PDF(Pubmed)
Abstract：
UNASSIGNED: Lean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing.
UNASSIGNED: This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness.
UNASSIGNED: Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (APOB). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L, p = 1.4 × 10-11) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%, p = 8.8 × 10-4). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia.
UNASSIGNED: In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype.
UNASSIGNED: Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.
UNASSIGNED: This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness.
UNASSIGNED: Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (APOB). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L, p = 1.4 × 10-11) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%, p = 8.8 × 10-4). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia.
UNASSIGNED: In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype.
UNASSIGNED: Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.
摘要：
未经证实：患有非酒精性脂肪性肝病（NAFLD）的瘦弱患者占患病人群的10-20％，并且可能具有异质性的疾病驱动因素。我们最近提出了对无内脏肥胖的瘦NAFLD患者进行评估，以了解罕见的单基因疾病驱动因素。这里,我们的目的是通过进行全外显子组测序,在一个特征明确的活检证实NAFLD患者队列中验证这一框架.
UNASSIGNED：这项前瞻性研究包括124例活检证实为NAFLD和配对肝活检的患者，这些患者接受了标准化研究访问，包括对肝脏脂肪和硬度的高级磁共振成像（MRI）评估。
UNASSIGNED：确定了6名瘦小型NAFLD患者并进行了全外显子组测序。两名瘦患者（33％）被确定为患有单基因疾病。单基因疾病的瘦患者年龄相似，以及无单基因疾病的瘦患者的人体测量和MRI特征。患者1在ALDOB（醛缩酶B）中具有罕见的纯合致病性突变，并被诊断为遗传性果糖不耐受。患者2在载脂蛋白B（APOB）中具有罕见的杂合突变。该APOB变体的致病性（p。Val1856CysfsTer2）在英国生物银行中进一步验证，并与较低的循环APOB水平（β=-0.51g/L，95%CI-0.65至-0.36g/L，p=1.4×10-11）和MRI上较高的肝脏脂肪（β=10.4％，95%CI4.3-16.5%，p=8.8×10-4)。因此，患者2被诊断为杂合子家族性低β脂蛋白血症.
UNASSIGNED：在这群特征良好的无内脏肥胖的瘦型NAFLD患者中，33%(2/6)有罕见的单基因疾病驱动因素，强调基因组分析在这种NAFLD亚型中的重要性。
UASSIGNED：尽管大多数非酒精性脂肪性肝病（NAFLD）患者超重或肥胖，一个子集是瘦的，可能有独特的基因突变，导致他们的脂肪肝疾病。我们表明，33%的研究参与者患有NAFLD谁是瘦的有独特的突变，导致他们的脂肪肝，这些突变对肝脏有影响。这项研究证明了NAFLD在瘦小个体中的遗传评估对识别疾病的不同亚型的价值。
UNASSIGNED：这项前瞻性研究包括124例活检证实为NAFLD和配对肝活检的患者，这些患者接受了标准化研究访问，包括对肝脏脂肪和硬度的高级磁共振成像（MRI）评估。
UNASSIGNED：确定了6名瘦小型NAFLD患者并进行了全外显子组测序。两名瘦患者（33％）被确定为患有单基因疾病。单基因疾病的瘦患者年龄相似，以及无单基因疾病的瘦患者的人体测量和MRI特征。患者1在ALDOB（醛缩酶B）中具有罕见的纯合致病性突变，并被诊断为遗传性果糖不耐受。患者2在载脂蛋白B（APOB）中具有罕见的杂合突变。该APOB变体的致病性（p。Val1856CysfsTer2）在英国生物银行中进一步验证，并与较低的循环APOB水平（β=-0.51g/L，95%CI-0.65至-0.36g/L，p=1.4×10-11）和MRI上较高的肝脏脂肪（β=10.4％，95%CI4.3-16.5%，p=8.8×10-4)。因此，患者2被诊断为杂合子家族性低β脂蛋白血症.
UNASSIGNED：在这群特征良好的无内脏肥胖的瘦型NAFLD患者中，33%(2/6)有罕见的单基因疾病驱动因素，强调基因组分析在这种NAFLD亚型中的重要性。
UASSIGNED：尽管大多数非酒精性脂肪性肝病（NAFLD）患者超重或肥胖，一个子集是瘦的，可能有独特的基因突变，导致他们的脂肪肝疾病。我们表明，33%的研究参与者患有NAFLD谁是瘦的有独特的突变，导致他们的脂肪肝，这些突变对肝脏有影响。这项研究证明了NAFLD在瘦小个体中的遗传评估对识别疾病的不同亚型的价值。
