Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
Liver Int. 2022 Jul;42(7):1585-1592. doi: 10.1111/liv.15186. Epub 2022 Feb 24.
Gallstones are increasingly common in children. Genetic analyses of adult cohorts demonstrated that the sterol transporter ABCG8 p.D19H and Gilbert UGT1A1*28 variants enhance the odds of developing gallstones. The genetic background of common lithiasis in children remains unknown.
Overall, 214 children with gallstone disease (1 month-17 years, 107 boys) were inclueded. The control cohorts comprised 214 children (age 6-17 years, 115 boys) and 172 adults (age 40-92 years, 70 men) without gallstones. The ABCG8 p.D19H and UGT1A1*28 polymorphisms as well as ABCB4 (c.504C>T rs1202283, c.711A>T rs2109505) and NPC1L1 variants (p.V1296V rs217434, c.-18C>A rs41279633) were genotyped using TaqMan assays. Serum concentrations of plant sterols and cholesterol precursors were measured by gas chromatography/mass spectrometry.
The ABCG8 risk allele was associated with an increased risk of stones (OR = 1.82, p = .03). Children carrying the p.19H allele presented with lower serum concentrations of surrogate markers of intestinal cholesterol absorption and decreased ratios of phytosterols to the cholesterol precursor desmosterol. Carriers of the common NPC1L1 rs217434 allele had an increased gallstone risk compared with stone-free adults (OR 1.90, p < .01). This variant also affected the ratio of phytosterols to cholesterol precursors (p = .03). Other tested variants were not associated with gallstone risk.
The p.D19H ABCG8 and, to a lesser extent, NPC1L1 rs217434 variants increase the risk of early-onset gallstone formation. These results point to the presence of a common lithogenic pathway in children and adults.
胆石症在儿童中越来越常见。对成人队列的基因分析表明，固醇转运体 ABCG8 p.D19H 和 Gilbert UGT1A1*28 变体增加了患胆石症的几率。儿童常见结石的遗传背景尚不清楚。
共纳入 214 例胆石症患儿（1 个月至 17 岁，男 107 例）。对照组包括 214 例儿童（6-17 岁，男 115 例）和 172 例无胆石症的成年人（40-92 岁，男 70 例）。采用 TaqMan 法检测 ABCG8 p.D19H 和 UGT1A1*28 多态性以及 ABCB4（c.504C>T rs1202283、c.711A>T rs2109505）和 NPC1L1 变体（p.V1296V rs217434、c.-18C>A rs41279633）。采用气相色谱/质谱法测定血清植物固醇和胆固醇前体浓度。
ABCG8 风险等位基因与结石风险增加相关（OR=1.82，p=0.03）。携带 p.19H 等位基因的儿童血清肠胆固醇吸收替代标志物浓度较低，植物固醇与胆固醇前体去甲胆固醇的比值降低。与无结石的成年人相比，常见 NPC1L1 rs217434 等位基因携带者的胆结石风险增加（OR 1.90，p<0.01）。该变体还影响植物固醇与胆固醇前体的比值（p=0.03）。其他测试的变体与胆结石风险无关。
p.D19H ABCG8 以及程度较轻的 NPC1L1 rs217434 变体增加了早发性胆石形成的风险。这些结果表明儿童和成人存在共同的成石途径。
