2型糖尿病和PNPLA3的次要等位基因始终可识别出与代谢功能障碍相关的高危脂肪性肝病。
Type 2 diabetes and the minor allele of PNPLA3 consistently identify high-risk metabolic dysfunction associated steatotic liver disease.
作者信息
Younossi Zobair M, Estep J Michael, Felix Sean, Lam Brian, Younossi Zaid, Racila Andrei, Stepanova Maria
机构信息
The Global NASH Council, Washington, DC, United States; Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, United States.
The Global NASH Council, Washington, DC, United States; Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, United States.
出版信息
Diabetes Res Clin Pract. 2025 Jan;219:111960. doi: 10.1016/j.diabres.2024.111960. Epub 2024 Dec 13.
BACKGROUND
Association of genetic factors with non-invasive tests (NITs) for MASLD has not been well established.
METHODS
Clinical and laboratory data, liver biopsy and/or liver stiffness measurement (LSM) by transient elastography were collected from MASLD patients seen in tertiary care hepatology practices. Minor allele frequency for genomic loci rs641738 (MBOAT7), rs58542926 (TM6SF2), rs738409 (PNPLA3), rs62305723 (HSD1713B) were evaluated for association with high ELF (≥11.3), high FIB-4 (≥3.25), high LSM (≥10 kPa), histologic fibrosis (stage 3/4 vs. stages 0-2).
RESULTS
Among 2289 MASLD patients with available polymorphism and liver fibrosis/NIT data [52 ± 13 years, 46 % male, BMI 36.6 ± 9.9, 35 % type 2 diabetes (T2D)], 53 % had high-risk allele (C > G) at rs738409 (PNPLA3), 70 % high-risk allele (C > T) at rs641738 (MBOAT7), 18 % high-risk minor allele (C > T) at rs58542926 (TM6SF2), 11 % low-risk minor allele (G > A) at rs62305723 (HSD17b13). Only PNPLA3-rs738409 (47 % CC, 40 % CG, 13 % GG) was significantly associated with higher NIT scores and histologic fibrosis: high ELF 2.8 % CC vs. 8.1 % CG/GG; high FIB-4 4.7 % CC vs. 11.6 % CG/GG; high LSM 10 % vs. 19 %; advanced histologic fibrosis 34 % CC vs. 60 % CG/GG (all p < 0.01). Similar associations of PNPLA3-rs738409 with NITs were observed in a subgroup of MASLD patients with T2D (n = 799; all p < 0.05). The PNPLA3-rs738409 CG/GG genotype, older age and T2D were independently associated with high ELF [OR (95 % CI) = 3.25 (2.03-5.20)], FIB-4 [OR = 2.75 (1.90-3.98)], LSM [OR = 2.71 (1.60-4.59)] scores and advanced histologic fibrosis [OR = 2.56 (1.81-3.62)].
CONCLUSIONS
The polymorphism rs738409 in the PNPLA3 gene, T2D, and older age were independent predictors of high-risk MASLD.
背景
遗传因素与非酒精性脂肪性肝病（MASLD）的非侵入性检测（NITs）之间的关联尚未完全明确。
方法
收集三级医疗肝病科诊治的MASLD患者的临床和实验室数据、肝活检及/或通过瞬时弹性成像进行的肝脏硬度测量（LSM）。评估基因组位点rs641738（MBOAT7）、rs58542926（TM6SF2）、rs738409（PNPLA3）、rs62305723（HSD1713B）的次要等位基因频率与高ELF（≥11.3）、高FIB-4（≥3.25）、高LSM（≥10kPa）、组织学纤维化（3/4期与0-2期）之间的关联。
结果
在2289例有可用多态性和肝纤维化/NIT数据的MASLD患者中[年龄52±13岁，男性46%，体重指数36.6±9.9，35%患有2型糖尿病（T2D）]，53%在rs738409（PNPLA3）处有高危等位基因（C>G），70%在rs641738（MBOAT7）处有高危等位基因（C>T），18%在rs58542926（TM6SF2）处有高危次要等位基因（C>T），11%在rs62305723（HSD17b13）处有低危次要等位基因（G>A）。只有PNPLA3-rs738409（47%为CC，40%为CG，13%为GG）与较高的NIT评分和组织学纤维化显著相关：高ELF时CC型为2.8%，CG/GG型为8.1%；高FIB-4时CC型为4.7%，CG/GG型为11.6%；高LSM时分别为10%和19%；高级组织学纤维化时CC型为34%，CG/GG型为60%（所有p<0.01）。在患有T2D的MASLD患者亚组（n=799；所有p<0.05）中也观察到PNPLA3-rs738409与NITs有类似关联。PNPLA3-rs738409的CG/GG基因型、年龄较大和T2D与高ELF[比值比（95%可信区间）=3.25（2.03-5.20）]、FIB-4[比值比=2.75（1.90-3.98）]、LSM[比值比=2.71（1.60-4.59）]评分及高级组织学纤维化[比值比=2.56（1.81-3.62）]独立相关。
结论
PNPLA3基因中的多态性rs738409、T2D和年龄较大是高危MASLD的独立预测因素。
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