Nonalcoholic fatty liver disease (NAFLD) is a burgeoning medical problem that affects 20%-34% of the population in Western countries.1 Although the prevalence of NAFLD is somewhat lower in Asia, the frequency is increasing, and the disorder is now being seen in younger individuals.2, 3
NAFLD is a multifactorial disorder. Major risk factors include obesity, insulin resistance, and a variation (rs738409) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) that substitutes methionine for isoleucine at residue 148 (I148M).1 Only one prior study has examined the relationship between this variant and NAFLD in China. In that study, the variant was associated with fibrosis but not steatosis.4 Here, we examined the relationship between PNPLA3-I148M and liver triglyceride content in 203 unrelated adults with NAFLD who were recruited from an outpatient liver clinic at the First Hospital of China Medical University, Shenyang, China. Hepatic steatosis was diagnosed by liver ultrasonography using established criteria5; all other known causes of hepatic steatosis were excluded (see legend to Table 1). A total of 202 ethnically-matched controls with normal liver enzyme levels and no steatosis, as determined by ultrasonography, were recruited from primary care outpatient clinics at the same institution.
|Characteristic||NAFLD (n = 203)||Control (n = 202)||P Value|
|Age (years)||46.6 ± 13.4||41.9 ± 13.1||1.80E-04|
|BMI (kg/m2) (median)||26.6 ± 4.9||23.2 ± 4.3||2.10E-17|
|ALT (IU/L)||44.3 ± 39.8||17.0 ± 8.0||1.00E-18|
|AST (IU/L)||31.4 ± 28.0||19.8 ± 4.3||1.80E-08|
|GGT (IU/L)||61.2 ± 16.1||24.8 ± 16.2||2.00E-04|
|Cholesterol (mmol/L)||5.2 ± 1.0||4.5 ± 1.1||1.20E-09|
|Triglyceride (mmol/L)||1.7 ± 1.2||1.0 ± 0.6||9.00E-18|
|LDL-C (mmol/L)||3.3 ± 1.1||2.6 ± 1.1||4.30E-12|
|HDL-C (mmol/L)||1.3 ± 0.6||1.9 ± 0.9||8.50E-14|
|Glucose (mmol/L)||6.0 ± 1.3||5.6 ± 1.3||9.80E-04|
|APOC3 combined variant||0.65||0.66||0.92|
After obtaining institutional review board approval and written informed consent from patients, fasting blood samples were collected. A higher proportion of cases were men (60% versus 49%; nominal P = 0.04) and their mean age was greater than that of controls (46.6 versus 41.9 years of age; P = 1.8 × 10−4). Levels of circulating liver enzymes, low density lipoprotein cholesterol (LDL-C), triglyceride, and glucose were significantly higher and high density lipoprotein cholesterol (HDL-C) levels were significantly lower in cases than in controls (Table 1).
The frequency of the I148M variant was significantly higher in cases (0.45) than in controls (0.31) (P = 1.5 × 10−4), and the association remained robust after adjusting for age, sex, and body mass index (P = 3.7 × 10−3) (Fig. 1). The odds ratio for hepatic steatosis was 1.73 for each copy of the G allele (95% confidence interval: 1.49, 1.99). The I148M variant was also associated with higher serum alanine aminotransferase levels (nominal P = 1.1 × 10−7, adjusted P = 2.0 × 10−6), but not with body mass index, fasting glucose, or with lipid/lipoprotein levels (data not shown). No association was found between NAFLD and two SNPs in the promoter region of APOC3 (Table 1).
This is the first report to document an association between PNPLA3-I148M and hepatic steatosis in a population from mainland China. The relatively high frequency of the risk allele in China makes it imperative to control the weight gain that accompanies urbanization and adoption of Western eating habits.