Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea.
Department of Applied Statistics, Chung-Ang University, Seoul, Republic of Korea.
Sci Rep. 2024 Apr 29;14(1):9753. doi: 10.1038/s41598-024-60152-0.
Genome-wide association studies have identified several genetic variants associated with nonalcoholic fatty liver disease. To emphasize metabolic abnormalities in fatty liver, metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been introduced; thus, we aimed to investigate single-nucleotide polymorphisms related to MAFLD and its subtypes. A genome-wide association study was performed to identify genetic factors related to MAFLD. We used a Korean population-based sample of 2282 subjects with MAFLD and a control group of 4669. We replicated the results in a validation sample which included 639 patients with MAFLD and 1578 controls. Additionally, we categorized participants into three groups, no MAFLD, metabolic dysfunction (MD)-MAFLD, and overweight/obese-MAFLD. After adjusting for age, sex, and principal component scores, rs738409 [risk allele G] and rs3810622 [risk allele T], located in the PNPLA3 gene, showed significant associations with MAFLD (P-values, discovery set = 1.60 × 10 and 4.84 × 10; odds ratios, 1.365 and 1.284, validation set = 1.39 × 10, and 7.15 × 10, odds ratios, 1.299 and 1.264, respectively). An additional SNP rs59148799 [risk allele G] located in the GATAD2A gene showed a significant association with MAFLD (P-values, discovery set = 2.08 × 10 and validation set = 0.034, odds ratios, 1.387 and 1.250). rs738409 was significantly associated with MAFLD subtypes ([overweight/obese-MAFLD; odds ratio (95% confidence interval), P-values, 1.515 (1.351-1.700), 1.43 × 10 and MD-MAFLD: 1.300 (1.191-1.416), 2.90 × 10]. There was a significant relationship between rs3810622 and overweight/obese-MAFLD and MD-MAFLD [odds ratios (95% confidence interval), P-values, 1.418 (1.258, 1.600), 1.21 × 10 and 1.225 (1.122, 1.340), 7.06 × 10, respectively]; the statistical significance remained in the validation set. PNPLA3 was significantly associated with MAFLD and MAFLD subtypes in the Korean population. These results indicate that genetic factors play an important role in the pathogenesis of MAFLD.
全基因组关联研究已经确定了几个与非酒精性脂肪性肝病相关的遗传变异。为了强调脂肪肝的代谢异常，引入了代谢（功能）相关的脂肪性肝病（MAFLD）；因此，我们旨在研究与 MAFLD 及其亚型相关的单核苷酸多态性。进行了全基因组关联研究以确定与 MAFLD 相关的遗传因素。我们使用了一个基于韩国人群的 2282 名 MAFLD 患者和一个 4669 名对照组的样本。我们在一个包含 639 名 MAFLD 患者和 1578 名对照的验证样本中复制了结果。此外，我们将参与者分为三组：无 MAFLD、代谢功能障碍（MD）-MAFLD 和超重/肥胖-MAFLD。在调整年龄、性别和主成分得分后，位于 PNPLA3 基因中的 rs738409[风险等位基因 G]和 rs3810622[风险等位基因 T]与 MAFLD 显著相关（发现集 P 值分别为 1.60×10 和 4.84×10；比值比为 1.365 和 1.284，验证集 P 值分别为 1.39×10 和 7.15×10；比值比为 1.299 和 1.264）。位于 GATAD2A 基因中的另一个 SNP rs59148799[风险等位基因 G]与 MAFLD 显著相关（发现集 P 值分别为 2.08×10 和验证集 P 值为 0.034；比值比为 1.387 和 1.250）。rs738409 与 MAFLD 亚型（超重/肥胖-MAFLD；比值比（95%置信区间），P 值，1.515（1.351-1.700），1.43×10 和 MD-MAFLD：1.300（1.191-1.416），2.90×10）显著相关。rs3810622 与超重/肥胖-MAFLD 和 MD-MAFLD 显著相关[比值比（95%置信区间），P 值，1.418（1.258, 1.600），1.21×10 和 1.225（1.122, 1.340），7.06×10，分别]；在验证集中仍具有统计学意义。PNPLA3 与韩国人群中的 MAFLD 和 MAFLD 亚型显著相关。这些结果表明遗传因素在 MAFLD 的发病机制中起重要作用。
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