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 tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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