Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study.
Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study.
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在一项前瞻性队列研究中，具有NAFLD的精益个体的基因组分析鉴定出单基因疾病。
DOI：
10.1016/j.jhepr.2023.100692
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发表时间：
2023-04
期刊：
影响因子：
8.3
通讯作者：
Ajmera, Veeral
中科院分区：
文献类型：
--
作者：
Zheng, Melanie;Huang, Daniel Q.;Konkwo, Chigoziri;Agrawal, Saaket;Khera, Amit V.;Loomba, Rohit;Vilarinho, Silvia;Ajmera, Veeral
非酒精性脂肪性肝病（NAFLD）瘦患者占受影响人群的10-20%，可能具有异质性疾病驱动因素。我们最近提出了对无内脏肥胖的瘦型NAFLD患者进行罕见单基因疾病驱动因素的评估。在这里，我们的目的是通过进行全外显子组测序，在一组经活检证实的NAFLD患者中验证这一框架。这项前瞻性研究包括124例经活检证实的NAFLD和配对肝活检患者，他们接受了标准化研究访视，包括肝脏脂肪和硬度的高级磁共振成像（MRI）评估。确定了6名瘦型NAFLD患者，并进行了全外显子组测序。两个瘦患者（33%）被确定为单基因疾病。单基因疾病的瘦型患者与非单基因疾病的瘦型患者具有相似的年龄、人体测量和MRI特征。患者1在ALDO B（醛缩酶B）中携带罕见的纯合致病突变，并被诊断为遗传性果糖不耐受。患者2携带载脂蛋白B（APOB）的罕见杂合突变。这种APOB变体的致病性（p.Val1856CysfsTer2）在英国生物库中得到进一步验证，并与较低的循环APOB水平相关（β = -0.51 g/L，95% CI -0.65至-0.36 g/L，p = 1.4 × 10-11）和MRI显示的较高肝脏脂肪（β =+10.4%，95% CI 4.3- 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。在这组特征良好的无内脏脂肪的瘦型NAFLD患者中，33%（2/6）具有罕见的单基因疾病驱动因素，突出了基因组分析在这种NAFLD亚型中的重要性。虽然大多数患有非酒精性脂肪性肝病（NAFLD）的人超重或肥胖，但一部分人很瘦，可能具有导致脂肪肝的独特基因突变。我们发现，33%的NAFLD研究参与者是瘦的，他们携带了导致脂肪肝的独特突变，并且这些突变的影响超出了肝脏。这项研究证明了在瘦个体中进行NAFLD遗传评估以识别疾病的不同亚型的价值。在一个特征明确的经活检证实的NAFLD患者队列中，124例患者中有6例（5%）为瘦型，无内脏肥胖。全外显子组测序揭示了6名瘦型患者中2名（33%）脂肪肝疾病的单基因原因：APOB突变导致杂合子家族性低β脂蛋白血症，ALDOB突变导致遗传性果糖不耐受。在英国生物样本库中验证了检测到的APOB变体（p.Val1856CysfsTer2）的致病性。单基因疾病在瘦型患者中的高发病率突出了这种NAFLD亚型中遗传评估的重要性。
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. 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. 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. 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. 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. In a well-characterized cohort of patients with biopsy-proven NAFLD, 6 out of 124 (5%) were lean without visceral adiposity. Whole-exome sequencing uncovered monogenic causes of fatty liver disease in 2 of 6 lean patients (33%): A mutation in APOB causing heterozygous familial hypobetalipoproteinemia and a mutation in ALDOB causing hereditary fructose intolerance. Pathogenicity of the detected APOB variant (p.Val1856CysfsTer2) was validated in the UK Biobank. High rate of monogenic disorders in lean patients highlights the importance of genetic assessment in this NAFLD subtype.
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影响因子：
3.5
作者：
Esposito, G;Vitagliano, L;Salvatore, F
通讯作者：
Salvatore, F
DOI：
10.1016/j.cgh.2020.11.005
发表时间：
2021-12
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Tamaki N;Munaganuru N;Jung J;Yonan AQ;Bettencourt R;Ajmera V;Valasek MA;Behling C;Loomba R
通讯作者：
Loomba R
影响因子：
11.1
作者：
Dongiovanni P;Stender S;Pietrelli A;Mancina RM;Cespiati A;Petta S;Pelusi S;Pingitore P;Badiali S;Maggioni M;Mannisto V;Grimaudo S;Pipitone RM;Pihlajamaki J;Craxi A;Taube M;Carlsson LMS;Fargion S;Romeo S;Kozlitina J;Valenti L
通讯作者：
Valenti L
影响因子：
30.8
作者：
Szustakowski, Joseph D.;Balasubramanian, Suganthi;Reid, Jeffrey G.
通讯作者：
Reid, Jeffrey G.
影响因子：
4.6
作者：
Pelusi, Serena;Baselli, Guido;Valenti, Luca Vittorio Carlo
通讯作者：
Valenti, Luca Vittorio Carlo