The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation

Nikolaj Thure Krarup; Niels Grarup; Karina Banasik; Martin Friedrichsen; Kristine Færch; Camilla Helene Sandholt; Torben Jørgensen; Pernille Poulsen; Daniel Rinse Witte; Allan Vaag; Thorkild I.A. Sørensen; Oluf Pedersen; Torben Hansen

doi:10.1371/journal.pone.0040376

The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation

Nikolaj Thure Krarup, Niels Grarup, Karina Banasik, Martin Friedrichsen, Kristine Færch, Camilla Helene Sandholt, Torben Jørgensen, Pernille Poulsen, Daniel Rinse Witte, Allan Vaag, Thorkild I.A. Sørensen, Oluf Pedersen, Torben Hansen

26 Citations (Scopus)

Abstract

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. Methods: The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (n_total = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). Results: The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10^-5) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10^-4). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. Conclusion: Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

Original language	English
Journal	P L o S One
Volume	7
Issue number	7
Number of pages	7
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0040376
Publication status	Published - 5 Jul 2012

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Krarup, N. T., Grarup, N., Banasik, K., Friedrichsen, M., Færch, K., Sandholt, C. H., Jørgensen, T., Poulsen, P., Witte, D. R., Vaag, A., Sørensen, T. I. A., Pedersen, O., & Hansen, T. (2012). The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation. P L o S One, 7(7). https://doi.org/10.1371/journal.pone.0040376

Krarup, NT, Grarup, N , Banasik, K, Friedrichsen, M, Færch, K, Sandholt, CH, Jørgensen, T, Poulsen, P, Witte, DR, Vaag, A , Sørensen, TIA , Pedersen, O & Hansen, T 2012, 'The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation', P L o S One, vol. 7, no. 7. https://doi.org/10.1371/journal.pone.0040376

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title = "The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation",

abstract = "Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. Methods: The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (ntotal = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). Results: The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10-5) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10-4). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. Conclusion: Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.",

author = "Krarup, {Nikolaj Thure} and Niels Grarup and Karina Banasik and Martin Friedrichsen and Kristine F{\ae}rch and Sandholt, {Camilla Helene} and Torben J{\o}rgensen and Pernille Poulsen and Witte, {Daniel Rinse} and Allan Vaag and S{\o}rensen, {Thorkild I.A.} and Oluf Pedersen and Torben Hansen",

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doi = "10.1371/journal.pone.0040376",

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T1 - The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation

AU - Krarup, Nikolaj Thure

AU - Grarup, Niels

AU - Banasik, Karina

AU - Friedrichsen, Martin

AU - Færch, Kristine

AU - Sandholt, Camilla Helene

AU - Jørgensen, Torben

AU - Poulsen, Pernille

AU - Witte, Daniel Rinse

AU - Vaag, Allan

AU - Sørensen, Thorkild I.A.

AU - Pedersen, Oluf

AU - Hansen, Torben

N1 - e40376 CURIS 2012 5200 075

PY - 2012/7/5

Y1 - 2012/7/5

N2 - Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. Methods: The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (ntotal = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). Results: The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10-5) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10-4). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. Conclusion: Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

AB - Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals. Methods: The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n = 63) examined by a hyperinsulinemic euglycemic clamp (ntotal = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n = 5,847) and traits related to metabolic disease (n = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR). Results: The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = -9.9% [-14.4%;-4.0% (95% CI)], p = 5.1×10-5) and fasting total cholesterol (β = -0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p = 1.5×10-4). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele. Conclusion: Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

U2 - 10.1371/journal.pone.0040376

DO - 10.1371/journal.pone.0040376

M3 - Journal article

C2 - 22792295

SN - 1932-6203

VL - 7

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 7

ER -

The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation

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