Pancreatitis Polygenic Risk Score is Associated with Acute Pancreatitis in Multifactorial Chylomicronemia Syndrome

IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of clinical lipidology Pub Date : 2024-07-01 DOI:10.1016/j.jacl.2024.04.063
Martine Paquette MSc, Amélie Taschereau, Véronique Desgagné PhD, Luigi Bouchard PhD, Sophie Bernard MD, Alexis Baass MD, Simon-Pierre Guay MD
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Abstract

Study Funding

This work was supported by the Cardiometabolic Health, Diabetes and Obesity Research Network (CMDO) from Le Fonds de recherche du Québec (FRQS). Luigi Bouchard received a Senior Research Scholar from the FRQS and is a member of the FRQS-Centre Hospitalier

Background/Synopsis

The most common cause of severe hypertriglyceridemia is multifactorial chylomicronemia syndrome (MCS). MCS is associated with an increased risk of acute pancreatitis (AP), but the risk is highly heterogenous between patients. The maximal concentration of triglycerides (TG) and the presence of a heterozygous rare pathogenic variant in a TG-related metabolism gene are known predictors of AP in MCS patients. Previous genome-wide association studies identified pancreatitis susceptibility genes. However, no study has assessed whether the accumulation of common variants in these pancreatitis susceptibility genes could help predict the risk of AP in MCS patients.

Objective/Purpose

To determine if a weighted polygenic risk score (PRS) including common variants in known pancreatitis susceptibility genes is associated with AP in MCS patients.

Methods

A total of 114 patients MCS underwent gene sequencing for the five canonical genes involved in TG metabolism (LPL, APOA5, APOC2, GPIHBP1, and LMF1). In addition, we genotyped eight single nucleotide polymorphisms (SNPs) in genes previously associated with pancreatitis (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1, and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus.

Results

A high pancreatitis-PRS score (defined as ≥ 0.44 and representing the median PRS score) was associated with a 2.94-fold increased risk of AP (p=0.02) among patients with MCS. The association between the pancreatitis-PRS and AP remained statistically significant after correction for known predictors of acute pancreatitis, including age, sex, body mass index, diabetes, the maximal TG concentration and the presence of a heterozygous pathogenic rare variant in a TG-related metabolism gene (p=0.04). MCS patients with a high pancreatitis - PRS and heterozygous for a pathogenic rare variant in a TG metabolism-related gene had a 9.50-fold increased risk of AP (p=0.001), compared to those with a low-PRS and no pathogenic variant.

Conclusions

This is the first study to show that the accumulation of common variants in known pancreatitis susceptibility genes is associated with AP in MCS patients. MCS patients with both a high pancreatitis-PRS score and a heterozygous pathogenic rare variant in a TG-related metabolism gene have higher risk of AP, similar to what is seen in monogenic form of severe hypertriglyceridemia. Genetic testing, including both rare and common variants, could help clinicians to identify MCS patients who may be at higher risk of acute pancreatitis and who may benefit from precision medicine.

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胰腺炎多基因风险评分与多因素乳糜微粒血症综合征急性胰腺炎有关
研究经费本研究得到了魁北克研究基金会(FRQS)心脏代谢健康、糖尿病和肥胖症研究网络(CMDO)的支持。路易吉-布沙尔(Luigi Bouchard)获得了魁北克研究基金会的高级研究奖学金,并且是魁北克研究基金会-医院中心的成员。多因素胆固醇血症综合征与急性胰腺炎(AP)风险增加有关,但不同患者的风险差异很大。甘油三酯(TG)的最大浓度和与 TG 相关的代谢基因中存在杂合性罕见致病变异是 MCS 患者患急性胰腺炎的已知预测因素。以往的全基因组关联研究发现了胰腺炎易感基因。但是,还没有研究评估这些胰腺炎易感基因中常见变异的累积是否有助于预测 MCS 患者的 AP 风险。方法共有 114 名 MCS 患者接受了参与 TG 代谢的五个典型基因(LPL、APOA5、APOC2、GPIHBP1 和 LMF1)的基因测序。此外,我们还对以前与胰腺炎相关的基因(ABCG8、CLDN2、CTRB1/2、CTRC、PRSS1、PRSS2、SPINK1 和 TWIST2)中的八个单核苷酸多态性 (SNP) 进行了基因分型。结果 在 MCS 患者中,胰腺炎-PRS 得分高(定义为≥ 0.44,代表 PRS 得分中位数)与 AP 风险增加 2.94 倍相关(P=0.02)。在校正了已知的急性胰腺炎预测因素(包括年龄、性别、体重指数、糖尿病、最大 TG 浓度和 TG 相关代谢基因中存在杂合致病性罕见变异)后,胰腺炎-PRS 与 AP 之间的关系仍具有统计学意义(p=0.04)。与低PRS和无致病变体的患者相比,胰腺炎-PRS高且TG代谢相关基因中存在致病性罕见变体的MCS患者罹患AP的风险增加了9.50倍(P=0.001)。同时具有高胰腺炎-PRS 评分和 TG 相关代谢基因中杂合致病性罕见变体的 MCS 患者罹患 AP 的风险较高,这与单基因重度高甘油三酯血症的情况类似。包括罕见变异和常见变异在内的基因检测可帮助临床医生识别急性胰腺炎风险较高、可能从精准医疗中获益的 MCS 患者。
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来源期刊
CiteScore
7.00
自引率
6.80%
发文量
209
审稿时长
49 days
期刊介绍: Because the scope of clinical lipidology is broad, the topics addressed by the Journal are equally diverse. Typical articles explore lipidology as it is practiced in the treatment setting, recent developments in pharmacological research, reports of treatment and trials, case studies, the impact of lifestyle modification, and similar academic material of interest to the practitioner. While preference is given to material of immediate practical concern, the science that underpins lipidology is forwarded by expert contributors so that evidence-based approaches to reducing cardiovascular and coronary heart disease can be made immediately available to our readers. Sections of the Journal will address pioneering studies and the clinicians who conduct them, case studies, ethical standards and conduct, professional guidance such as ATP and NCEP, editorial commentary, letters from readers, National Lipid Association (NLA) news and upcoming event information, as well as abstracts from the NLA annual scientific sessions and the scientific forums held by its chapters, when appropriate.
期刊最新文献
Burden of atherogenic lipids and association with cardiac allograft vasculopathy in heart transplant recipients. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. Identification and functional analysis of novel homozygous LMF1 variants in severe hypertriglyceridemia. Complex dyslipidemia induced by Lorlatinib therapy: A case study. Lipoprotein(a) in clinical practice: The role in long-term in-stent restenosis.
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