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


CONCLUSIONS
Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. nikolaj.krarup@sund.ku.dk
Nikolaj Thure
NT
Krarup
Niels
N
Grarup
Karina
K
Banasik
Martin
M
Friedrichsen
Kristine
K
Færch
Camilla Helene
CH
Sandholt
Torben
T
Jørgensen
Pernille
P
Poulsen
Daniel Rinse
DR
Witte
Allan
A
Vaag
Thorkild
T
Sørensen
Oluf
O
Pedersen
Torben
T
Hansen
D015992:Body Mass Index; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood*; D003718:Denmark; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D005215:Fasting / Q000097:blood; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics; D007333:Insulin Resistance; D008049:Lipase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood*; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D002784:Cholesterol; D008049:Lipase; D008565:Membrane Proteins; D014280:Triglycerides; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent