first AF event, assessed from the cumulative event rate after 15 year follow-up increased smoothly with increased AF-GRS (Supplemental Figure).”
Quote in the paperSubstantial claim - Findingown data
The magnitude of effect conferred by individual SNPs in the MDC study was consistent with the original discovery reports (correlation coefficient = 0.98; P=1.2×10−8).
“The magnitude of effect conferred by individual SNPs in MDC was consistent with the original discovery reports (correlation coefficient = 0.98, P=1.2×10−8, Supplemental Figure).”
Quote in the paperNot a substantial claim - Findingown data
The rate of likely cardioembolic stroke among those with a low AF-GRS and hypertension was similar to that among those with a high AF-GRS but without hypertension.
“In contrast to the results with overall ischemic stroke, the rate of likely cardioembolic stroke among those with a low AF-GRS (1st quartile) and hypertension was similar to that among those with a high AF-GRS (4th quartile) but without hypertension: 0.19 and 0.20 per 1000 person years for young individuals and 1.04 and 1.22 per 1000 person-years for old individuals (Supplemental Table IV).”
Quote in the paperNot a substantial claim - Findingown data
The risk per quintile increase in AF-GRS was 1.20 (95%CI 1.16 to 1.24).
“The risk per quintile increase in AF-GRS was 1.20 (95 %CI 1.16 to 1.24), a magnitude of risk that is comparable to the dichotomized smoking status (HR = 1.26; 95%CI, 1.13 to 1.40) or dichotomized diabetes (HR = 1.32; 95%CI, 1.11 to 1.58) in this study (Supplemental Table).”
Quote in the paperSubstantial claim - Findingown data
For 10 of the 12 SNPs, the association with incident AF exceeded nominal significance in the MDC study (P<0.05).
“For 10 of these SNPs, the association exceeded nominal significance in the MDC study (P<0.05, Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Adding the AF-GRS to CHADS2 score improved reclassification for likely cardioembolic stroke (continuous NRI = 0.166; 95%CI 0.0175 to 0.315; P=0.03).
“The continuous NRI indicated that adding the AF-GRS to CHADS2 score improved reclassification (continuous NRI = 0.166 (95%CI 0.0175 to 0.315, P=0.03)).”
Quote in the paperSubstantial claim - Findingown data
For likely cardioembolic stroke, the hazard ratio for those in the top compared with the bottom AF-GRS quintile was 1.81 (95%CI 1.20 to 2.73; P=0.005; Ptrend=0.009).
“The hazard ratio for those in the top compared with the bottom quintile was 1.81 (95%CI, 1.20 to 2.73, P=0.005, Ptrend=0.009, Supplemental Table V).”
Quote in the paperSubstantial claim - Findingown data
Having a high AF-GRS without hypertension confers AF risk equivalent to having hypertension with a low AF-GRS, in both younger and older individuals.
“This rate of AF was similar to rate among those with a high AF-GRS (Q5) but without hypertension (2.37 per 1000 person-years, 95%CI, 1.74 to 3.15).”
- Also stated in: § A multi-locus AF-GRS and risk for incident AF · plain
“This equivalent magnitude of the AF-GRS and hypertension as AF risk factors was also observed among individuals above the median age.”
- Also stated in: § Discussion · hedged
“having a high AF-GRS seems to confer risk equivalent to having hypertension: those with a high AF-GRS but no hypertension had a rate of future AF events similar to the rate of those with a low AF-GRS but with hypertension.”
Quote in the paperSubstantial claim - Also stated in: § A multi-locus AF-GRS and risk for incident AF · plain
- Findingown data
The AF-GRS is associated with likely cardioembolic stroke events after adjustment for established risk factors.
“We found that the AF-GRS was associated with these likely cardioembolic stroke events after adjustment for established risk factors (age, sex, BMI, systolic and diastolic blood pressure, use of antihypertensive medication, smoking, diabetes, coronary events, and heart failure).”
Quote in the paperSubstantial claim - Findingown data
For all 12 SNPs, the effect size estimates for incident AF in the MDC study were in the same direction as those reported in the literature.
“We tested the association of each SNP with incident AF and for all 12 SNPs, the effect size estimates were in the same direction as those reported in the literature.”
Quote in the paperNot a substantial claim - Study design and conductown data
The study did not have sufficient information about stroke subtypes to provide a risk estimate for validated cardioembolic stroke.
“In addition, although we could provide an estimate of the effect of the AF-GRS on risk for overall ischemic stroke, we did not have sufficient information about stroke subtypes to provide a risk estimate for validated cardioembolic stroke, a stroke subtype that is most strongly associated with AF.”
Quote in the paperNot a substantial claim - Study design and conductcitation
Incident AF has been well validated in this study.
“Although incident AF have been well validated in this study,28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Smith JG Platonov PG Hedblad B Engström G Melander O Atrial fibrillation in the Malmö Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol 2010 25 95 102 19936945 source
Not checked in the free run.
- Interpretationreasoning
The generalizability of the AF-GRS findings to other ethnicities or age groups is uncertain.
“The study population is Swedish middle-aged to elderly individuals; hence, the generalizability to other ethnicities or age groups is uncertain.”
Quote in the paperNot a substantial claim - Premisecitation
The 12 SNPs in the AF-GRS are all the SNPs that have been reported to be associated with AF at a genome-wide significance level (P<5×10−8).
“These are all the SNPs that have been reported to be associated with AF at a genome-wide significance level (P<5×10−8), including 4 SNPs at PITX2 locus.18-23”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [18] Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007 448 353 357 17603472 source
Not checked in the free run.
- cites [19] Lubitz SA Sinner MF Lunetta KL Makino S Pfeufer A Rahman R Independent Susceptibility Markers for atrial fibrillation on Chromosome 4q25. Circulation 2010 122 976 984 20733104 PMC2978508 source
Not checked in the free run.
- cites [20] Benjamin EJ Rice KM Arking DE Pfeufer A van Noord C Smith AV Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009 41 879 881 19597492 PMC2761746 source
Not checked in the free run.
- cites [21] Gudbjartsson DF Holm H Gretarsdottir S Thorleifsson G Walters GB Thorgeirsson G A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009 41 876 878 19597491 PMC2740741 source
Not checked in the free run.
- cites [22] Ellinor PT Lunetta KL Glazer NL Pfeufer A Alonso A Chung MK Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010 42 240 244 20173747 PMC2871387 source
Not checked in the free run.
- cites [23] Ellinor PT Lunetta KL Albert CM Glazer NL Ritchie MD Smith AV Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012 44 670 675 22544366 PMC3366038 source
Not checked in the free run.
- Interpretationown data
The associations of SNPs with AF in the discovery GWAS seem to generalize to the community-based, prospective setting.
“First, the associations of SNPs with AF in the discovery GWAS seem to generalize to the community-based, prospective setting.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The incidence rate of AF might have been underestimated because ICD code information was derived from hospitalized participants and did not include AF diagnosis by general practitioners.
“Although incident AF have been well validated in this study,28 the incidence rate might have been underestimated because ICD code information was derived from hospitalized participants and did not include AF diagnosis by general practitioners.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Smith JG Platonov PG Hedblad B Engström G Melander O Atrial fibrillation in the Malmö Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol 2010 25 95 102 19936945 source
Not checked in the free run.
- Study design and conductcitation
The definition of atrial fibrillation used in the study had a 94% validation rate from ECG records.
“This definition of atrial fibrillation was shown to have a 94% validation rate from ECG records.28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Smith JG Platonov PG Hedblad B Engström G Melander O Atrial fibrillation in the Malmö Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol 2010 25 95 102 19936945 source
Not checked in the free run.
- Premisecitation
The AF-GRS comprises 12 SNPs that had been previously shown to be associated with AF at genome-wide significance.
“The AF-GRS comprised 12 SNPs that had been previously shown to be associated with AF at genome-wide significance.”
- Also stated in: § Modeling of genetic risk score · plain
“The AF-GRS includes 12 SNPs (Table 1). These are all the SNPs that have been reported to be associated with AF at a genome-wide significance level (P<5×10−8), including 4 SNPs at PITX2 locus.18-23”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [18] Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007 448 353 357 17603472 source
Not checked in the free run.
- cites [19] Lubitz SA Sinner MF Lunetta KL Makino S Pfeufer A Rahman R Independent Susceptibility Markers for atrial fibrillation on Chromosome 4q25. Circulation 2010 122 976 984 20733104 PMC2978508 source
Not checked in the free run.
- cites [20] Benjamin EJ Rice KM Arking DE Pfeufer A van Noord C Smith AV Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009 41 879 881 19597492 PMC2761746 source
Not checked in the free run.
- cites [21] Gudbjartsson DF Holm H Gretarsdottir S Thorleifsson G Walters GB Thorgeirsson G A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009 41 876 878 19597491 PMC2740741 source
Not checked in the free run.
- cites [22] Ellinor PT Lunetta KL Glazer NL Pfeufer A Alonso A Chung MK Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010 42 240 244 20173747 PMC2871387 source
Not checked in the free run.
- cites [23] Ellinor PT Lunetta KL Albert CM Glazer NL Ritchie MD Smith AV Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012 44 670 675 22544366 PMC3366038 source
Not checked in the free run.
- Also stated in: § Modeling of genetic risk score · plain
- Premisecitation
In the Women's Genome Health Study, those in the top quintile of AF-GRS had a greater than two-fold increased risk for incident AF in a model adjusted for non-genetic factors.
“In the WGHS analysis, those in the top quintile of AF-GRS had a greater than two-fold increased risk for incident AF in a model that adjusted for non-genetic factors.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Everett BM Cook NR Conen D Chasman DI Ridker PM Albert CM Novel genetic markers improve measures of atrial fibrillation risk prediction. Eur Heart J 2013 34 2243 2251 23444395 PMC3730133 source
Not checked in the free run.
- Study design and conductcitation
All ischemic stroke events that occurred within the catchment area of Malmö hospitals (92% of all events) were validated within the stroke registry in Malmö (STROMA).
“All ischemic stroke events that occurred within the catchment area of Malmö hospitals (92% of all events) were validated within the stroke registry in Malmö (STROMA),29 in which original medical records were examined including computed tomography and other imaging modalities, where available.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Jerntorp P Berglund G Stroke registry in Malmö, Sweden. Stroke 1992 23 357 361 1542896 source
Not checked in the free run.
- May combine two claims. 5
- Classified as probably not a substantial claim. 7
May combine two claims.
Interpretationown dataAn AF-GRS can identify 20% of individuals who are at approximately two-fold increased risk for incident AF and at 23% increased risk for ischemic stroke.
“An AF-GRS can identify 20% of individuals who are at approximately two-fold increased risk for incident AF and at 23% increased risk for ischemic stroke.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitationAsymptomatic AF is often undiagnosed and is likely underdiagnosed in this study.
“Asymptomatic AF is often undiagnosed41 and is likely underdiagnosed in this study as well.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Charitos EI Pürerfellner H Glotzer TV Ziegler PD Clinical Classifications of Atrial Fibrillation Poorly Reflect its Temporal Persistence: Insights From 1195 Patients Continuously Monitored with Implantable Devices. J Am Coll Cardiol 2014 63 2840 2848 24814497 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe SNP panel focused on genetic loci thought to be directly associated with AF and did not include SNPs associated with AF risk factors such as blood pressure or BMI.
“Also our SNP panel focused on genetic loci thought to be directly associated with AF and did not include SNPs associated with AF risk factors such as blood pressure or BMI.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationnone givenThe clinical value of using genetic markers to identify asymptomatic individuals at high risk for AF depends on the availability of an effective intervention that can alter health outcomes.
“The clinical value of using genetic markers to identify a subset of asymptomatic individuals at high risk for AF will depend on the availability of an effective intervention (diagnostic or therapeutic) that, when implemented in those at a high genetic risk, can alter health outcomes.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAn AF-GRS based on 12 SNPs can identify a subset of the population at more than two-fold increased risk for AF and ~25% increased risk for ischemic stroke.
“In conclusion, an AF-GRS based on 12 SNPs can identify a subset of the population at more than two-fold increased risk for AF and ~25% increased risk for ischemic stroke.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationInformation about family history of AF was not routinely available for this cohort.
“And information about family history of AF was not routinely available for this cohort.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Lubitz SA Yin X Fontes JD Magnani JW Rienstra M Pai M Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA 2010 304 2263 2269 21076174 PMC3073054 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenTo obtain unbiased estimates of the c-statistics, the data were randomly split into equal sized training and test sets.
“To obtain unbiased estimates of the c-statistics, the data were randomly split into equal sized training and test sets.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe association analyses used Cox models that adjusted for established AF risk factors.
“we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke.”
- Also stated in: § Statistical Analysis · plain
“The association of each SNP with incident AF was assessed from Cox proportional hazards regression models that were adjusted for age, sex, BMI, systolic and diastolic blood pressure, use of antihypertensive medications, current smoking, prevalent diabetes, coronary events, and heart failure.”
Quote in the paperSubstantial claim- Also stated in: § Statistical Analysis · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNone of the 12 SNPs deviated from Hardy-Weinberg equilibrium assumptions (P>0.1).
“None of the 12 SNPs deviated from Hardy-Weinberg equilibrium assumptions (P>0.1).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLubitz et al. found that an AF-GRS comprising 12 SNPs was associated with AF in populations of European descent and in a case-control study of a Japanese population.
“They found that this AF-GRS was associated with AF in populations of European descent as well as in a case-control study of a Japanese population, thus providing support for the notion that an AF-GRS could be used in diverse ethnic settings.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Lubitz SA Lunetta KL Lin H Arking DE Trompet S Li G Novel genetic markers associate with atrial fibrillation risk in europeans and Japanese. J Am Coll Cardiol 2014 63 1200 1210 24486271 PMC4009240 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationcitationThe association of an AF-GRS in a Japanese population could indicate that an AF-GRS would be useful in other populations.
“However, the association of an AF-GRS in a Japanese population could indicate that an AF-GRS would be useful in other populations.37”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Lubitz SA Lunetta KL Lin H Arking DE Trompet S Li G Novel genetic markers associate with atrial fibrillation risk in europeans and Japanese. J Am Coll Cardiol 2014 63 1200 1210 24486271 PMC4009240 source
Not checked in the free run.
The paper relies on this without support.
Genetic biomarkers are fixed throughout a life course and assayable early in life.
“Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need.”
The paper relies on this without support.
There is a clinical need for biomarkers to identify individuals at higher risk for AF.
“Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF.”
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?
Several AF risk variants are also associated with cardioembolic or ischaemic stroke, possibly due to silent AF.
“Several of the AF risk variants are also associated with cardioembolic or ischaemic stroke, possibly due to silent AF (see section 4.1).62,65,66”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [66]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Reported NRI disagrees with the stated reclassification percentages
MajorThe stated percentages imply an event contribution of 54% − 46% = 8% and a nonevent contribution of 59% − 41% = 18%, for a continuous NRI of 0.26, not 0.225. Rounding the percentages to whole numbers cannot account for the difference.
“continuous NRI =0.225; (95%CI 0.187 to 0.323, P<0.0001)”
“Among those with incident events, 54% were reclassified to higher risk and 46% to lower risk, while among those without events, 59% were reclassified to lower risk and 41% were reclassified to higher risk.”
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2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
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Copeptin predicts coronary artery disease cardiovascular and total mortality
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- Authors
- Tada, H., Shiffman, D., Smith, J. G., Sjögren, M., Lubitz, S. A., Ellinor, P. T., Louie, J. Z., Catanese, J. J., Engström, G., Devlin, J. J., Kathiresan, S., & Melander, O.
- Affiliations
- Broad Institute (US)
- ORCID
- Venue
- Stroke
- Published
- 2014-10
- Volume
- 45
- Issue
- 10
- Pages
- 2856-2862
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- PMC
- PMC4346099
- OpenAlex
- W2168489193
- Semantic Scholar
- d74b61a72ed6a0a141e4d1e4f2fa1d679b5618be
- Cited by
- 110
- References
- 41
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 14 · 2016: 22 · 2015: 11 · 2014: 2
- FWCI
- 11.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF14OC0009819, NNF13OC0005339)
- National Heart, Lung, and Blood Institute (K23HL114724)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- atrial fibrillation, polygenic risk score, single nucleotide polymorphisms, ischemic stroke, genetic biomarkers, risk prediction, risk reclassification, Malmö Diet and Cancer Study, genome-wide association study
- MeSH terms
- Aged, Atrial Fibrillation, Female, Genotype, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Cohort Studies, Proportional Hazards Models, Genetic Predisposition to Disease, Stroke, Polymorphism, Single Nucleotide, Multiplex Polymerase Chain Reaction
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