PLoS One. 2015 Jul 22;10(7):e0132640. doi: 10.1371/journal.pone.0132640.

Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects

 

Kentaro Oniki1, Junji Saruwatari1, Tomoko Izuka1, Ayami Kajiwara1, Kazunori Morita1, Misaki Sakata1, Koji Otake2, Yasuhiro Ogata2, Kazuko Nakagawa1,3.

1 Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

2 Japanese Red Cross Kumamoto Health Care Center, Kumamoto, Japan

3 Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

 

Abstract

In normal weight subjects (body mass index < 25 kg/m2), non-alcoholic fatty liver disease (NAFLD) is likely to coexist with metabolic diseases. The patatin-like phospholipase 3 (PNPLA3) polymorphism rs738409 (c.444C>G) is associated with the risk of NAFLD and/or renal dysfunction; however, the influence of the weight status on the associations remains unknown. We aimed to clarify the associations of the PNPLA3 polymorphism with the risk of NAFLD and/or renal dysfunction, while also paying careful attention to the weight status of the subjects. Cross-sectional and retrospective longitudinal studies with 5.5 ± 1.1 years of follow-up were conducted in 740 and 393 Japanese participants (61.2 ± 10.5 and 67.5 ± 6.0 years), respectively, during a health screening program. Among 591 subjects who did not have a habitual alcohol intake and/or hepatitis B or C virus infections, the PNPLA3 G/G genotype was associated with the risk for NAFLD in normal weight subjects [odds ratio (95% CI): 3.06 (1.11-8.43), P < 0.05]. Among all subjects, carriers of the PNPLA3 G/G genotype with a normal weight had a lower eGFR than those of the C/C genotype [partial regression coefficient (SE): -3.26 (1.48), P < 0.05]. These associations were replicated in the longitudinal analyses. Among the overweight subjects, none of the genotypes were significantly associated in the cross-sectional and longitudinal analyses; however, the power of the analyses was small, especially in the analyses among overweight subjects. The findings of this study suggest that carriers of the PNPLA3 G/G genotype with a normal weight status should nevertheless be carefully monitored for the presence of NAFLD and/or renal dysfunction.

PMID: 26200108

 

Supplements:

Non-alcoholic fatty liver disease (NAFLD) is a major worldwide health problem that is an early indicator of type 2 diabetes, renal dysfunction and cardiovascular disease (1, 2). Even though the disease is strongly associated with obesity (1, 2), it has been found in a high percentage of Asian patients with normal weight [body mass index (BMI) < 25 kg/m2] (3, 4). NAFLD patients with normal weight appear to have different characteristics compared to overweight or obese patients (i.e., the differential distribution of visceral adipose tissue, recent increase in body weight and intake of high cholesterol diet and peculiar genetic background) (3). Therefore, clarifying the risk factors for NAFLD among the normal weight subjects will help to identify susceptible populations for the early prevention and treatment of NAFLD and its complications, especially in Asian population.

 

The rs738409 polymorphism (encoding I148M) in the patatin-like phospholipase 3 (PNPLA3) gene has been consistently recognized to be a major genetic factor for the development of NAFLD and advanced liver diseases (5-7). PNPLA3 is expressed in the liver and has acyl hydrolase activity (8). The PNPLA3 rs738409 polymorphism has been associated with the loss of the protein’s hydrolyzing function and with the hepatic triglyceride accumulation (8). The recent cross-sectional study also reported that the presence of the PNPLA3 rs738409 polymorphism was associated with a lower estimated glomerular filtration rate (eGFR) and a higher prevalence of microalbuminuria and chronic kidney disease (9). However, these effects of the PNPLA3 polymorphism among normal weight subjects remains unknown. The primary objective of this exploratory study is to investigate the relationships of the PNPLA3 genotype with the risk for NAFLD and decline in the renal function among Japanese participants of the health screening program, while also paying careful attention to the weight status of the subjects.

 

We analyzed the associations between the PNPLA3 genotype and the risk of NAFLD stratified by weight status using a logistic regression model. The risk of NAFLD was significantly higher in the normal weight subjects with the PNPLA3 C/G or G/G genotypes than in those with the C/C genotype (Figure 1). Next, we further analyzed the associations between the PNPLA3 genotype and a decline in the eGFR stratified by weight status using a multiple linear regression model. The eGFR value was significantly lower in the normal weight subjects with the PNPLA3 G/G genotype than in those with the C/C genotype (Figure 1). These associations were not observed in overweight individuals.

 

This importance of this study is that for the first time the effects of the PNPLA3 rs738409 polymorphism on the risk for NAFLD and decline in eGFR were significant in normal weight subjects. In Asians, the prevalence of NAFLD is equivalent to that in Caucasians, despite having lower BMI (3, 4). Asians with NAFLD have been known to exhibit a predominantly impaired insulin secretion (3). Among the normal weight subjects, the presence of NAFLD was more strongly associated with the prevalence of diabetes, hypertension and metabolic syndrome compared to the obese/overweight subjects (4). The findings of this study suggest that even though carriers of the PNPLA3 G/G genotype may have a normal weight status, they should nevertheless be carefully monitored for the presence of NAFLD and a decline in the renal function. The information regarding the PNPLA3 genotype in normal weight subjects may be utilized for health promotion, especially in Asian population, although further investigations with a larger number of subjects are needed to verify and further clarify these findings.

 

 

JS fig1

Figure 1. The longitudinal changes in the prevalence of NAFLD and in the mean value of eGFR stratified by the PNPLA3 genotype among normal weight subjects.

 

References

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  5. Anstee QM, Day CP. The genetics of NAFLD. Nature reviews Gastroenterology & hepatology. 2013;10(11):645-55.
  6. Shen JH, Li YL, Li D, Wang NN, Jing L, Huang YH. The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis. Journal of lipid research. 2015;56(1):167-75.
  7. Shen J, Wong GL, Chan HL, Chan HY, Yeung DK, Chan RS, et al. PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome. Alimentary pharmacology & therapeutics. 2014;39(5):532-9.
  8. Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. The Journal of biological chemistry. 2011;286(43):37085-93.
  9. Musso G, Cassader M, Gambino R. PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in NAFLD. Hepatology. 2014; doi: 10.1002/hep.27643.

 

Contact:

Junji Saruwatari, PhD

Associate Professor

Division of Pharmacology and Therapeutics,

Graduate School of Pharmaceutical Sciences,

Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973,

Fax: +81-96-371-4512

Tel: +81-96-371-4512

E-mail: junsaru@gpo.kumamoto-u.ac.jp

 

 

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