Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

Sara B. Seidelmann, Elena Feofanova, Bing Yu, Nora Franceschini, Brian Claggett, Mikko Kuokkanen, Hannu Puolijoki, Tapani Ebeling, Markus Perola, Veikko Salomaa, Amil Shah, Josef Coresh, Elizabeth Selvin, Calum A. MacRae, Susan Cheng, Eric Boerwinkle, Scott D. Solomon

Research output: Contribution to journalArticle

Abstract

Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

Original languageEnglish (US)
Pages (from-to)1763-1773
Number of pages11
JournalJournal of the American College of Cardiology
Volume72
Issue number15
DOIs
StatePublished - Oct 9 2018

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Sodium-Glucose Transporter 1
Symporters
Confidence Intervals
Glucose
Glucose Intolerance
Glucose Tolerance Test
Mendelian Randomization Analysis
Haplotypes
Population
Exome
Intestinal Absorption
Mutation Rate
Missense Mutation
Random Allocation
Hyperglycemia
African Americans
Genes

Keywords

  • glucose tolerance
  • Mendelian randomization
  • SGLT1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Seidelmann, S. B., Feofanova, E., Yu, B., Franceschini, N., Claggett, B., Kuokkanen, M., ... Solomon, S. D. (2018). Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. Journal of the American College of Cardiology, 72(15), 1763-1773. https://doi.org/10.1016/j.jacc.2018.07.061

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. / Seidelmann, Sara B.; Feofanova, Elena; Yu, Bing; Franceschini, Nora; Claggett, Brian; Kuokkanen, Mikko; Puolijoki, Hannu; Ebeling, Tapani; Perola, Markus; Salomaa, Veikko; Shah, Amil; Coresh, Josef; Selvin, Elizabeth; MacRae, Calum A.; Cheng, Susan; Boerwinkle, Eric; Solomon, Scott D.

In: Journal of the American College of Cardiology, Vol. 72, No. 15, 09.10.2018, p. 1763-1773.

Research output: Contribution to journalArticle

Seidelmann, SB, Feofanova, E, Yu, B, Franceschini, N, Claggett, B, Kuokkanen, M, Puolijoki, H, Ebeling, T, Perola, M, Salomaa, V, Shah, A, Coresh, J, Selvin, E, MacRae, CA, Cheng, S, Boerwinkle, E & Solomon, SD 2018, 'Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk', Journal of the American College of Cardiology, vol. 72, no. 15, pp. 1763-1773. https://doi.org/10.1016/j.jacc.2018.07.061
Seidelmann SB, Feofanova E, Yu B, Franceschini N, Claggett B, Kuokkanen M et al. Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. Journal of the American College of Cardiology. 2018 Oct 9;72(15):1763-1773. https://doi.org/10.1016/j.jacc.2018.07.061
Seidelmann, Sara B. ; Feofanova, Elena ; Yu, Bing ; Franceschini, Nora ; Claggett, Brian ; Kuokkanen, Mikko ; Puolijoki, Hannu ; Ebeling, Tapani ; Perola, Markus ; Salomaa, Veikko ; Shah, Amil ; Coresh, Josef ; Selvin, Elizabeth ; MacRae, Calum A. ; Cheng, Susan ; Boerwinkle, Eric ; Solomon, Scott D. / Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. In: Journal of the American College of Cardiology. 2018 ; Vol. 72, No. 15. pp. 1763-1773.
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abstract = "Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47{\%} male), those who carried a haplotype of 3 missense mutations (frequency of 6.7{\%})—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95{\%} confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95{\%} CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95{\%} CI: −36.6 to 4.1; OR: 0.39; 95{\%} CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95{\%} CI: −6.4 to −0.02; OR: 0.81; 95{\%} CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95{\%} CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95{\%} CI: 0.35 to 0.81), heart failure (HR: 0.53; 95{\%} CI: 0.24 to 0.83), and death (HR: 0.66; 95{\%} CI: 0.42 to 0.90). Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.",
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TY - JOUR

T1 - Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

AU - Seidelmann, Sara B.

AU - Feofanova, Elena

AU - Yu, Bing

AU - Franceschini, Nora

AU - Claggett, Brian

AU - Kuokkanen, Mikko

AU - Puolijoki, Hannu

AU - Ebeling, Tapani

AU - Perola, Markus

AU - Salomaa, Veikko

AU - Shah, Amil

AU - Coresh, Josef

AU - Selvin, Elizabeth

AU - MacRae, Calum A.

AU - Cheng, Susan

AU - Boerwinkle, Eric

AU - Solomon, Scott D.

PY - 2018/10/9

Y1 - 2018/10/9

N2 - Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

AB - Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

KW - glucose tolerance

KW - Mendelian randomization

KW - SGLT1

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