Drug Response Alleles

Our genes can affect the way our bodies metabolize certain drugs and environmental toxins.  Various SNPs have been identified that affect the metabolism of various pharmaceuticals.
rs3892097 = T (The risk of developing Parkinson's disease as a result of pesticide exposure can go up as much as 3 to 8 times).  If that is not bad enough, according to SNPedia, "If two copies of this (or similar) changes are inherited, poor metabolism ('PM') of debrisoquine [PMID 2211621] is observed. Many other drugs are typically first metabolized by CYP2D6 including dextromorphan, sparteine, metoprolol, nortriptyline and many other antidepressants and codeine. Of course, sometimes the active form of a drug is the one post-CYP2D6 metabolism; an example of this is tamoxifen, where the active form (endoxifen) is formed primarily via CYP2D6 metabolism; less functioning CYP2D6 can mean less benefit from taking the drug."

rs1065852 = A (poor metabolism of Debrisoquine)
rs130060 = C "The encoded protein may be involved in several neuropsychiatric disorders and therefore is often a target of antidepressant and other psychotherapeutic drugs."
rs12248560 = T (Ultra fast metabolizer of estrogen, tamoxifen, proton pump inhibitors, antidepressants, etc)
rs4244285 = A (Poor metabolizer of several popular drugs including Plavix)
rs16947 = A (Ultrarapid metabolizer of Debrisoquine)

ABCG2 Gene Function

Since I have been stuck the last few days talking about gout, what about this ABCG2 gene?  What does it do?  According to GeneCards the ABCG2 gene encodes for a protein involved in transporting molecules.  It is a xenobiotic transporter.  It likely serves as a cellular defense mechanism against mitoxantrone and anthracyclines.  It is a high capacity urate exporter, hence the association with hyperuricemia and gout.  Interestingly, the protein plays a role in porphyrin homeostatsis, by the "export of protoporphyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme" (see ABCG2).  I wonder if the PPIX function somehow has something to do with why only a small portion of people with hyperuricemia develop gout.  I also suspect there's a significant environmental component to developing the disease.  We also do not know all there is to know about the ABCG2 gene, so more functions are likely to be discovered.

There are some things worth mentioning when it comes to living with gout.  First, an excessive intake to high fructose corn syrup seems to cause some twinges in my big toe.  Maybe this is due to SLC2A9 being involved with fructose, glucose, and uric acid transport.  The ABCG2 gene may also be involved in transporting sugars.  Second, taking iron supplements seemed to be the cause of twinges and almost a full blown gout attack after a month of taking the supplements.  Perhaps my ABCG2 "transport protein" was getting overloaded by the extra iron I was taking.  I also note that my FECH gene codes for an enzyme that converts protoporphyrin IX into heme.  But a mutation (rs2272783) reduces the enzymes activity to about 70% of normal.  No issues with photosensitivity here but interesting nonetheless. 

Dysfunctional ABCG2 Gene?

I'm homozygous for five uncommon mutations on the ABCG2 gene, one of which is the Q141K mutation (rs2231142) which was shown to be a loss of function mutation.  I'm not sure of the relevance of the other 4 mutations.

rs2231142 MAF = 0.1194
rs4148157 MAF = 0.1006
rs2054576 MAF = 0.0998
rs1481012 MAF = 0.1188
rs4148155 MAF = 0.1180

Thinking that the genotypes may have been miscalled, I looked on OpenSNP to see if the minor allele frequency in that database was similar to the dbSNP database.  Sure enough, they were close, indicating that the genotypes are probably correct.  So how did I end up being homozygous in so many uncommon mutations on the same gene?  Perhaps my parents come from populations where the minor allele is more common.  Native American father + British isles descent mother?  De novo (not inherited from parents) point mutations? Whatever the case is I identified one other person on OpenSNP so far that has the same homozygous cluster.  Luckily for them, they do not also have any of the more serious SLC2A9 mutations (rs16890979 and/or rs6449213).  I wonder if they have gout.

Variants Genotyped Incorrectly

There are a few SNPs genotyped that seem to be incorrect.  Searching on the X chromosome, I noticed that there is a "DI" for my genotype for rs72554313.  However, there are a few "DI"s on OpenSNP indicating that the genotype is most likely incorrect and I'm not a carrier for Ornithine transcarbamylase (OTC) deficiency .  Another genotype that is probably incorrect is i5036486 on the F8 gene.  There are a few "DI"s on OpenSNP and even a few "DD"s indicating that I'm probably not a carrier for hemophilia.  Whew! 

Being a carrier for something on the X chromosome is serious because any boys would have a 50/50 chance of inheriting the disorder and girls have a 50/50 chance of being carriers.  Carriers do not always get off "scot free" either.  I've heard of carriers of hemophilia having symptoms of the disease.  I suppose it has to do with X-activation (lyonization).

There is another "probably incorrect" genotype on Chromosome 6 for rs7769409 on the CYP21A2 gene.  It is associated with congenital adrenal hyperplasia.  Several people on OpenSNP have the carrier genotype for the rare condition indicating that the genotypes were miscalled.

Resistance SNPs

Some variants offer some protection against certain disease or at least slow down the progression of disease.  Or so we think...

rs1799864 = A (minor allele A is associated with slower HIV progression).
rs1799990 = G (If heterozygous some resistance to prion diseases like Creutzfeldt Jacobs).
rs601338 = A (If homozygous for minor allele A there is some resistance to norovirus but may have increased risk for celiac and IBD).
rs8177374 = T (With minor allele T less susceptible to malaria, tuberculosis, bacteremia and pneumococcal disease).  Good thing I have one T!  The minor allele is not the most common either with minor allele frequency (MAF) of 0.084. 
rs2853826 = G (Some resistance to developing Parkinson's disease.  The snp is on the mtDNA. Interesting).
rs4804803 = A (Some protection against tuberculosis).
rs1334512 = G (Decreased risk for developing severe malaria).

Mutations Related to Gout

23andme tests for various gout related SNPs (single nucleotide polymorphisms).  There seems to be two main genes where defects are known to be contributors to gout, ABCG2 and SLC2A9.  About 8 months prior to taking the 23andme test, I started noticing something very disturbing whenever I had to stand for any length of time.  Namely, my joints started aching like I had been hard on them all day when in fact I was only standing for more than an hour or two.  It made helping with Thanksgiving dinner difficult since I kept on having to take a break.  I started running on the treadmill and taking whey protein months before Thanksgiving but did not think it was related to my pain.  And it was not a lot of whey protein and not even every day. Eventually I started to limp all day.  The limping continued until I finally experienced my first gout attack the morning after I helped my husband with the flower beds.  I told my husband that I could not walk since the pain in my big toe was excruciating.  He suggested that it could be gout and had to explain to me what gout was.  After playing video games all day and taking ibuprofen regularly all weekend I finally saw a podiatrist who diagnosed me with gout.  I was 27.  A few weeks later, I was able to access my 23andme raw data and found that I had several mutations that can contribute to gout.  Gout related snps:

rs2231142 = T is the risk allele (TT causes a 53% reduced urate transport rate)
rs16890979 = C (CC means having a 3.4x risk of gout)
rs6449213 = C (CC means 4x risk of hyperuracemia)
rs737267 = G (Increased risk of gout)
rs12498742 = A (Increased risk of gout)
rs72552713 = A (According to dbSNP this is a stop-gain mutation)
rs4994 = G (G May be associated with hyperuricemia)

The rs2231142 snp is in the ABCG2 gene as is the rs72552713 snp.  The others are in SLC2A9.  There may be other mutations I'm not aware of, but having TT for rs2231142 is not helping me any.  I'm heterozygous for rs16890979, rs737267, rs12498742, and the not so common rs4994.

So I was an otherwise healthy 27 year old with gout.  Not overweight, was exercising, and drank wine or beer fewer than 3 times a week.  But I was probably putting too much pressure on my feet by running on the treadmill and adding more protein to my diet did not help.  Protein can get converted to uric acid.  I am now 31 and noticed that joints in my fingers (especially my right thumb) got achy in addition to my big toe throbbing after standing up all day last Thursday.  My joints still ache a week later.  Last year, I was close to having another gout attack after taking iron supplements for a month.  I periodically take cherry extract to stop a gout attack before it starts.  I hope this continues to offer protection for years to come.