Westra W M, Rygiel A M, Mostafavi N, de Wit G M J, Roes A L, Moons L M G, Peppelenbosch M P, Ouburg S, Morré S A, Jacobs M, Siersema P D, Repping S, Wang K K, Krishnadath K K
CEMM, Amsterdam UMC-AMC, Amsterdam, The Netherlands.
Department of Gastroenterology and Hepatology, Mayo Foundation, Rochester, MN, USA.
Dis Esophagus. 2020 Sep 4;33(9). doi: 10.1093/dote/doaa011.
Barrett's esophagus (BE) is a metaplastic condition of the distal esophagus, resulting from longstanding gastroesophageal reflux disease (GERD). BE predisposes for the highly malignant esophageal adenocarcinoma (EAC). Both BE and EAC have the highest frequencies in white males. Only a subset of patients with GERD develop BE, while <0.5% of BE will progress to EAC. Therefore, it is most likely that the development of BE and EAC is associated with underlying genetic factors. We hypothesized that in white males, Y-chromosomal haplogroups are associated with BE and EAC. To investigate this we conducted a multicenter study studying the frequencies of the Y-chromosomal haplogroups in GERD, BE, and EAC patients. We used genomic analysis by polymerase chain reaction and restriction fragment length polymorphism to determine the frequency of six Y-chromosomal haplogroups (DE, F(xJ,xK), K(xP), J, P(xR1a), and R1a) between GERD, BE, and EAC in a cohort of 1,365 white males, including 612 GERD, 753 BE patients, while 178 of the BE patients also had BE-associated EAC. Univariate logistic regression analysis was used to compare the outcomes. In this study, we found the R1a (6% vs. 9%, P = 0.04) and K (3% vs. 6%, P = 0.035) to be significantly underrepresented in BE patients as compared to GERD patients with an odds ratio (OR) of 0.63 (95% CI 0.42-0.95, P = 0.03) and of 0.56 (95% CI 0.33-0.96, P = 0.03), respectively, while the K haplogroup was protective against EAC (OR 0.30; 95% CI 0.07-0.86, P = 0.05). A significant overrepresentation of the F haplogroup was found in EAC compared to BE and GERD patients (34% vs. 27% and 23%, respectively). The F haplogroup was found to be a risk factor for EAC with an OR of 1.5 (95% CI 1.03-2.19, P = 0.03). We identified the R1a and K haplogroups as protective factors against development of BE. These haplogroups have low frequencies in white male populations. Of importance is that we could link the presence of the predominantly occurring F haplogroup in white males to EAC. It is possible that this F haplogroup is associated to genetic variants that predispose for the EAC development. In future, the haplogroups could be applied to improve stratification of BE and GERD patients with increased risk to develop BE and/or EAC.
巴雷特食管（BE）是一种远端食管的化生状态，由长期胃食管反流病（GERD）引起。BE易引发高度恶性的食管腺癌（EAC）。BE和EAC在白人男性中发病率最高。只有一部分GERD患者会发展为BE，而BE患者中进展为EAC的比例不到0.5%。因此，BE和EAC的发生很可能与潜在的遗传因素有关。我们推测，在白人男性中，Y染色体单倍群与BE和EAC有关。为了对此进行研究，我们开展了一项多中心研究，调查GERD、BE和EAC患者中Y染色体单倍群的频率。我们采用聚合酶链反应和限制性片段长度多态性进行基因组分析，以确定1365名白人男性队列中GERD、BE和EAC患者的六个Y染色体单倍群（DE、F(xJ,xK)、K(xP)、J、P(xR1a)和R1a）的频率，其中包括612名GERD患者、753名BE患者，且178名BE患者同时患有与BE相关的EAC。采用单因素逻辑回归分析比较结果。在本研究中，我们发现与GERD患者相比，R1a单倍群（6%对9%，P = 0.04）和K单倍群（3%对6%，P = 0.035）在BE患者中的比例显著偏低，优势比（OR）分别为0.63（95%可信区间0.42 - 0.95，P = 0.03）和0.56（95%可信区间0.33 - 0.96，P = 0.03），而K单倍群对EAC具有保护作用（OR 0.30；95%可信区间0.07 - 0.86，P = 0.05）。与BE和GERD患者相比，EAC患者中F单倍群的比例显著过高（分别为34%对27%和23%）。F单倍群被发现是EAC的一个危险因素，OR为1.5（95%可信区间1.03 - 2.19，P = 0.03）。我们确定R1a和K单倍群是预防BE发生的保护因素。这些单倍群在白人男性群体中的频率较低。重要的是，我们发现白人男性中主要出现F单倍群与EAC有关。这个F单倍群可能与易引发EAC的遗传变异有关。未来，这些单倍群可用于改善BE和GERD患者的分层，这些患者发生BE和/或EAC的风险增加。
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