PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis

Langsted, Anne; Nordestgaard, Børge G.; Benn, Marianne; Tybjærg‐Hansen, Anne; Kamstrup, Pia R.

doi:10.1210/jc.2016-1206

Cited by 91 publications

(58 citation statements)

References 32 publications

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“…In addition, genetically determined small isoforms of Lp(a), as a result of either kringle repeats or the above‐mentioned SNPs, were associated with cardiovascular events; that is, Mendelian randomization studies have supported a causal relationship 11, 21, 22, 23. This concept was further supported by the finding that genetically determined low levels of Lp(a) due to loss of function of the proprotein convertase subtilisin/kexin type‐9 protein were associated with reduced risks of both MI and AS 24. The atherogenic properties of Lp(a) were demonstrated when Lp(a) was shown to entrap cholesterol in the intima by recruiting inflammatory cells and binding oxidized phospholipids; moreover, Lp(a) was also shown to interrupt fibrinolytic processes 1, 25…”

Section: Discussionmentioning

confidence: 92%

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Ljungberg

Holmgren

Bergdahl

et al. 2017

JAHA

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BackgroundAortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.Methods and ResultsWe identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni‐ and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07‐1.55]), but not in 132 patients without CAD (1.04 [0.83‐1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16‐1.76]) but not in those without CAD (0.87 [0.69‐1.10]).ConclusionsHigh levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

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Section: Discussionmentioning

confidence: 92%

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Ljungberg

Holmgren

Bergdahl

et al. 2017

JAHA

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“…Along the same lines, identification of genetic mutations or variants that confer protection against disease via loss-offunction effects (LoF), akin to those of a therapeutic agent, hold great promise for devising therapeutic schemes (2)(3)(4)(5) to restore or prevent some or all disease symptoms, either in all patients or, more likely, in specific subsets of patients with well-defined genetic lesions of affected pathways. A well-established example is provided by studies of the PCSK9 locus, where therapeutic agents designed to inhibit PCSK9 were prospectively developed in response to the detected protective effects of PCSK9 LoF variants on LDL cholesterol levels and coronary artery disease risk (6,7). Similar success has increasingly been reported in other human diseases (8) (albeit not neuropsychiatric or neurodevelopmental disorders so far) and has prompted efforts to identify additional such advantageous LoF variants (9).…”

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confidence: 99%

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

Diamantopoulou

Sun

Mukai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Identification of protective loss-of-function (LoF) mutations holds great promise for devising novel therapeutic interventions, although it faces challenges due to the scarcity of protective LoF alleles in the human genome. Exploiting the detailed mechanistic characterization of animal models of validated disease mutations offers an alternative. Here, we provide insights into protective-variant biology based on our characterization of a model of the 22q11.2 deletion, a strong genetic risk factor for schizophrenia (SCZ). Postnatal brain up-regulation ofMirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Here, we demonstrate that mice in which theDf(16)Adeficiency is combined with a LoFMirta22allele show rescue of key SCZ-related deficits, namely prepulse inhibition decrease, working memory impairment, and social memory deficits, as well as synaptic and structural plasticity abnormalities in the prefrontal cortex. Additional analysis of homozygousMirta22knockout mice, in which no alteration is observed in the above-mentioned SCZ-related phenotypes, highlights the deleterious effects ofMirta22up-regulation. Our results support a causal link between dysregulation of a miRNA target and SCZ-related deficits and provide key insights into beneficial LoF mutations and potential new treatments.

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“…Conversely, loss‐of‐function PCSK9 mutations are associated with lower serum LDL‐C levels, lower lifelong exposure of vascular structures to LDL, and marked reduction of risk of coronary heart disease 27, 28, 29. Moreover, healthy subjects with severe loss of PCSK9 function have been shown to have serum LDL‐C concentrations as low as 14 mg/dL without apparent adverse health effects 28, 30…”

Section: Mechanism Of Action Of Pcsk9 Inhibitorsmentioning

confidence: 99%

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

Handelsman

Lepor

2018

JAHA

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PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis

Abstract: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.

Cited by 91 publications

References 32 publications

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

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