Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study

Coco M. Fuhri Snethlage; Manon Balvers; Bart Ferwerda; Elena Rampanelli; Pleun de Groen; Bart O. Roep; Hilde Herrema; Timothy J. McDonald; Daniël H. van Raalte; Michael N. Weedon; Richard A. Oram; Max Nieuwdorp; Nordin M.J. Hanssen

doi:10.1007/s00125-024-06204-6

Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study

Coco M. Fuhri Snethlage^*
, Manon Balvers
, Bart Ferwerda
, Elena Rampanelli
, Pleun de Groen
, Bart O. Roep
, Hilde Herrema
, Timothy J. McDonald
, Daniël H. van Raalte
, Michael N. Weedon
, Richard A. Oram
, Max Nieuwdorp
, Nordin M.J. Hanssen

^*Corresponding author for this work

University of Amsterdam
Leiden University
University of Plymouth

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Aims/hypothesis: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. Methods: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0–29.0], HbA_1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. Results: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β −1.53; 95% CI −2.76, −0.29). Conclusions/interpretation: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function. Graphical Abstract: (Figure presented.)

Original language	English
Pages (from-to)	1865-1876
Number of pages	12
Journal	Diabetologia
Volume	67
Issue number	9
DOIs	https://doi.org/10.1007/s00125-024-06204-6
Publication status	Published - Sept 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CGM
Polygenic risk score
Residual beta cell function
Type 1 diabetes

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Associations-between-diabetes-related-genetic-risk-scores-and-residual-beta-cell-function-in-type-1-diabetes.pdfFinal published version, 1.95 MBLicence: CC BY

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Fuhri Snethlage, C. M., Balvers, M., Ferwerda, B., Rampanelli, E., de Groen, P., Roep, B. O., Herrema, H., McDonald, T. J., van Raalte, D. H., Weedon, M. N., Oram, R. A., Nieuwdorp, M., & Hanssen, N. M. J. (2024). Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study. Diabetologia, 67(9), 1865-1876. https://doi.org/10.1007/s00125-024-06204-6

@article{29661e95825b4fc198d8c977a0873d24,

title = "Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study",

abstract = "Aims/hypothesis: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. Methods: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0–29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. Results: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95\% CI 0.69, 0.89 and OR 0.84: 95\% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95\% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4\% 1.41; 95\% CI 1.01 to 1.96) and lower glucose coefficient of variance (β −1.53; 95\% CI −2.76, −0.29). Conclusions/interpretation: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function. Graphical Abstract: (Figure presented.)",

keywords = "CGM, Polygenic risk score, Residual beta cell function, Type 1 diabetes",

author = "\{Fuhri Snethlage\}, \{Coco M.\} and Manon Balvers and Bart Ferwerda and Elena Rampanelli and \{de Groen\}, Pleun and Roep, \{Bart O.\} and Hilde Herrema and McDonald, \{Timothy J.\} and \{van Raalte\}, \{Dani{\"e}l H.\} and Weedon, \{Michael N.\} and Oram, \{Richard A.\} and Max Nieuwdorp and Hanssen, \{Nordin M.J.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = sep,

doi = "10.1007/s00125-024-06204-6",

language = "English",

volume = "67",

pages = "1865--1876",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "9",

}

Fuhri Snethlage, CM, Balvers, M, Ferwerda, B , Rampanelli, E, de Groen, P, Roep, BO, Herrema, H, McDonald, TJ, van Raalte, DH, Weedon, MN, Oram, RA, Nieuwdorp, M & Hanssen, NMJ 2024, 'Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study', Diabetologia, vol. 67, no. 9, pp. 1865-1876. https://doi.org/10.1007/s00125-024-06204-6

TY - JOUR

T1 - Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes

T2 - the GUTDM1 study

AU - Fuhri Snethlage, Coco M.

AU - Balvers, Manon

AU - Ferwerda, Bart

AU - Rampanelli, Elena

AU - de Groen, Pleun

AU - Roep, Bart O.

AU - Herrema, Hilde

AU - McDonald, Timothy J.

AU - van Raalte, Daniël H.

AU - Weedon, Michael N.

AU - Oram, Richard A.

AU - Nieuwdorp, Max

AU - Hanssen, Nordin M.J.

PY - 2024/9

Y1 - 2024/9

N2 - Aims/hypothesis: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. Methods: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0–29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. Results: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β −1.53; 95% CI −2.76, −0.29). Conclusions/interpretation: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function. Graphical Abstract: (Figure presented.)

AB - Aims/hypothesis: Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. Methods: Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0–29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. Results: Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β −1.53; 95% CI −2.76, −0.29). Conclusions/interpretation: Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function. Graphical Abstract: (Figure presented.)

KW - CGM

KW - Polygenic risk score

KW - Residual beta cell function

KW - Type 1 diabetes

UR - https://www.scopus.com/pages/publications/85196802394

U2 - 10.1007/s00125-024-06204-6

DO - 10.1007/s00125-024-06204-6

M3 - Article

C2 - 38922416

SN - 0012-186X

VL - 67

SP - 1865

EP - 1876

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study

Abstract

UN SDGs

Keywords

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