Since DAG (FA18:1) has been implicated in hepatic insulin resistance, the unaltered proportion of DAG (FA18:1) in I148MPNPLA3 carriers with fatty liver may explain the normal insulin sensitivity in these subjects.
Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver.
The presence of the minor PNPLA3p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05).
This study aimed to confirm the association of the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant with non-alcoholic fatty liver disease (NAFLD) and the degree of steatosis, as well as the additive effect of body mass index (BMI) or the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M and TM6SF2 E167K variants in NAFLD.
Reduction of Caloric Intake Might Override the Prosteatotic Effects of the PNPLA3p.I148M and TM6SF2 p.E167K Variants in Patients with Fatty Liver: Ultrasound-Based Prospective Study.
In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR)=0.44, P=0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR=2.06, P=0.005), more abdominal visceral adipose tissue (OR=1.08 per 10 cm(2), P<0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥4.9 (OR=2.50, P=0.001).
We showed for the first time, to our knowledge, that carriers of the PNPLA3 148M allele with either fatty liver plus obesity or obesity alone have lower fasting circulating retinol concentrations.
However, PNPLA3rs2294918rs2294918" genes_norm="80339">E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage.
Interleukin-28B (IL28B) and patatin-like phospholipase domain containing 3 (PNPLA3) gene polymorphisms are associated with hepatitis C virus (HCV) clearance and fatty liver, respectively.
The G-allele of PNPLA3rs738409 was associated with NAFLD (odds ratio [OR] 1.55, 95% confidence interval 1.13-2.11, P = 0.006) and moderate-to-severe steatosis (OR 3.77, 95% confidence interval 1.78-7.98, P = 0.001) adjusted for age, sex, and BMI standard deviation score.
The presence of the TM6SF2 c.499A allele in the donor (p=0.014), the PNPLA3 c.444G allele in the donor (p<0.001), posttransplant BMI (p<0.001) and serum triglycerides (p=0.047) independently predicted increased liver fat content on multivariable analysis whereas noncirrhotic liver disease as an indication for liver transplantation was associated with lower risk of steatosis (p=0.003).
The genetic polymorphism with an rs738409" genes_norm="80339">isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis.
A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children.
The presence of the PNPLA3 allle [M] was associated with increased hepatic triglyceride content (P = .03), steatosis detected by magnetic resonance imaging (P = 0.04), and decreased serum glucose concentrations (P = .04).
PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels.
At multivariable regression analysis, SGA at birth increased fourfold the likelihood of severe steatosis (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.43-10.9, P=0.008) and threefold the likelihood of NAFLD Activity Score (NAS)≥5 (OR 2.98, 95% CI 1.06-8.33, P=0.037) independently of homeostasis model assessment of insulin resistance and PNPLA3 genotype.
Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results.In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409).
Previous studies of the PNPLA3I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis.
Our data show a paradoxical dissociation between hepatic DNL and hepatic fat content due to the PNPLA3 148M allele indicating that increased DNL is not a key feature in all individuals with hepatic steatosis, and reinforces the contribution of decreased mobilization of hepatic triglycerides for hepatic lipid accumulation in subject with the PNPLA3 148M allele.