Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity.
OBJECTIVE
The insulin responsive adiponutrin or patatin-like phospholipase 3 (PNPLA3, previously ADPN) gene shows association with obesity and in vitro adipocyte lipolysis. This study aimed to replicate the association between PNPLA3 variants and obesity, and to investigate their effect on insulin resistance and beta-cell function.


METHODS
rs738409 (Met148Ile) and rs2072907 (C to G) were genotyped using TaqMan allelic discrimination assay in a Swedish population-based sample (n=1811). Oral glucose tolerance test (OGTT) with data from three time points (0, 30, and 120 min) were available from individuals under the age of 50 years (n=973).


RESULTS
Both variant alleles were associated with decreased prevalence of obesity (P<0.05); odds ratio 0.75 (0.61-0.93) per carried Ile-allele for rs738409 and 0.80 (0.64-1.00) per carried G-allele for rs2072907. For obesity as a quantitative trait, there was no association in the whole population, but in obese subjects body mass index (BMI; P=0.023) and waist (P=0.0098) were higher in carriers of the Ile-allele. The Ile-carriers also displayed decreased insulin secretion in response to OGTT (30 min insulin; P=0.007, insulinogenic index; P=0.0051) with no significant differences in fasting plasma glucose (P=0.31), beta-cell function (disposition index; P=0.17) or homeostasis model of assessment insulin resistance (HOMA-IR; P=0.063). The correlation between BMI and HOMA-IR differed (Met/X versus Ile/Ile, P=0.028), Met-allele carriers were seemingly more insulin resistant at a lower BMI. The rs2072907 variant shows similar results for insulin secretion. The significance of this finding remained after adjusting for age, gender, and level of self-reported leisure-time physical activity.


CONCLUSIONS
We confirm the association between PNPLA3 and obesity. In addition, the rs738409 variant was associated with insulin secretion. There seems to be a differential effect of the Ile-allele depending on the degree of obesity, possibly as a consequence of insulin resistance.
Johansson
Lovisa E
LE
Department of Clinical Sciences Malmö, Malmö University Hospital MAS, Lund University, Malmö, Sweden. lovisa.johansson@med.lu.se
Lindblad
Ulf
U
Larsson
Charlotte A
CA
Råstam
Lennart
L
Ridderstråle
Martin
M
D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D015995:Prevalence; D013548:Sweden / Q000453:epidemiology
D007328:Insulin; D008565:Membrane Proteins; C436316:adiponutrin