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Two Common Genetic Variants Linked to Barrett's Esophagus


 

FROM NATURE GENETICS

Two common genetic variants on chromosomes 6p21 and 16q24 were found to be associated with Barrett’s esophagus in the first genome-wide association study of susceptibility to the disorder, according to a letter to the editor published online Sept. 9 in Nature Genetics.

Genetic factors have long been suspected to play a role in the development of Barrett’s esophagus since relative risks for the disorder, as well as for gastroesophageal reflux disease and esophageal adenocarcinoma, are increased two- to fourfold in first-degree relatives of affected patients.

However, "extensive candidate gene and linkage searches have to date been unsuccessful in identifying genetic variants that are associated with risk of Barrett’s esophagus," wrote Dr. Zhan Su of the Wellcome Trust Centre for Human Genetics in Oxford, England, and his associates.

Their findings provide the first direct evidence that the etiology of Barrett’s esophagus has a genetic component, the researchers noted.

Dr. Su and his colleagues performed the genome-wide association study as part of a Wellcome Trust consortium study of the genetic components of 15 common disorders and traits. They identified the two genetic variants in a discovery analysis and confirmed the findings in another five replication cohorts.

The discovery analysis involved genotyping of 1,852 adults with histologically confirmed Barrett’s esophagus who were recruited from sites across the United Kingdom. A representative sample of 5,172 control subjects also was analyzed. A total of 521,744 single-nucleotide polymorphisms (SNPs) were typed.

The 100 SNPs that were associated to some degree with Barrett’s esophagus were then analyzed in a separate cohort of 1,105 cases from two clinical trials, 4,421 controls from another U.K. sample, and 2,578 controls from yet another U.K .sample.

The top 16 SNPs from these analyses were then analyzed in a second replication cohort of 473 cases and 1,780 controls from a Dutch genotyping database. Two of the SNPs were found to be significantly associated with Barrett\'’s esophagus: rs9257809 on chromosome 6p21 and rs9936833 on chromosome 16q24.

It is notable that the closest coding gene to the rs9936833 SNP on chromosome 16q24 is a gene that encodes a protein involved in the development of the gastrointestinal tract. It has been reported that, when this gene is inactivated, structural alterations in the esophagus, especially atresia, occur. The rs9257809 SNP on 6p21 is near the telomeric edge of the major histocompatibility complex region.

The two SNPs were then examined further in an Irish cohort of 245 cases and 473 controls, a U.K. cohort of 1,765 cases and 1,586 controls, and a cohort of 2,398 cases and 2,167 controls from Europe, Australia, and the United States.

Overall, the two SNPs "showed compelling evidence for association," with Barrett’s esophagus, reflected in the significance of the combined P values for rs9257809 (odds ratio, 1.21) and rs9936833 (odds ratio, 1.14), the investigators reported (Nat. Genet. 2012 Sept. 9 [doi:10.1038/ng.2408]).

In a subgroup analysis involving only patients who had histologic evidence of intestinal metaplasia, the same two SNPs were again strongly associated with Barrett’s esophagus. Neither SNP, however, was associated with either the circumferential extent or the maximal length of the affected segment of esophagus.

Given that men are known to be more susceptible than women to Barrett’s esophagus, the investigators also performed a sex-stratified analysis of the data and found that the association between both SNPs and the disorder was stronger in men than in women. "This finding warrants further investigation," they noted.

Similarly, given the known association between obesity and Barrett’s esophagus, the researchers analyzed the 40 SNPs that previously have been linked with either body mass index or waist-to-hip ratio. These latter SNPs were "more likely than expected by chance to show effects in the same direction in association with Barrett’s esophagus, suggesting that genetic effects may in part underpin the epidemiologic observation that BMI is a risk factor for Barrett’s esophagus," Dr. Su and his associates said.

"Given that Barrett’s esophagus has an accepted status as a precursor lesion, the SNPs that we have identified could also essentially be risk factors for esophageal adenocarcinoma and may give clues as to the biology of both of these important phenotypes," they added.

The financial disclosures of Dr. Su and his 143 coauthors are listed in the online version of this article.

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