Genes-R-Us — First genetic predisposition for Barrett’s esophagus is identified
Posted: Wednesday, October 17, 2012 8:00 pm
It is a good thing if the title of this column appears really boring to you. If so, chances are good that neither you, nor family or friend, have had a close encounter with the premalignant lesions that characterize Barrett’s esophagus and that are associated with chronic gastro-esophageal reflux disease (GERD).
The esophagus extends from the very back of the throat all the way to the stomach. This condition was first identified in 1950 by Dr. Norman Rupert Barrett, an Australian surgeon. For the last 30 years there has been a 3 percent increase each year over the previous year.
Increasing age, being male, smoking, being overweight, and having GERD are all risk factors for Barrett’s esophagus.
Although only a tiny number of those who develop Barrett’s esophagus will go on to develop esophageal cancer (EAC), having Barrett’s esophagus increases ones chances to develop EAC by more than 40 times that of the general population. The survival rate for EAC is quite poor, with a 9 to 15 percent five-year survival rate.
A recently published study in the journal, Nature Genetics, establishes the first genetic predisposition towards developing Barrett’s esophagus. (http://bit.ly/RxVxle) Altogether over 8,000 people with Barrett’s esophagus and 17,000 controls were used in the multi-phase and multi-ethnic study.
Two primary single point DNA variations, or SNPs, increase one’s predisposition to develop Barrett’s esophagus according to the study. The most significant SNP is found in the major histocompatibility complex (MHC) region on chromosome 6. The genes that are part of the MHC relate to the function of our adaptive and innate immune systems.
The risk SNP, rs925809, sits between two genes (intergenic) in the MHC region. One gene has been associated with smoking behavior and the other with several autoimmune skin diseases. However, the MHC region is very long and gene rich so it is not possible to make a connection with any particular gene at this point.
Having the DNA base of ‘A’ for rs9257809 increases ones chances by 38 percent to develop Barrett’s esophagus if male, and by 11 percent if female. These are not huge effects but nevertheless real — and obviously sex-specific.
The second most significant SNP is found on chromosome 16 near the gene FOXF1. The risk allele is ‘C’ for rs9936833, adding another 14 percent risk. Abnormalities in FOXF1 signaling have previously been linked to esophageal cancer. (http://1.usa.gov/T5KDFp)
A number of other SNPs that were previously associated with an increased risk of obesity also add additional significant but small incremental risks.
How the ‘A’ value for SNP rs9257809 and the ‘C’ value for the SNP rs9936833 increases one’s odds to develop this inflammatory condition is far from clear as neither of these SNPs are causal. What do I mean by that?
Since DNA tends to be inherited in chunks, SNPs do not occur randomly. These two SNPs are more like sign posts. Given that they lie near the MHC and FOXF1 regions — that make sense biologically — imply that these regions may be a fertile locus to look further with more sensitive methods like whole genome sequencing.
The two risk-inducing SNPs are very common. Common in this context means that thousands of human generations have elapsed between the first human appearance of a particular SNP and present times.
We have two values for each SNP; one from each parent. For the SNP in the MHC region, rs9257809, possible combinations are (A, A), (A, G), or (G, G); and with an increased risk of Barrett’s esophagus of 76 percent, 38 percent, or no added risk, respectively for a man. (And 22 percent, 11 percent, or no added risk for a female.)
Based on a popular SNP database most of us are of genotype (A, A) for rs9257809 — 91 percent or more depending on race. My father is (A, A), carrying the highest risk. I am (A, G), as is my mother. I was feeling pretty special about my genotype, especially since my husband is (A, A), until I discovered that my son, Jacob, is (G, G). Just one more reason for Jacob to appreciate his parents.
Nancy@NancyMiller Latimer.com has worked in scientific research and development for 27 years. She blogs at NeuronalBeauty.BlogSpot.com. Published in The Messenger 10.17.12