Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Radiology of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Hepatol Commun. 2024 Jun 5;8(6). doi: 10.1097/HC9.0000000000000388. eCollection 2024 Jun 1.
Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether genetic variants of phospholipid metabolism modify these relationships.
This case-control study consecutively recruited 600 patients who underwent MRI-based proton density fat fraction examination (240 participants with serum metabonomics analysis, 128 biopsy-proven cases) as 3 groups: healthy control, nonobese MASLD, and obese MASLD, (n = 200 cases each). Ten variants of phospholipid metabolism-related genes [phospholipase A2 Group VII rs1805018, rs76863441, rs1421378, and rs1051931; phospholipase A2 receptor 1 (PLA2R1) rs35771982, rs3828323, and rs3749117; paraoxonase-1 rs662 and rs854560; and ceramide synthase 4 (CERS4) rs17160348)] were genotyped using SNaPshot.
The T-allele of CERS4 rs17160348 was associated with a higher risk of both obese and nonobese MASLD (OR: 1.95, 95% CI: 1.20-3.15; OR: 1.76, 95% CI: 1.08-2.86, respectively). PLA2R1 rs35771982-allele is a risk factor for nonobese MASLD (OR: 1.66, 95% CI: 1.11-1.24), moderate-to-severe steatosis (OR: 3.24, 95% CI: 1.96-6.22), and steatohepatitis (OR: 2.61, 95% CI: 1.15-3.87), while the paraoxonase-1 rs854560 T-allele (OR: 0.50, 95% CI: 0.26-0.97) and PLA2R1 rs3749117 C-allele (OR: 1.70, 95% CI: 1.14-2.52) are closely related to obese MASLD. After adjusting for sphingomyelin level, the effect of the PLA2R1 rs35771982CC allele on MASLD was attenuated. Furthermore, similar effects on the association between the CERS4 rs17160348 C allele and MASLD were observed for phosphatidylcholine, phosphatidic acid, sphingomyelin, and phosphatidylinositol.
The mutations in PLA2R1 rs35771982 and CERS4 rs17160348 presented detrimental impact on the risk of occurrence and disease severity in nonobese MASLD through altered phospholipid metabolism.
异常的磷脂代谢与代谢相关脂肪性肝病（MASLD）的发生和发展有关。我们旨在阐明磷脂代谢的遗传变异是否会改变这些关系。
这项病例对照研究连续招募了 600 名接受基于 MRI 的质子密度脂肪分数检查的患者（240 名进行了代谢组学分析，128 名经活检证实），分为三组：健康对照组、非肥胖性 MASLD 组和肥胖性 MASLD 组（每组 200 例）。对 10 个与磷脂代谢相关基因的变体[磷脂酶 A2 组 VII rs1805018、rs76863441、rs1421378 和 rs1051931；磷脂酶 A2 受体 1（PLA2R1）rs35771982、rs3828323 和 rs3749117；对氧磷酶-1 rs662 和 rs854560；和神经酰胺合酶 4（CERS4）rs17160348]进行了 SNaPshot 基因分型。
CERS4 rs17160348 的 T 等位基因与肥胖和非肥胖性 MASLD 的发病风险均升高（OR：1.95，95%CI：1.20-3.15；OR：1.76，95%CI：1.08-2.86）。PLA2R1 rs35771982 等位基因是发生非肥胖性 MASLD 的危险因素（OR：1.66，95%CI：1.11-1.24）、中重度脂肪变性（OR：3.24，95%CI：1.96-6.22）和脂肪性肝炎（OR：2.61，95%CI：1.15-3.87），而对氧磷酶-1 rs854560 的 T 等位基因（OR：0.50，95%CI：0.26-0.97）和 PLA2R1 rs3749117 的 C 等位基因（OR：1.70，95%CI：1.14-2.52）与肥胖性 MASLD 密切相关。调整鞘磷脂水平后，PLA2R1 rs35771982CC 等位基因对 MASLD 的影响减弱。此外，CERS4 rs17160348C 等位基因与 MASLD 之间的关联也观察到类似的效果，与磷酸胆碱、磷脂酸、鞘磷脂和磷脂酰肌醇有关。
PLA2R1 rs35771982 和 CERS4 rs17160348 的突变通过改变磷脂代谢对非肥胖性 MASLD 的发生和疾病严重程度产生有害影响。
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