Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose

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Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality : reduced risk not explained by lower plasma glucose. / Bechmann, Louise E.; Emanuelsson, Frida; Nordestgaard, Børge G.; Benn, Marianne.

I: Cardiovascular Research, Bind 119, Nr. 14, 2023, s. 2482-2493.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Bechmann, LE, Emanuelsson, F, Nordestgaard, BG & Benn, M 2023, 'Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose', Cardiovascular Research, bind 119, nr. 14, s. 2482-2493. https://doi.org/10.1093/cvr/cvad122

APA

Bechmann, L. E., Emanuelsson, F., Nordestgaard, B. G., & Benn, M. (2023). Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose. Cardiovascular Research, 119(14), 2482-2493. https://doi.org/10.1093/cvr/cvad122

Vancouver

Bechmann LE, Emanuelsson F, Nordestgaard BG, Benn M. Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose. Cardiovascular Research. 2023;119(14):2482-2493. https://doi.org/10.1093/cvr/cvad122

Author

Bechmann, Louise E. ; Emanuelsson, Frida ; Nordestgaard, Børge G. ; Benn, Marianne. / Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality : reduced risk not explained by lower plasma glucose. I: Cardiovascular Research. 2023 ; Bind 119, Nr. 14. s. 2482-2493.

Bibtex

@article{f8e2e9bc7b574e6cbdeee1217aa890bb,
title = "Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose",
abstract = "Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2, mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose.",
keywords = "Glucose, Heart failure, Ischaemic heart disease, Lipoprotein(a), Myocardial infarction, Sodium-glucose co-transporter 2, Sodium-glucose co-transporter 2 inhibitors",
author = "Bechmann, {Louise E.} and Frida Emanuelsson and Nordestgaard, {B{\o}rge G.} and Marianne Benn",
note = "Publisher Copyright: {\textcopyright} 2023 Oxford University Press. All rights reserved.",
year = "2023",
doi = "10.1093/cvr/cvad122",
language = "English",
volume = "119",
pages = "2482--2493",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "14",

}

RIS

TY - JOUR

T1 - Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality

T2 - reduced risk not explained by lower plasma glucose

AU - Bechmann, Louise E.

AU - Emanuelsson, Frida

AU - Nordestgaard, Børge G.

AU - Benn, Marianne

N1 - Publisher Copyright: © 2023 Oxford University Press. All rights reserved.

PY - 2023

Y1 - 2023

N2 - Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2, mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose.

AB - Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2, mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose.

KW - Glucose

KW - Heart failure

KW - Ischaemic heart disease

KW - Lipoprotein(a)

KW - Myocardial infarction

KW - Sodium-glucose co-transporter 2

KW - Sodium-glucose co-transporter 2 inhibitors

U2 - 10.1093/cvr/cvad122

DO - 10.1093/cvr/cvad122

M3 - Journal article

C2 - 37516996

AN - SCOPUS:85178369249

VL - 119

SP - 2482

EP - 2493

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 14

ER -

ID: 375727335