I have a partial DNA diagnosis! I’ve known for several years that my digestive problems are probably genetic in part because many family members have similar problems – but not identical problems. Some of my likely genetic culprits have now been identified.
A significant gene is SLC6A4 s/s. This is the gene responsible for transporting serotonin. Yes, we normally associate serotonin with brain function but 90% of it is made and used in the gut by Enterochromaffin (EC) cells in the lining of the digestive system. (Some of it is transported by the blood from the digestive system to the brain and other places in the body that use it). Serotonin is essential to proper digestion. It is involved in the regulation of mucous secretion in the lining of the digestive system and the modulation of muscle contractions that move stuff through the digestive system. The “s/s” variant means I have two short alleles, one from each parent. The problem is in the re-uptake of serotonin which, after use, should be gathered up and stored in the EC cells till needed again. This re-uptake job is the responsibility of SLC6A4 but the s/s variant makes it a lazy worker. The result is that I have more serotonin than typical. This variant is common in people who have my digestive symptoms. The increased levels of serotonin in the gut cause diarrhea (and cause, in the brain, better cognitive function and more positive moods). The deletion of SLC6A4 in “knockout mice” caused them to suffer chronic diarrhea from too much serotonin (but I suspect they were so blissful they didn’t care). Scientists continue to study SLC6A4 and serotonin to get a better understanding of their role in digestion.
Another significant gene is HGT1A1*28/*28. The double *28 indicates that I have inherited a totally dysfunctional gene from both parents. The problem is an extra TA in the chain – that’s what the *28 indicates. When HGT1A1 functions properly, it regulates the metabolization of ingested toxins. The problem with this gene probably explains why I cannot tolerate any food that, when hot, had contact with non-stick coated, plastic or synthetic cookware. There are also many toxins in foods, especially vegetables and legumes. I googled HGT1A1*28 and turned up over 90,000 scholarly articles. Most of them say I should never be prescribed a certain cancer drug ─ good thing I don’t have cancer. A few articles note that people with this genetic issue have a very low risk of heart disease because it results in an increased level of an anti-oxidant – bilirubin ─ that prevents the buildup of atherosclerosis ─ that explains why my arteries are so clean! I couldn’t find any information about HGT1A1*28 and digestive health.
Additional genetic issues with several CYP genes have been identified. They contribute to the problem of metabolizing what I eat.
My CYP1A2 is over active, indicated by the asterisked modifiers CYP1A2*1A/*1F. I inherited a normal variant from one parent (*1A) but a fast metabolizing variant from the other parent (*1F). It might slightly make up for the inactive HGT1A1 in metabolizing toxins. According to Dr. Google, vegetables such as cabbages, cauliflower and broccoli are known to stimulate the activity of this gene, as do proton-pump inhibitors given for acid reflux. That may explain why I cannot tolerate these things. However, Dr. Google says that peppermint suppresses it, which may explain why I’ve found peppermint supplements helpful. The best is that I metabolize caffeine well, thanks to CYP1A2*1F.
The activity level of my CYP3A5*3/*3 is poor – something to do with improperly spliced mRNA. Apparently, this genetic variant is common among Caucasians – so, it might not, by itself, be the cause of my digestive problems. This gene is active in the synthesis of cholesterol and other oils. I cannot tolerate oil but can tolerate animal and poultry fats containing cholesterol. Maybe this explains why I feel a need to eat a lot of animal fat - I eat more in order to get enough cholesterol.
I inherited contradictory CYP2C19 genes from my parents, indicated by CYP2C19*2/*17. One parent gave me variant *2 which makes the gene non-functional but the other parent gave me variant *17 which makes the gene an ultra-rapid metabolizer. Dr. Google says poor function of CYP2C19 makes me an “obligate carnivore”. No wonder why I can eat and feel a need to eat a lot of animal meat and fat!
My CYP2D6 is under-active, having inherited a normal copy from one parent indicated by *1 but an inactive copy from the other indicated by *4. CYP2D6 metabolizes about 25% of oral drugs. It partly explains why so many drugs are toxic to me – this may explain the nasty side-effects of codeine and other drugs, including why a normal dose is an overdose.
My CYP3A4*1/*22 is under-active. CYP3A4 oxidizes toxins so they can be removed from the body. One parent gave me a normal functioning variant (*1) but the other parent gave me variant *22 which reduces enzyme activity by 50%. Foods that are identified as inhibiting the function of this gene include pomegranate juice and cranberry juice, which I drink daily without negative effects (?). Fish oil and omega oils, grapefruit and black pepper, all of which I cannot tolerate, are said to inhibit this gene. If I were inclined to self-medicate with marijuana, I would need a reduced dose.
This genetic test was not comprehensive. Its purpose was to identify which oral drugs ought not to be prescribed to me because they are too toxic. The test results included a very long list of common oral drugs. There may be other genes involved in my digestive health issues but which have not been identified because they are not relevant to drug toxicity.
The genes responsible for my generally low production of stomach acid, bile and digestive enzymes have yet to be identified.
No, I don’t really understand it either. Nor do the scientists – research of genetics and digestive health is at such a preliminary stage.
 The l/l (long/long) variant is common in people who suffer constipation and depression: PMID: 22457857 Serotonin Transporter Gene (SLC6A4). That variant is excessively efficient at the job of serotonin re-uptake leaving the person with inadequate serotonin to move stuff through the digestive system and to moderate moods.