EBM Research Center, Kyoto University Graduate School of Medicine, Japan.
BMC Med Genet. 2010 Dec 22;11:172. doi: 10.1186/1471-2350-11-172.
In a genome-wide association scan, the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat content. We investigated whether this SNP is associated with the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) in the Japanese population.
SNP rs738409 was genotyped by the Taqman assay in 253 patients with NAFLD (189 with nonalcoholic steatohepatitis [NASH] and 64 with simple steatosis) and 578 control subjects. All patients with NAFLD underwent liver biopsy. Control subjects had no metabolic disorders. For a case-control study, the χ(2)-test (additive model) was performed. Odds ratios (ORs) were adjusted for age, gender, and body mass index (BMI) by using multiple logistic regression analysis with genotypes (additive model), age, gender, and BMI as the independent variables. Multiple linear regression analysis was performed to test the independent effect of risk allele on clinical parameters while considering the effects of other variables (age, gender, and BMI), which were assumed to be independent of the effect of the SNP.
The risk allele (G-allele) frequency of rs738409 was 0.44 in the control subjects and 0.60 in patients with NAFLD; this shows a strong association with NAFLD (additive model, P = 9.4 x 10(-10)). The OR (95% confidence interval) adjusted for age, gender, and BMI was 1.73 (1.25-2.38). Multiple linear regression analysis indicated that the G-allele of rs738409 was significantly associated with increases in aspartate transaminase (AST) (P = 0.00013), alanine transaminase (ALT) (P = 9.1 x 10(-6)), and ferritin levels (P = 0.014), and the fibrosis stage (P = 0.011) in the patients with NAFLD, even after adjustment for age, gender, and BMI. The steatosis grade was not associated with rs738409.
We found that in the Japanese population, individuals harboring the G-allele of rs738409 were susceptible to NAFLD, and that rs738409 was associated with plasma levels of ALT, AST, and ferritin, and the histological fibrosis stage. Our study suggests that PNPLA3 may be involved in the progression of fibrosis in NAFLD.
在全基因组关联扫描中，载脂蛋白样磷脂酶 3 基因（PNPLA3）中的单核苷酸多态性（SNP）rs738409 与肝脂肪含量增加强烈相关。我们研究了该 SNP 是否与日本人群中非酒精性脂肪性肝病（NAFLD）的发生和进展有关。
采用 Taqman 检测法对 253 例 NAFLD 患者（189 例非酒精性脂肪性肝炎[NASH]和 64 例单纯性脂肪变性）和 578 例对照进行 SNP rs738409 基因分型。所有 NAFLD 患者均行肝活检。对照组无代谢紊乱。对于病例对照研究，采用卡方检验（加性模型）进行分析。采用多变量 logistic 回归分析，以基因型（加性模型）、年龄、性别和体重指数（BMI）为自变量，对优势比（OR）进行调整。采用多元线性回归分析，在考虑其他变量（年龄、性别和 BMI）的影响的同时，检验风险等位基因对临床参数的独立影响，假设这些变量与 SNP 的影响无关。
对照组 rs738409 的风险等位基因（G 等位基因）频率为 0.44，NAFLD 患者为 0.60；这与 NAFLD 有很强的相关性（加性模型，P=9.4x10(-10)）。经年龄、性别和 BMI 调整后的 OR（95%置信区间）为 1.73（1.25-2.38）。多元线性回归分析表明，rs738409 的 G 等位基因与天门冬氨酸转氨酶（AST）（P=0.00013）、丙氨酸转氨酶（ALT）（P=9.1x10(-6)）和铁蛋白水平（P=0.014）的升高以及 NAFLD 患者的纤维化分期（P=0.011）显著相关，即使在调整年龄、性别和 BMI 后也是如此。脂肪变性程度与 rs738409 无关。
我们发现，在日本人群中，携带 rs738409 G 等位基因的个体易患 NAFLD，rs738409 与 ALT、AST 和铁蛋白的血浆水平以及组织学纤维化分期有关。我们的研究表明，PNPLA3 可能参与了 NAFLD 纤维化的进展。
