Rare Genetic Variants in LDLR , APOB , and PCSK9 Are Associated With Aortic Stenosis
Open accessAbstract
BACKGROUND: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism ( LDLR , APOB , and PCSK9 ). METHODS: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us). RESULTS: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39–5.20]; P =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26–6.32]; P =4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: –32.3 mg/dL; P <5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31–0.75]; P =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30–0.97]; P =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P =1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (–6.9 cm/s; P =0.022). CONCLUSIONS: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.
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- Findingown data
The associations with peak aortic valve velocity were consistent for rare protein-disrupting variants in LDLR and PCSK9.
“Further, we observed consistent associations with peak velocity as a quantitative measure of aortic valve function for rare protein-disrupting variants in LDLR and PCSK9.”
Quote in the paperNot a substantial claim - Findingown data
Among 57,371 UKB imaging substudy participants, peak velocity across the aortic valve was greater in carriers of protein-disrupting LDLR variants (+12.2 cm/s; P=1.6e-5).
“Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P=1.6e-5)”
Quote in the paperSubstantial claim - Findingown data
UKB participants without CAD history at enrollment who carried protein-truncating LDLR variants had a greater incidence of CAD (HR 3.96 [2.06-7.62]; P=3.7e-5).
“We observed an even greater incidence of CAD in 79 carriers of proteintruncating variants in LDLR without a history of CAD at study enrollment (HR, 3.96 [2.06-7.62];P=3.7e-5).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of LDLR truncating variants had LDL-C 49.24 mg/dL, or 34%, higher than noncarriers.
“LDL-C levels were 49.24 (42.49-55.99)mg/dL or 34% higher in carriers of LDLRtv”
Quote in the paperSubstantial claim - Findingown data
In UKB participants who underwent cardiac MRI, carriers of predicted protein-disrupting PCSK9 variants had lower peak aortic valve velocity than noncarriers, by 6.94 cm/s (95% CI 1.00-12.88 lower; P=0.022).
“Conversely, peak velocities across the aortic valve were lower in 67 carriers of predicted protein-disrupting variants in PCSK9 (-6.94 cm/s [-1.00 to -12.88]; P=0.022).”
Quote in the paperSubstantial claim
- Findingown data
In UKB, carriers of protein-disrupting LDLR variants had mean LDL-C 42.57 mg/dL, or 30%, higher than noncarriers.
“LDL-C values were on average 42.57(40.03-45.11)mg/dL or 30% higher in carriers of protein-disrupting variants in LDLR compared with noncarriers (P=4.4e-237)”
Quote in the paperSubstantial claim - Findingown data
In meta-analysis, carriers of LDLR protein-truncating variants had more than 9-fold odds of aortic stenosis (OR 9.29, 95% CI 4.37-19.80; P=7.0e-9; I2=0.00).
“carriers of which had >9-fold odds of AS compared with noncarriers (OR, 9.29 [4.37-19.80];P=7.0e-9;I 2 = 0.00).”
Quote in the paperSubstantial claim - Findingown data
UKB participants without CAD history at enrollment who carried protein-disrupting APOB or PCSK9 variants had a lower incidence of CAD (HR 0.73 [0.57-0.93]; P=0.01).
“Conversely, 2008 carriers of protein-disrupting variants in APOB or PCSK9 without a history of CAD at study enrollment had a lower incidence of CAD (HR, 0.73 [0.57-0.93];P=0.01).”
Quote in the paperNot a substantial claim - Findingown data
In UKB participants who underwent cardiac MRI, carriers of predicted protein-disrupting APOB variants did not show a significant difference in peak aortic valve velocity compared with noncarriers (-0.59 cm/s [95% CI -4.31 to 3.13]; P=0.76).
“We did not observe significant differences in peak velocities across the aortic valve in 171 carriers of predicted protein-disrupting variants in APOB (-0.59 cm/s [-4.31 to 3.13]; P=0.76).”
Quote in the paperNot a substantial claim - Findingown data
Among UKB noncarriers, 5430 (1.3%) had prevalent or incident aortic stenosis over a median follow-up of 13.6 years.
“Among 404 381 noncarriers, 5430 (1.3%) had either prevalent or incident AS during a median of 13.6 years (interquartile range, 12.8-14.3) of follow-up.”
Quote in the paperNot a substantial claim - Findingown data
In UKB, carriers of protein-disrupting APOB variants had mean LDL-C 34.07 mg/dL, or 24%, lower than noncarriers.
“34.07 (32.00-36.14)mg/dL or 24% lower in carriers of protein-disrupting variants in APOB (P=1.9e-228)”
Quote in the paperNot a substantial claim - Findingown data
UKB participants without AS history at enrollment who were heterozygous carriers of the common PCSK9 missense variant R46L had a lower incidence of AS (HR 0.77 [0.65-0.92]; P=0.0366).
“Consistent with the associations in rare variant carriers, we also observed a lower incidence of AS in 13 679 het- erozygous carriers of the common PCSK9 missense vari- ant R46L without a history of AS at study enrollment (HR, 0.77 [0.65-0.92]; P=0.0366; Figure S4; Table S14).”
Quote in the paperSubstantial claim - Findingown data
During a median 13.6 years of follow-up, UKB participants without CAD history at enrollment who carried protein-disrupting LDLR variants had a higher but not statistically significant incidence of CAD (HR 1.34 [0.95-1.88]; P=0.094).
“During a median of 13.6 years (interquartile range, 12.8-14.3) of follow-up based on hospital inpatient and death registry data, we observed a higher albeit not statistically significant incidence of CAD in 614 carriers of protein-disrupting variants in LDLR without a history of CAD at study enrollment (hazard ratio [HR], 1.34 [0.95-1.88];P=0.094; Table S13).”
Quote in the paperNot a substantial claim - Findingown data
In UKB after excluding participants with prevalent or incident coronary artery disease, carriers of protein-disrupting LDLR variants still had increased aortic stenosis risk (OR 2.56, 95% CI 1.34-4.88; P=0.0043).
“We still observed significantly increased risk of AS in 70 remaining carriers of protein-disrupting variants in LDLR (OR, 2.56 [1.34-4.88];P=0.0043)”
Quote in the paperSubstantial claim - Findingown data
In UKB, noncarriers had a mean LDL-C of 142.96 mg/dL.
“In UKB, noncarriers had mean LDL-C values of 142.96 (SD 33.19) mg/dL.”
Quote in the paperNot a substantial claim - Findingown data
UKB participants without AS history at enrollment who carried protein-disrupting LDLR variants had a higher incidence of AS (HR 3.44 [2.34-5.05]; P=3.5e-10).
“Similarly, 687 carriers of protein-disrupting variants in LDLR without a history of AS at study enrollment had a higher incidence of AS (HR, 3.44 [2.34-5.05];P=3.5e-10; Figure S3B; Figure 4; Table S14).”
Quote in the paperSubstantial claim - Findingown data
In meta-analysis of UKB and All of Us, carriers of protein-disrupting LDLR variants had increased aortic valve replacement risk (OR 3.78, 95% CI 2.26-6.32; P=4.1e-7; I2=0).
“the risk of AVR was increased in carriers of protein-disrupting variants in LDLR (OR, 3.78 [2.26-6.32];P=4.1e-7;I 2 =0; Figure S2; Table S9).”
Quote in the paperSubstantial claim - Findingown data
In UKB with additional adjustment for lipoprotein(a), carriers of protein-disrupting APOB or PCSK9 variants had reduced coronary artery disease risk (OR 0.44, 95% CI 0.21-0.82; P=6.7e-3).
“significantly reduced risk of CAD in carriers of protein-disrupting variants in APOB or PCSK9 (OR, 0.44 [0.21-0.82];P=6.7e-3; Table S8).”
Quote in the paperNot a substantial claim - Findingown data
UKB participants without AS history at enrollment who carried protein-truncating LDLR variants had an even greater incidence of AS (HR 11.28 [6.06-20.98]; P=2.0e-14).
“We observed an even greater incidence of AS in 98 carriers of proteintruncating variants in LDLR without a history of AS at study enrollment (HR, 11.28 [6.06-20.98];P=2.0e-14).”
Quote in the paperSubstantial claim - Findingown data
The associations between rare protein-disrupting variants in LDLR, APOB, and PCSK9 and AS risk remained consistent when the outcome was incident AS after enrollment and when AVR was used as a procedural outcome.
“These observations remained consistent when assessing incident AS risk after study enrollment and AVR as a procedural outcome.”
Quote in the paperSubstantial claim - Findingown data
UKB participants without AS history at enrollment who carried protein-disrupting APOB or PCSK9 variants had a lower incidence of AS (HR 0.57 [0.34-0.96]; P=0.034).
“Conversely, 2046 carriers of protein-disrupting variants in APOB or PCSK9 without a history of AS at study enrollment had a lower incidence of AS (HR, 0.57 [0.34-0.96];P=0.034; Figure 4; Figure S3B; Table S14).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of protein-disrupting variants in either APOB or PCSK9 had mean LDL-C 32.32 mg/dL, or 23%, lower than noncarriers.
“LDL-C levels were on average 32.32 (30.86-33.78)mg/dL or 23% lower in participants who carried protein-disrupting variants in either APOB or PCSK9 compared with noncarriers (P<5e-324).”
Quote in the paperSubstantial claim - Findingown data
In UKB participants who underwent cardiac MRI, carriers of predicted protein-disrupting LDLR variants had higher peak aortic valve velocity than noncarriers, by 12.23 cm/s (95% CI 6.67-17.79; P=1.6e-5).
“We observed greater peak velocities across the aortic valve in 76 carriers of predicted protein-disrupting variants in LDLR (+12.23 cm/s [6.67-17.79cm/s]; P=1.6e-5; Figure 3).”
Quote in the paperSubstantial claim - Findingown data
In UKB, heterozygous PCSK9 R46L carriers had LDL-C 13.74 mg/dL, or 10%, lower than noncarriers.
“The LDL-C values of 13 047 heterozygous R46L carriers in UKB were on average 13.74 (13.17-14.31)mg/dL or 10% lower compared with noncarriers (P<5e-324; Table S2; Fig- ure S1).”
Quote in the paperNot a substantial claim - Findingown data
In UKB, carriers of predicted damaging missense LDLR variants had LDL-C 41.40 mg/dL, or 29%, higher than noncarriers.
“values were on average 41.40 (38.67-44.13)mg/dL or 29% higher in carriers of predicted damaging missense variants in LDLR (P=1.2e-193)”
Quote in the paperSubstantial claim - Findingown data
Among UKB imaging substudy participants, peak velocity across the aortic valve was lower in carriers of protein-disrupting PCSK9 variants (-6.9 cm/s; P=0.022).
“lower in carriers of protein-disrupting variants in PCSK9 (-6.9 cm/s; P=0.022).”
Quote in the paperSubstantial claim - Findingown data
In All of Us, carriers of protein-disrupting LDLR variants had increased aortic stenosis risk (OR 3.25, 95% CI 1.37-7.71; P=0.0076).
“In All of Us, the risk of AS was similarly increased in carriers of protein-disrupting variants in LDLR (OR, 3.25 [1.37-7.71]; P=0.0076)”
Quote in the paperSubstantial claim - Findingown data
In All of Us, carriers of protein-disrupting APOB or PCSK9 variants had reduced aortic stenosis risk (OR 0.25, 95% CI 0.07-0.85; P=0.027).
“reduced in carriers of protein-disrupting variants in PCSK9 or APOB (OR, 0.25 [0.07-0.85]; P=0.027; Table S5).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of PCSK9 truncating variants had LDL-C 34.84 mg/dL, or 24%, lower than noncarriers.
“34.84 (31.91-37.77)mg/dL or 24% lower in carriers of PCSK9tv (P=4.1e-120; Figure 1A).”
Quote in the paperNot a substantial claim - Findingown data
In meta-analysis of UKB and All of Us, PCSK9 R46L was associated with reduced aortic stenosis risk (OR 0.77, 95% CI 0.66-0.89; P=3.5e-4; I2=0.00).
“The PCSK9 R46L variant was also associated with reduced risk of AS in a meta-analysis of 17 815 carriers from UKB and All of Us (OR, 0.77 [0.66-0.89]; P=3.5e-4; I 2 = 0.00; Table S5).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of APOB truncating variants had LDL-C 69.72 mg/dL, or 49%, lower than noncarriers.
“69.72 (66.45-72.99)mg/dL or 49% lower in carriers of APOBtv (P<5e-324)”
Quote in the paperNot a substantial claim - Findingnone given
Absolute differences in AS risk between genetic groups were greater at more advanced age.
“Absolute differences in the risk of AS between genetic groups were greater with more advanced age.”
Quote in the paperNot a substantial claim - Findingown data
In UKB, carriers of predicted damaging missense PCSK9 variants had LDL-C 27.00 mg/dL, or 19%, lower than noncarriers.
“27.00 (24.15-29.85)mg/dL or 19% lower (P=7.2e-77) in carriers of predicted damaging missense variants in PCSK9 (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of predicted damaging missense APOB variants had LDL-C 12.39 mg/dL, or 8.7%, lower than noncarriers.
“12.39 (9.77-15.01)mg/dL or 8.7% lower (P=1.9e-20) in carriers of predicted damaging missense variants in APOB”
Quote in the paperNot a substantial claim - Findingown data
In meta-analysis, carriers of protein-disrupting variants in APOB or PCSK9 had lower aortic stenosis risk (OR 0.49, 95% CI 0.32-0.75; P=0.0012; I2=0.25).
“the risk of AS was significantly lower compared with noncarriers (OR, 0.49 [0.32-0.75];P=0.0012;I 2 = 0.25).”
Quote in the paperSubstantial claim - Findingown data
In meta-analysis, carriers of protein-disrupting LDLR variants had increased aortic stenosis risk (OR 3.52, 95% CI 2.38-5.19; P=2.0e-10; I2=0.00).
“carriers of protein-disrupting variants in LDLR had an increased risk of AS (odds ratio [OR], 3.52 [2.38-5.19];P=2.0e-10;I 2 = 0.00; Figure 2; Table S3).”
Quote in the paperSubstantial claim - Findingown data
In UKB after excluding coronary artery disease, carriers of protein-disrupting APOB or PCSK9 variants had directionally concordant but not statistically significant reduced aortic stenosis risk (OR 0.67, 95% CI 0.39-1.15; P=0.15).
“directionally concordant, albeit not statistically significant, reductions in the risk of AS in 1941 remaining carriers of protein-disrupting variants in APOB or PCSK9 (OR, 0.67 [0.39-1.15];P=0.15; Table S7).”
Quote in the paperSubstantial claim - Findingown data
In meta-analysis, carriers of protein-disrupting APOB or PCSK9 variants had lower aortic valve replacement risk (OR 0.54, 95% CI 0.30-0.97; P=0.039; I2=0.47).
“the risk of AVR was lower in partic- ipants who carried predicted protein-disrupting variants in APOB or PCSK9 (OR, 0.54 [0.30-0.97]; P=0.039; I 2 = 0.47).”
Quote in the paperSubstantial claim - Findingown data
In UKB, there were 404,381 noncarriers of predicted truncating or damaging missense variants in these genes or the PCSK9 R46L variant.
“we also identified 404 381 participants (56.6±8.1 years; 54% women) who did not carry predicted truncating or damaging missense variants in these genes or the PCSK9 R46L missense variant (hereafter termed “noncarriers”; Table S1).”
Quote in the paperSubstantial claim - Findingown data
In UKB, carriers of protein-disrupting PCSK9 variants had mean LDL-C 30.79 mg/dL, or 22%, lower than noncarriers.
“30.79 (28.74-32.84)mg/dL or 22% lower in carriers of protein-disrupting variants in PCSK9 (P=2.0e-190;Table 2; Tables S1 and S2).”
Quote in the paperNot a substantial claim - Premisecitation
Randomized controlled trials of lipid-lowering therapy in the early 2000s failed to slow progression or improve outcomes in aortic stenosis.
“Several randomized controlled trials of lipid-lowering therapy were conducted in the early 2000s, and all failed to slow progression or improve outcomes in AS. [12][13][14]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12][13][14]
Not checked in the free run.
- Premisecitation
Patients with familial hypercholesterolemia have an increased risk of aortic stenosis.
“An increased risk of AS has been described in patients with familial hypercholesterolemia, 5,6”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Mendelian randomization studies of common genetic variants support a causal relationship between higher LDL-C and increased aortic stenosis risk.
“Mendelian randomization studies evaluating common genetic variants across the genome have supported a causal relationship between higher levels of LDL-C (low-density lipoprotein cholesterol) and increased AS risk.7,[9][10][11]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 7,[9][10][11]
Not checked in the free run.
- Premisecitation
Genome-wide association studies have found associations between aortic stenosis and genetic loci harboring genes encoding the low-density lipoprotein receptor and lipoprotein(a).
“genome-wide association studies have found associations between AS and genetic loci that harbor genes encoding the low-density lipoprotein receptor and Lp(a) (lipoprotein[a]).7,8”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
The clinical trials aimed to halt progression of established AS.
“All of the clinical trials aimed to halt the progression of established AS.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Three randomized controlled trials of lipid-lowering therapy to delay AS progression all reported no significant benefit.
“lipid-lowering therapy to delay progression of AS has been evaluated in 3 randomized controlled trials; however, all trials reported no significant benefit.[12][13][14]”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
The SEAS trial (1873 patients) testing simvastatin and ezetimibe in advanced AS (mean peak velocity ≈3.1±0.55 m/s) did not show a significant reduction in AS progression or AVR rate.
“Similarly, the larger SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis; 1873 patients) that tested simvastatin and ezetimibe in patients with advanced AS (mean peak velocity, ≈3.1±0.55 m/s) did not demonstrate a significant reduction in AS progression or the rate of AVR. 14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] source
Not checked in the free run.
- Interpretationreasoning
Based on rare protein-disrupting LDLR variants, the expected odds ratio for aortic stenosis per 38.67 mg/dL increase in LDL-C is 3.16 (95% CI 2.13-4.69).
“Based on rare predicted protein-disrupting variants in LDLR, which were associated with increased LDL-C levels, the expected odds ratios for AS and CAD would be 3.16 (95% CI, 2.13-4.69)and 1.93 (95% CI, 1.56-2.40),respectively, per 38.67-mg/dL (1-mmol/L) increase in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationreasoning
Early and sustained lipid-lowering therapy may slow or prevent aortic stenosis development.
“Early and sustained lipid-lowering therapy may slow or prevent aortic stenosis development.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationnone given
Common variant Mendelian randomization studies may not accurately capture potential nonlinear associations at very low or very high LDL-C levels.
“Common variant Mendelian randomization studies may also not accurately capture potential nonlinear associations at very low or very high levels of LDL-C.”
Quote in the paperSubstantial claim - Interpretationreasoning
Based on PCSK9 R46L, the expected odds ratio for coronary artery disease per 38.67 mg/dL reduction in LDL-C is 0.47 (95% CI 0.38-0.57).
“Similarly, based on the common missense variant R46L in PCSK9, the expected odds ratios for AS and CAD would be 0.47 (95% CI, 0.30-0.72)and 0.47 (95% CI, 0.38-0.57),respectively, per 38.67-mg/dL (1 mmol/L) reduction in LDL-C.”
Quote in the paperNot a substantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationreasoning
Based on rare protein-disrupting APOB or PCSK9 variants, the expected odds ratio for coronary artery disease per 38.67 mg/dL reduction in LDL-C is 0.61 (95% CI 0.49-0.77).
“Based on rare predicted proteindisrupting variants in APOB or PCSK9, which were associated with reduced LDL-C levels, the expected odds ratios for AS and CAD would be 0.47 (95% CI, 0.27-0.82)and 0.61 (95% CI, 0.49-0.77),respectively, per 38.67-mg/dL (1-mmol/L) reduction in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationown data
Lower AS risk in participants with genetically lower LDL-C suggests that the risk of AS attributable to lipids might be cumulative over the lifetime.
“Lower risk of AS in participants with genetically lower levels of LDL-C suggests that the risk of AS potentially attributable to lipids might be cumulative over the lifetime,”
Quote in the paperSubstantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
- Premisecitation
Statins, unlike novel therapies specifically targeting PCSK9, can induce increases in Lp(a) levels.
“because statins, in contrast with novel therapies that specifically target PCSK9, can induce increases in Lp(a) levels.37”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] source
Not checked in the free run.
- Interpretationown data
Using rare protein-disrupting APOB and PCSK9 variants associated with 32 mg/dL lower LDL-C and 47% lower odds of AS in UKB, the authors estimate that a 38.67 mg/dL (1 mmol/L) genetic reduction in LDL-C may confer 53% lower odds of AS.
“Based on rare protein-disrupting variants in APOB and PCSK9, which were associated with 32-mg/dL lower LDL-C levels and 47% lower odds of AS in our current analysis of the UKB, we estimate that a 38.67-mg/ dL (1-mmol/L) genetic reduction in LDL-C levels may confer a 53% lower odds of AS.”
Quote in the paperSubstantial claim - Premisecitation
The 53% estimates are comparable to the 45% reduction in AS odds per 38.67 mg/dL genetic LDL-C reduction previously reported in 9692 EPIC-Norfolk participants using a genetic risk score of 10 common PCSK9 locus variants including R46L.
“Both estimates are also comparable to the 45% reduction in the odds of AS per 38.67mg/dL (1-mmol/L) genetic reduction in LDL-C reported previously in 9692 participants of the EPIC-Norfolk study based on a genetic risk score calculated using 10 common”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] source
Not checked in the free run.
- Premisecitation
Previous Mendelian randomization studies aggregating common genetic variants estimated that a 38.67 mg/dL (1 mmol/L) lower LDL-C was associated with 12% to 45% lower odds or hazards of AS.
“Causal effect estimates from these studies, converted to risk reductions, have ranged between 12% and 45% lower odds or hazards of AS per 38.67-mg/ dL (1-mmol/L) reduction in LDL-C.7,[9][10][11]”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Causal effect estimates from rare high-impact LDL-C-lowering genetic variants may more accurately reflect expected benefits of long-lasting medical therapy targeting specific proteins in lipoprotein metabolism than estimates from diverse common variants.
“In contrast with diverse common variants, causal effect estimates from rare high-impact LDL-C-lowering genetic variants may more accurately reflect the expected benefits of long-lasting medical therapy targeting specific proteins involved in lipoprotein metabolism.”
Quote in the paperSubstantial claim - Interpretationown data
A causal effect estimate of 53% lower odds of AS per 38.67 mg/dL genetic LDL-C reduction was calculated from the 14 mg/dL lower LDL-C and 24% lower odds of AS observed for the common PCSK9 R46L missense variant.
“This estimate is strikingly consistent with a causal effect estimate of 53% lower odds of AS per 38.67 mg/dL (1 mmol/L) genetic reduction in LDL-C calculated based on the 14 mg/dL lower LDL-C levels and 24% lower odds of AS that we observed for the common intermediate-impact PCSK9 R46L missense variant.”
Quote in the paperSubstantial claim - Interpretationreasoning
Based on PCSK9 R46L, the expected odds ratio for aortic stenosis per 38.67 mg/dL reduction in LDL-C is 0.47 (95% CI 0.30-0.72).
“Similarly, based on the common missense variant R46L in PCSK9, the expected odds ratios for AS and CAD would be 0.47 (95% CI, 0.30-0.72)and 0.47 (95% CI, 0.38-0.57),respectively, per 38.67-mg/dL (1 mmol/L) reduction in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationreasoning
Findings from allelic series of rare and common variation suggest that benefits of LDL-C reduction achieved by inhibiting PCSK9 may be approximately linear up to levels associated with halving AS risk in a primary prevention population.
“These findings from allelic series of rare and common variation suggest that the potential benefits of LDL-C reduction achieved by inhibiting PCSK9 may be approximately linear up to levels associated with a halving of AS risk in a primary prevention population.”
Quote in the paperSubstantial claim - Interpretationown data
This study provides support for LDL-C as a causal and high-impact risk factor for aortic stenosis.
“This study provides support for low-density lipoprotein cholesterol as a causal and high-impact risk factor for aortic stenosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationreasoning
Based on rare protein-disrupting APOB or PCSK9 variants, the expected odds ratio for aortic stenosis per 38.67 mg/dL reduction in LDL-C is 0.47 (95% CI 0.27-0.82).
“Based on rare predicted proteindisrupting variants in APOB or PCSK9, which were associated with reduced LDL-C levels, the expected odds ratios for AS and CAD would be 0.47 (95% CI, 0.27-0.82)and 0.61 (95% CI, 0.49-0.77),respectively, per 38.67-mg/dL (1-mmol/L) reduction in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationreasoning
Based on rare protein-disrupting LDLR variants, the expected odds ratio for coronary artery disease per 38.67 mg/dL increase in LDL-C is 1.93 (95% CI 1.56-2.40).
“Based on rare predicted protein-disrupting variants in LDLR, which were associated with increased LDL-C levels, the expected odds ratios for AS and CAD would be 3.16 (95% CI, 2.13-4.69)and 1.93 (95% CI, 1.56-2.40),respectively, per 38.67-mg/dL (1-mmol/L) increase in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
- Interpretationown data
The observation of greater peak velocities in LDLR protein-disrupting variant carriers strengthens existing evidence for an association between AS and familial hypercholesterolemia caused by truncating or predicted damaging missense LDLR variants.
“The former observation strengthens existing evidence for an association between AS and familial hypercholesterolemia caused by truncating variants or predicted damaging missense variants in LDLR.5,6”
Quote in the paperSubstantial claim0 of 2 sources checked - Study design and conductown data
The authors were not able to evaluate associations in participants with bicuspid aortic valves because of small numbers of diagnoses in the biobanks.
“Similarly, we were not able to evaluate associations in participants with bicuspid aortic valves because of small numbers of diagnoses in the biobanks.”
Quote in the paperNot a substantial claim - Interpretationown data
Together, these findings provide further support for a true causal association between LDL-C and AS.
“Together, these findings provide further support for a true causal association between LDL-C and AS.”
Quote in the paperSubstantial claim - Study design and conductown data
The authors addressed potential detection bias by showing that the LDLR protein-disrupting variant association with AS persisted after excluding participants diagnosed with CAD.
“We addressed these potential sources of bias firstly by demonstrating that the association of proteindisrupting variants in LDLR with AS persisted even after excluding participants who had been diagnosed with CAD.”
Quote in the paperSubstantial claim - Interpretationown data
Concordant associations with peak aortic velocity as a quantitative measure of aortic valve function provided additional support for a causal role of LDLR and PCSK9.
“Further support for a true causal role for LDLR and PCSK9 was provided by concordant associations with peak aortic velocity as a quantitative measure of aortic valve function.”
Quote in the paperSubstantial claim - Study design and conductown data
The authors addressed potential bias by observing similar associations with AVR as a strict procedural outcome.
“Second, we observed similar associations with AVR as a strict procedural outcome, which is particularly meaningful in the context of previous neutral clinical trials of lipid-lowering therapies that used AVR as the study end point.[12][13][14]”
Quote in the paperSubstantial claim0 of 3 sources checked - Study design and conductown data
The authors addressed potential bias by finding directionally consistent associations between rare LDL-C-associated variants and peak aortic valve velocity, a quantitative measure not affected by detection bias because imaging was performed in a prospective research protocol in almost 60,000 people.
“Third, we found directionally consistent associations between rare LDL-C-associated variants and peak velocity across the aortic valve, a quantitative measure of aortic valve function that is not affected by detection bias because the imaging was performed in the context of a prospective research protocol in almost 60 000 people.”
Quote in the paperSubstantial claim - Interpretationown data
Modification of aortic valve function well before clinically significant disease provides additional rationale for LDL inhibition as a preventive treatment in individuals at risk for AS.
“Modification of aortic valve function well before what is considered clinically significant disease provides additional rationale for LDL inhibition as a preventive treatment in individuals at risk for AS.”
Quote in the paperSubstantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
- Study design and conductcitation
An important limitation of genetic studies using electronic health record data is the possibility of detection bias and informative presence bias.
“An important limitation of any genetic study using electronic health record data is the possibility of detection bias and informative presence bias.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] source
Not checked in the free run.
- May combine two claims. 20
- The quote only partly states this claim. 3
- Classified as probably not a substantial claim. 16
May combine two claims.
Findingown dataIn UKB, compared with 1.3% AS risk in noncarriers, carrying a protein-disrupting LDLR variant was associated with a 3% absolute increase in AS risk, and carrying a protein-disrupting APOB or PCSK9 variant was associated with a 0.6% lower absolute AS risk.
“In the population-based UKB, which enrolled participants 40 to 69 years of age with >13 years of follow-up, compared with a risk of 1.3% in noncarriers, carrying a protein-disrupting variant in LDLR was associated with a 3% absolute increase in the risk of AS, and carrying a protein-disrupting variant in APOB or PCSK9 was associated with a 0.6% lower absolute risk of AS.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn UKB, carriers of protein-disrupting APOB or PCSK9 variants had reduced coronary artery disease risk (OR 0.66, 95% CI 0.55-0.80; P=2.4e-5).
“significantly reduced risk of CAD in carriers of protein-disrupting variants in APOB or PCSK9 (OR, 0.66 [0.55-0.80];P=2.4e-5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong 5621 UKB patients with AS, 671 (11.9%) had been diagnosed by enrollment, whereas among 33070 with CAD, 14953 (45.2%) had been diagnosed by enrollment.
“Among 5621 patients with AS, only 671 (11.9%) had been diagnosed by the time of enrollment in UKB.For comparison, among 33 070 patients with a diagnosis of CAD in UKB, 14 953 (45.2%) had already been diagnosed by the time of enrollment.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAfter quality control, UKB included 421,049 unrelated participants with 5621 aortic stenosis cases, and All of Us included 195,519 unrelated participants with 1087 aortic stenosis cases.
“we identified a total of 421 049 unrelated participants (54% women; n=5621 patients with AS) in UKB and a total of 195 519 unrelated participants (61.3% women; n=1087 patients with AS) in All of Us.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn UKB with additional adjustment for lipoprotein(a), carriers of protein-disrupting LDLR variants had increased coronary artery disease risk (OR 3.04, 95% CI 1.84-4.70; P=6.8e-5).
“we observed significantly increased risk of CAD in carriers of protein-disrupting variants in LDLR (OR, 3.04 [1.84-4.70];P=6.8e-5)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn UKB, there were 691 carriers of protein-disrupting variants in LDLR, 1106 in APOB, and 1037 in PCSK9.
“we identified a total of 691 carriers in LDLR (56.3±8.3 years; 57% women), 1106 carriers in APOB (56.4±8.0 years; 55% women), and 1037 carriers in PCSK9 (56.7±8.3 years; 47% women; Table 1).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn UKB, carriers of protein-disrupting APOB or PCSK9 variants had reduced aortic stenosis risk (OR 0.53, 95% CI 0.34-0.85; P=0.0081).
“The risk of AS was reduced in 2046 participants who car- ried predicted protein-disrupting variants in APOB or PCSK9, 14 (0.68%) of whom had either prevalent or incident AS (OR, 0.53 [0.34-0.85]; P=0.0081).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationObservational cohort studies have reported associations between dyslipidemia and increased risk of aortic stenosis or aortic valve calcification.
“Observational cohort studies have reported associations between dyslipidemia and increased risk of AS or aortic valve calcification.3,4”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductcitationAlphaMissense likely pathogenic predictions were used to classify missense variants as predicted-damaging.
“We used the “likely pathogenic” annotation, as reported by Cheng et al, 23 to classify missense variants as predicted-damaging.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cheng et al, 23
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationIn both datasets, LOFTEE was used to identify predicted truncating variants in LDLR, APOB, and PCSK9, excluding low-confidence or flagged variants.
“we used the Loss Of Function Transcript Effect Estimator (LOFTEE) algorithm to identify predicted truncating variants (tv) in LDLR (LDLRtv), APOB (APOBtv), and PCSK9 (PCSK9tv), excluding those variants that were annotated by LOFTEE as low-confidence or flagged based on characteristics associated with increased false-positive rates.22”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningAltering AS risk might require earlier and more sustained reduction in lipid levels.
“and therefore that altering AS risk might require earlier and more sustained reduction in lipid levels.”
Quote in the paperNot a substantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductown dataUKB participants were restricted to unrelated individuals with electronic health records linked to genetic data.
“We further restricted to samples who were unrelated and had electronic health records data linked to their genetic data.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataRare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of aortic stenosis, respectively.
“Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
Classified as probably not a substantial claim.
Study design and conductreasoningTo address detection bias, UKB analyses excluded participants with coronary artery disease at baseline or during follow-up.
“we performed additional stringent sensitivity analyses in UKB by evaluating the associations of each variant category with AS after excluding all participants with CAD at baseline or during study follow-up.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataPeak velocity analyses used REGENIE with adjustment for imaging device serial number, age, age squared, sex, genotyping array, and the first 10 principal components.
“We conducted burden testing for variants in APOB, LDLR, and PCSK9 using REGENIE v3.3 32 with peak velocity as the outcome, adjusting for the imaging device serial number, age, age 2 , sex, genotyping array, and the first 10 genomic principal components.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] source
Not checked in the free run.
May combine two claims.
PremisecitationAggregation of small to moderate effects across diverse genomic loci is susceptible to bias from pleiotropic effects, which may partly explain attenuation of effect sizes when controlling for Lp(a).
“However, the aggregation of small to moderate effects across diverse genomic loci is susceptible to bias because of pleiotropic effects; this may partly explain findings such as attenuation of effect sizes when controlling for Lp(a), as observed in a recent Mendelian randomization study.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataPrimary disease association analyses used Firth logistic regression with adjustment for age, age squared, sex, genotyping array, and the first 10 genomic principal components.
“we conducted Firth logistic regression analyses with AS (or CAD) as the outcome and variant carrier status, age, age 2 , sex, genotyping array (only in UKB), and the first 10 genomic principal components as independent variables.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningUKB MRI was performed as part of a prospective research protocol, making associations with aortic valve function less subject to confounding by indication than health-system imaging.
“Because participants in UKB underwent magnetic resonance imaging (MRI) as part of a prospective research protocol, associations with aortic valve function in this sample are less subject to confounding by indication than imaging obtained within health care systems.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataVariants were restricted to rare variants with maximum minor allele frequency thresholds of 0.1% in All of Us, 0.1% in UKB for disease outcomes, and 0.01% in UKB for peak velocity.
“we filtered both variant categories to rare variants only (defined as a maximum minor allele frequency of 0.1% in All of Us, 0.1% in UKB for analyses of discrete disease outcomes, and 0.01% in UKB for analyses of peak velocity across the aortic valve).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe SALTIRE and ASTRONOMER trials, which tested statins in AS, were limited by small sample sizes (n=150 and n=269), short median follow-up (25 and 42 months), and advanced AS stages (mean peak velocity 3.43±0.64 and 3.18±0.42 m/s), factors that may have contributed to their neutral outcome.
“The SALTIRE (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression) and ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) trials, which evaluated statin efficacy in AS, were constrained by small sample sizes (n=150 and n=269), 12,13 limited median follow-up periods (25 and 42 months), and a focus on advanced AS stages (mean peak velocity, 3.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe relative contribution of LDL-C levels to AS risk in any given population may depend on other health characteristics, including other AS risk factors.
“The relative contribution of LDL-C levels to the risk of AS in any given population may depend on other health characteristics, including the presence of other risk factors for AS.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe causal estimates derived in this study are based on lipid levels measured in late adulthood; the impacts of rare variants on LDL-C levels could differ if measured earlier in life.
“The causal estimates derived in this study are based on lipid levels measured in late adulthood; the impacts of rare variants on LDL-C levels could differ if measured earlier in life.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMRI may produce greater aortic valve area estimates than echocardiography.
“Although MRI generally demonstrates good overlap with echocardiography, MRI may produce greater aortic valve area estimates than echocardiography.39”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe study concluded that rare variants in LDLR, APOB, and PCSK9, which were taken to alter LDL-C levels over life, were linked to markedly higher or lower AS risk (and AVR risk), respectively.
“In conclusion, we found that rare genetic variants in LDLR, APOB, and PCSK9 that conferred lifelong higher or lower LDL-C levels were associated with substantially increased and reduced risk of AS (and AVR), respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
May combine two claims.
Study design and conductreasoningPredicted protein-disrupting variants in PCSK9 and APOB may have included variants associated with familial hypercholesterolemia, which may have weakened observed protective effect estimates.
“More specifically, predicted protein-disrupting variants in PCSK9 and APOB may also have included variants that are rather associated with familial hypercholesterolemia; this may have weakened observed protective effect estimates.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningTo maximize statistical power, the authors included variants predicted to be protein-disrupting by in silico algorithms; individual variant misclassification is possible, and protein-disrupting variants may have gain-of-function or loss-of-function effects.
“To maximize statistical power, we included variants that were predicted to be protein-disrupting by in silico algorithms; misclassification of individual variants is possible, and protein-disrupting variants may have either gain-offunction or loss-of-function effects.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe authors did not examine ancestry-specific variant associations because of limited numbers of patients with AS.
“We did not examine ancestry-specific variant associations caused by the limited numbers of patients with AS; future increases in biobank sample sizes may enable more detailed analyses.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe observation of lower peak velocities in PCSK9 protein-disrupting variant carriers is noteworthy because most UKB participants are healthy with peak velocities in the normal range, so relatively large protective effect sizes would be needed to detect significant differences.
“The latter observation is particularly noteworthy because the majority of participants in UKB are healthy individuals with peak velocities in the normal range, thereby requiring relatively large effect sizes in the protective direction to detect significant differences.”
Quote in the paperSubstantial claim- Rests on an assumption: Most UKB participants are healthy individuals with peak velocities in the normal range.
May combine two claims.
Study design and conductown dataBecause associations of APOB and PCSK9 variants with LDL-C and AS were directionally consistent, the authors combined these data in selected analyses, while acknowledging that they affect LDL-C through different mechanisms.
“Because the associations of variants in APOB and PCSK9 with LDL-C and AS were directionally consistent, we combined these data in selected analyses, but we acknowledge that they affect LDL-C levels through different mechanisms.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe study does not assess AS progression but rather the risk of incident AS with respect to lifelong differences in LDL-C.
“Finally, it is important to note that our study does not assess AS progression but rather the risk of incident AS with respect to lifelong differences in LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
May combine two claims.
Study design and conductnone givenThis study uses peak velocity measured with MRI, which is not a standard modality for assessing aortic valve function.
“This study uses peak velocity as measured with MRI, which is not a standard modality for the assessment of aortic valve function.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningIt is not certain why significant associations between peak flow and genetic variants were observed for PCSK9 but not APOB; this could reflect different mechanisms, limited statistical power, or difficulty finding protective effects in a sample with mostly normal aortic function.
“It is not certain why we observed significant associations between peak flow and genetic variants in PCSK9 but not in APOB; this could reflect different mechanisms, limited statistical power, or the difficulty of finding protective effects in a sample with mostly normal aortic function.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningGiven earlier randomized trials in which lipid-lowering therapy did not slow AS progression, the findings suggest that lipid-lowering treatment may need to start early and continue long-term to best prevent AS.
“In the context of earlier randomized clinical trials of lipid-lowering therapy failing to slow progression of AS, our findings suggest that lipid-lowering therapy may need to be early and sustained to maximally prevent AS development.”
Quote in the paperSubstantial claim- Rests on an assumption: Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
May combine two claims.
Study design and conductreasoningAggregation of data from large biobanks allows more robust conclusions, but carrier and case counts are still relatively small, and misclassification of AS in biobank data is possible.
“Aggregation of data from large biobanks allows for more robust conclusions, but the carrier and case counts are still relatively small, and we acknowledge the potential of misclassification of AS in biobank data.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The rare protein-disrupting variants in LDLR, APOB, and PCSK9 affect aortic stenosis risk only through their effect on LDL-C, without independent pleiotropic pathways.
“We derived simple causal estimates of the expected change in the odds of AS and CAD per 38.67 mg/dL (1 mmol/L) reduction or increase in LDL-C based on each variant category”
The paper relies on this without support.
The rare variant categories are valid proxies for lifelong differences in LDL-C exposure.
“Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively.”
The paper relies on this without support.
Rare protein-disrupting variants in LDLR, APOB, and PCSK9 produce durable, lifelong, sustained changes in LDL-C levels.
“In contrast with these trials, the rare genetic variants analyzed in this study are expected to lead to durable, lifelong, and sustained changes in LDL-C levels.”
The paper relies on this without support.
Most UKB participants are healthy individuals with peak velocities in the normal range.
“The latter observation is particularly noteworthy because the majority of participants in UKB are healthy individuals with peak velocities in the normal range, thereby requiring relatively large effect sizes in the protective direction to detect significant differences.”
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?
Rare genetic variants in ApoB and PCSK9, identified as proxies for lifelong lower LDL-C levels, are associated with reduced CAVD risk.
“Rare genetic variants in ApoB and PCSK9, identified through LOFTEE and AlphaMissense algorithms as proxies for lifelong lower LDL-C levels, are associated with reduced CAVD risk [42].”
From Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization (2025) · cites this paper as [42]
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.
Combined PCSK9 carrier group has an incompatible percentage of women
MinorThe text says 47% of the combined PCSK9 carrier group were women, although women make up 59% of truncating-variant carriers and 55% of damaging-missense carriers. Combining those two groups cannot produce 47%, even allowing for the small overlap implied by their carrier counts.
“1037 carriers in PCSK9 (56.7±8.3 years; 47% women; Table 1)”
“514 carriers of PCSK9tv (56.7±8.3 years; 59% women; Table S1).We also identified an additional 594 participants who carried predicted damaging missense mutations (as predicted by AlphaMissense) in LDLR (56.4±8.2 years; 56% women), 635 in APOB (56.3±8.1 years; 55% women), and 528 in PCSK9 (56.7±8.2 years, 55% women).”
UK Biobank APOB carrier count differs between text and table
MinorThe text reports 1106 carriers of protein-disrupting APOB variants, whereas Table 1 lists 1016 for the same UK Biobank carrier group.
“we identified a total of 691 carriers in LDLR (56.3±8.3 years; 57% women), 1106 carriers in APOB (56.4±8.0 years; 55% women), and 1037 carriers in PCSK9”
“Noncarriers LDLR APOB PCSK9 n 404 381 691 1016 1037”
Lp(a)-adjusted analysis switches outcomes mid-description
MinorThe sensitivity analysis is introduced as an analysis of AS, but both reported adjusted associations are described as risks of CAD. The text does not establish which outcome those estimates represent.
“Next, we evaluated the associations of proteindisrupting variants in LDLR, APOB, and PCSK9 with AS with additional adjustment for circulating Lp(a) levels”
“Even with this adjustment, we observed significantly increased risk of CAD in carriers of protein-disrupting variants in LDLR (OR, 3.04 [1.84-4.70];P=6.8e-5), and significantly reduced risk of CAD in carriers of protein-disrupting variants in APOB or PCSK9 (OR, 0.44 [0.21-0.82];P=6.7e-3; Table S8).”
The citation lists haven’t been fetched yet
References 36 · Cited by 26
Research works printed but not linked: 1
- Paszke A Gross S Massa F Lerer A Bradbury J Chanan G Killeen T Lin Z Gimelshein N Antiga L et al. PyTorch: an imperative style high-performance deep learning library [Internet]. arXiv [cs.LG]. 2019. Accessed January 16 2023. https://proceedings.neurips.cc/paper/2019/hash/bdbca288fee7f92f2bfa9f7012727740-Abstract.html
- Authors
- Rämö, J. T., Jurgens, S. J., Kany, S., Choi, S. H., Wang, X., Smirnov, A. N., Friedman, S. F., Maddah, M., Khurshid, S., Ellinor, P. T., & Pirruccello, J. P.
- Affiliations
- Broad Institute (US)
- Boston University (US)
- Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA.
- Corresponding author
- Pirruccello, James P.
- ORCID
- Venue
- Circulation
- Published
- 2024-11-26
- Volume
- 150
- Issue
- 22
- Pages
- 1767-1780
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC11915876
- OpenAlex
- W4402129630
- Cited by
- 26
- References
- 36
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 1
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- other-oa
- Locations
- Circulation (publishedVersion)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Funders
- Sigrid Juselius Foundation
- Dutch Heart Foundation (03-007-2022-0035)
- Deutsche Forschungsgemeinschaft (521832260)
- National Institutes of Health (K08HL159346, R01HL092577, R01HL157635, 1R01NS134597-01, 3OT2OD035404-01S3)
- American Heart Association (18SFRN34110082, 961045, 23CDA1050571)
- European Union (MAESTRIA 965286)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- aortic stenosis, LDL receptor, apolipoprotein B, PCSK9, LDL cholesterol, loss-of-function mutations, aortic valve replacement, aortic valve calcification, genetic risk, lipid metabolism, aortic valve disease, UK Biobank, All of Us
- MeSH terms
- Proprotein Convertase 9, Aged, Aortic Valve, Aortic Valve Stenosis, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Receptors, LDL, Genetic Variation, Genetic Predisposition to Disease, Apolipoprotein B-100
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