Park S Lani, Li Yuqing, Sheng Xin, Hom Victor, Xia Lucy, Zhao Kechen, Pooler Loreall, Setiawan V Wendy, Lim Unhee, Monroe Kristine R, Wilkens Lynne R, Kristal Bruce S, Lampe Johanna W, Hullar Meredith, Shepherd John, Loo Lenora L M, Ernst Thomas, Franke Adrian A, Tiirikainen Maarit, Haiman Christopher A, Stram Daniel O, Le Marchand Loïc, Cheng Iona
Keck School of Medicine University of Southern California Los Angeles CA USA.
Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco CA USA.
Hepatol Commun. 2020 Jun 25;4(8):1112-1123. doi: 10.1002/hep4.1533. eCollection 2020 Aug.
The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population-specific genetic variants associated with liver fat. We conducted a genome-wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population-based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin-like phospholipase domain containing 3 () at 22q13 was confirmed to be associated with percent liver fat ( = 3.52 × 10) but more strongly in women than men ( heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA-IR) (beta = 0.028; = 0.009) and circulating levels of insulin (beta = 0.022; = 0.020) and alanine aminotransferase (beta = 0.016; = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [] and collagen type XIX alpha 1 chain [] ( = 1.42 × 10) was also observed. Rs7724941 was associated with HOMA-IR (beta = 0.12; = 0.0005), insulin (beta = 0.11; = 0.0003), triglycerides (beta = 0.059; = 0.01), high-density lipoprotein (beta = -0.046; = 0.04), and sex hormone binding globulin (beta = -0.084; = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). : We replicated the rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.
全球脂肪肝发病率的上升是一个重大的公共卫生问题。因此，识别与肝脏脂肪相关的全球及特定人群的基因变异至关重要。我们对基于人群的多族裔队列肥胖表型研究中的1709名参与者进行了一项全基因组关联研究（GWAS），通过磁共振成像评估肝脏脂肪百分比和非酒精性脂肪性肝病（NAFLD）。我们的参与者包括美国五个种族/族裔群体的老年人：非裔美国人（n = 277）、日裔美国人（n = 424）、拉丁裔（n = 348）、夏威夷原住民（n = 274）和欧裔美国人（n = 386）。位于22q13的含patatin样磷脂酶结构域3（PNPLA3）中的已确定错义风险变异rs738409被证实与肝脏脂肪百分比相关（P = 3.52 × 10⁻⁴），但在女性中比男性更强（异质性P = = 0.002）。其频率与五个种族/族裔群体中NAFLD的患病率相关。Rs738409还与胰岛素抵抗的稳态模型评估（HOMA-IR）相关（β = 0.028；P = 0.009）以及胰岛素循环水平（β = 0.022；P = 0.020）和丙氨酸转氨酶（β = 0.016；P = 0.030）相关。还观察到肝脏脂肪百分比与rs77249491（位于6q13，在含1结构域的肢体区域1（LIMD1）和ⅪX型胶原α1链（COL19A1）之间）存在新的关联（P = 1.42 × 10⁻⁵）。Rs7724941与HOMA-IR（β = 0.12；P = 0.0005）、胰岛素（β = 0.11；P = 0.0003）、甘油三酯（β = 0.059；P = 0.01）、高密度脂蛋白（β = -0.046；P = 0.04）和性激素结合球蛋白（β = -0.084；P = 0.0012）相关。该变异存在于日裔美国人（次要等位基因频率[MAF]，8%）和夏威夷原住民（MAF，2%）中。结论：我们在多族裔人群中重复了rs738409的关联，并在日裔美国人和夏威夷原住民中鉴定出一种新的肝脏脂肪风险变异。需要对东亚和大洋洲人群的肝脏脂肪百分比进行GWAS以重复rs77249491的关联。
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