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Abstract：
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 × 10-15 and 4.84 × 10-10; odds ratios, 1.365 and 1.284, validation set = 1.39 × 10-4, and 7.15 × 10-4, 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 × 10-8 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 × 10-12 and MD-MAFLD: 1.300 (1.191-1.416), 2.90 × 10-9]. 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 × 10-8 and 1.225 (1.122, 1.340), 7.06 × 10-6, 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.
摘要：
全基因组关联研究已经确定了与非酒精性脂肪肝疾病相关的几种遗传变异。为了强调脂肪肝的代谢异常，代谢(功能障碍)相关的脂肪肝疾病(MAFLD)已经被引入；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鉴定与MAFLD相关的遗传因素。我们使用了基于韩国人群的2282名MAFLD受试者和一个4669名对照组的样本。我们在包括639例MAFLD患者和1578例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，没有MAFLD,代谢功能障碍（MD）-MAFLD，和超重/肥胖-MAFLD。在调整了年龄之后,性别,和主成分得分，rs738409[风险等位基因G]和rs3810622[风险等位基因T]，位于PNPLA3基因中，显示与MAFLD显著相关(P值，发现集=1.60×10-15和4.84×10-10；赔率比，1.365和1.284，验证集=1.39×10-4，和7.15×10-4，赔率比，分别为1.299和1.264）。位于GATAD2A基因中的另一个SNPrs59148799[风险等位基因G]显示出与MAFLD的显着关联（P值，发现集=2.08×10-8，验证集=0.034，赔率比，1.387和1.250）。rs738409与MAFLD亚型显著相关([超重/肥胖-MAFLD;比值比(95%置信区间),P值，1.515(1.351-1.700),1.43×10-12和MD-MAFLD：1.300（1.191-1.416），2.90×10-9]。rs3810622与超重/肥胖-MAFLD和MD-MAFLD之间存在显著关系[优势比（95%置信区间），P值，1.418(1.258,1.600),1.21×10-8和1.225（1.122，1.340），7.06×10-6，分别]；统计显著性保留在验证集中。在韩国人群中，PNPLA3与MAFLD和MAFLD亚型显着相关。这些结果表明遗传因素在MAFLD的发病中起重要作用。
