EDITORIAL What We Know and What We Need to Know About Familial Gastroesophageal Reﬂux Disease and Barrett’s Esophagus arrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC), a cancer that continues to carry a poor prognosis.1 The exponential increase in both BE and EAC over the past 4 decades2,3 undoubtedly is related to some, as yet uncharacterized, changing environmental agent. Both BE and EAC arise as a consequence of chronic inﬂammatory injury to the distal esophagus from gastric reﬂuxate. Although BE and EAC traditionally have been considered environmental diseases, the fact that they occur predominantly in white men is a clue to an underlying genetic susceptibility. Alterations in the environment that have caused an increased incidence of these diseases also have led to the recent recognition of familial aggregation. BE and EAC are now proposed to be complex diseases caused by an interplay of genetic susceptibility with environmental factors that include, but are not limited to, gastroesophageal reﬂux, diet, central obesity, and smoking.
Familial Aggregation of Gastroesophageal Reﬂux Disease, Barrett’s Esophagus, and Esophageal Adenocarcinoma There is evidence implicating genetic factors, even in the development of gastroesophageal reﬂux disease (GERD). Two studies, one by Romero et al4 and one by Trudgill et al,5 have shown a signiﬁcantly increased prevalence of GERD among family members of patients with BE and EAC. The higher concordance of reﬂux symptoms found in monozygotic twins compared with dizygotic twins with an estimated polygenic heritability of 30% to 40% further strengthens a genetic hypothesis.6–8 However, molecular studies that identify genetic factors to explain familial GERD are awaited. Familial aggregation is the ﬁrst evidence/recognition of the genetic basis of disease. Numerous case reports starting in the 1970s documented familial clusters of BE and EAC.7,9–12 The prevalence of veriﬁed BE within these families was well over 20%, compared with a less than 3% prevalence in the general population.13 The next step in the evidence chain was a hospital-based, case-control study in which we showed aggregation of BE and associated cancers in Caucasian families.14 This phenomenon was termed familial Barrett’s esophagus.15 Subsequently, the prevalence of familial BE in patients with these diseases was estimated to be 6% to 7.3%.16,17 In a follow-up prospective study, we showed that endoscopic screening of relatives of familial BE probands identiﬁed new BE
cases. This ﬁnding added credence to the familial clustering hypothesis, and also provided practical implications for high-risk screening.18 Familial aggregation must be interpreted cautiously. Aggregation of BE and EAC could be owing to common environmental exposures in families, such as smoking,19,20 diet, a genetic or inherited susceptibility to risk factors such as obesity or GERD,21–23 a genetic susceptibility to the development of metaplastic or neoplastic esophageal epithelium, or a combination of these effects. BE and EAC occur at a younger age in affected members of multiply affected BE families.24,25 Appearance of disease in younger individuals, which normally would not manifest until older ages in sporadic cases, also is supportive of the genetic hypothesis. Based on previous studies,14,24 we postulated that, similar to other metaplastic and neoplastic diseases, the development of Barrett’s epithelium and subsequent adenocarcinomas is caused by complex pathways involving inherited germline mutations and environmentally induced acquired somatic mutations. A study of inheritance patterns in 70 BE families by The Familial Barrett Esophagus Consortium suggested that inheritance of familial BE is autosomal dominant.24 Furthermore, our segregation analysis of 881 familial BE pedigrees provided reasonable epidemiologic evidence in support of the inheritance of one or more rare, autosomal-dominant susceptibility alleles.15 These ﬁndings suggest Mendelian inheritance, not necessarily monogenic, with markedly reduced penetrance as a result of environmental factors.
Findings From Genetic Linkage and Genome-Wide Association Studies More recent genetic linkage studies and genome-wide association studies (GWAS) have provided direct evidence of a genetic predisposition. A linkage study followed by a ﬁne mapping association study of familial BE identiﬁed association with single nucleotide polymorphisms (SNPs) in the MSR1 (8p), ASCC1 (10q), and CTHRC1 (8q) genes,26 which are involved in macrophage function and inﬂammatory pathways. A GWAS by the Barrett’s and Esophageal Adenocarcinoma Consortium showed that both BE and EAC are inﬂuenced by multiple germline genetic variants of small effect. By using genome-wide genotype data on unrelated cases and controls, as opposed to traditional twin studies of heritability, Barrett’s and Esophageal Adenocarcinoma Consortium investigators measured the array heritability for BE and EAC to be 35% and 25%, respectively.27 They also found a signiﬁcant polygenic overlap and a strong genetic correlation between BE and EAC, suggesting substantial shared genetic architecture between BE and EAC. Clinical Gastroenterology and Hepatology 2014;-:-–-
Sun et al
A large GWAS study, the ﬁrst of its kind, using unrelated BE cases and controls, identiﬁed 2 SNPs on 2 chromosomes, namely 6p21 and 16q24, to be associated signiﬁcantly with risk of BE.28 The 16q24 is of particular interest because its closest protein coding gene, termed FOXF1, serves as a transcription factor in the hedgehog signaling pathway. FOXF1 has an important role in the development of the foregut during organogenesis.29 It also has been shown that certain FOXF1 variants that are responsible for increased BE risk also increase the risk of EAC in Caucasians.30 A recent unrelated case-control GWAS that looked at EACs as well as BE, in addition to conﬁrming the previous associations with FOXF1 and HLA loci, identiﬁed new susceptibility loci on chromosomes 19p, 9q, and 3p, in the region of genes associated with oncogenic activity and transcription factors in esophageal speciﬁcation and esophageal development.31 The ﬁnding that the previously identiﬁed Barrett’s esophagus association locus also has a role in EAC risk suggests that much of the genetic basis for EAC lies in the development of BE. These associations have provided direct evidence that BE has a genetic component, and imply that we may be close to ﬁnding important pathways in the development of BE and EAC. Future linkage and GWAS studies that concentrate on familial Barrett’s esophagus in multiplex Barrett’s families may identify new genetic susceptibility variants because of the increased genetic components in such samples. The study by Verbeek et al32 in this issue adds to the growing evidence for the familiality of BE and EAC. They studied a large European cohort of 838 index patients with BE or EAC and their relatives by administering questionnaires. A diagnosis of familial BE was made after histologic conﬁrmation of intestinal metaplasia in 1 or more ﬁrst- or second-degree relatives of the index patient. The prevalence of familial BE was found to be 7%, consistent with previous results in US populations,16,17 They also found familial BE cases to have a signiﬁcantly younger age of onset of heartburn and EAC diagnosis than nonfamilial cases, and reﬂux symptoms were reported more frequently among ﬁrst-degree relatives of familial BE cases than those of nonfamilial BE cases—not only strengthening the earlier reports of younger affection status in familial BE,24,25 but also consistently supporting the genetic hypothesis of GERD, BE, and EAC.
Inferences and Conclusions Advances have been made over the past decade in our understanding of genetic and environmental factors associated with GERD, BE, and EAC, which can guide the development of risk prediction models in populations and families. Genetic susceptibility variants of BE identiﬁed in epidemiologic studies need to be validated further by functional analysis, and more susceptibility genes probably remain to be discovered by more powerful
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approaches such as by studying more genetically informative samples. The complexity of familial BE suggests we need further studies to determine the genetic causal variants and explain the mechanisms by which these variants control the development of BE and EAC. There are several regression models developed to predict BE and EAC risk in case-control populations with moderate prediction accuracy.33–35 New screening and prediction tools with better performance to predict risk, especially in BE families, are needed, however, unless based on known causal mechanisms, a model cannot be expected to apply to populations other than the one in which it was estimated. The discovery of SNPs at major loci of gene transcription that are known to play a role in metaplastic and dysplastic changes show that we are closer than ever before to ﬁnding the genes associated with BE and EAC. Assessing individual genetic susceptibility may help target high-risk patients for endoscopic screening programs rather than using a cost-ineffective, population-wide approach. XIANGQING SUN, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio APOORVA KRISHNA CHANDAR, MBBS, MA, MPH Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio ROBERT ELSTON, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio AMITABH CHAK, MD Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio
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Conﬂicts of interest The authors disclose no conﬂicts. http://dx.doi.org/10.1016/j.cgh.2014.03.008