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How many drugs have race-specific instructions?

#21
I was already familiar with BiDil. This is a good example of a case where the use of race in biomedicine used to be widely-accepted, but no longer is. The most prevalent current perspective about BiDil is the one presented here and here. I'm not sure if BiDil is still prescribed to black people, but if it is, this is something doctors can no longer discuss doing in public.

This is why I asked about drugs where instructions to vary the dosage based on race are included in the packaging of the drug itself. Presumably with a drug like Crestor, doctors would not be endangering their careers if they mention that they've followed the instructions with which the drug is packaged.
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#22
(2014-Dec-03, 23:59:24)Tetrapteryx Wrote: I was already familiar with BiDil. This is a good example of a case where the use of race in biomedicine used to be widely-accepted, but no longer is. The most prevalent current perspective about BiDil is the one presented here and here. I'm not sure if BiDil is still prescribed to black people, but if it is, this is something doctors can no longer discuss doing in public.This is why I asked about drugs where instructions to vary the dosage based on race are included in the packaging of the drug itself. Presumably with a drug like Crestor, doctors would not be endangering their careers if they mention that they've followed the instructions with which the drug is packaged.


And yet there are massive race-conscious, in the genomic sense, studies e.g.,

"What does genomic medicine mean for diverse populations?"

Quote:"Personalized medicine involves being able to optimize drug selection, dose, and treatment duration, while averting adverse drug reactions for the individual patient. Genetic variants can serve as useful biomarkers for the absorption, distribution, metabolism, and excretion (ADME) of specific drugs. However, our understanding of the distribution of human pharmacogenomic variation remains limited and there persists poor representation of ethnically diverse samples from various parts of the world in such studies. Global studies of ADME genes (Li et al. 2011; Ramos et al. 2013) demonstrate wide differences among populations in these variants that have such a high clinical importance. Specific examples are particularly instructive. Warfarin, the most commonly used anticoagulant worldwide, is characterized by a narrow therapeutic index and wide inter and intraindividual variation in the dose required for the target therapeutic response. Genetic variation in VKORC1 and CYP2C9 explain ∼30–60% of the variation in therapeutic warfarin dose in European and Asian populations, but explain less variability for individuals of African descent. This difference is largely driven by allele frequency differences (Limdi et al. 2010; Suarez-Kurtz and Botton 2013). A recent GWAS in African Americans (Perera et al. 2013) identified a novel CYP2C single-nucleotide polymorphism that has a clinically relevant effect on warfarin dose in African Americans, independent of the previously described CYP2C9*2 and CYP2C9*3 variants. This implies that incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction for this specific population. Other examples exist for: childhood acutlymphoblastic leukemia, which shows marked ethnic differences in survival and for which a recent study found that Native American ancestry was associated with risk of relapse and modifications to treatment mitigated this ancestry-related risk of relapse (Yang et al. 2011); and hepatitis C virus treatment response and spontaneous clearance, for which an IL28B polymorphism explains at least half of the difference in response rates observed in Caucasians and African–Americans who received the same treatment with comparable adherence (Ge et al. 2009).

Therefore, the available evidence suggests that: (1) populations often show considerable differences at clinically relevant loci, including disease risk loci and loci that predict drug response; (2) most studies that produce data that can be useful for genomic medicine have been carried out largely in European ancestry populations. Thus, the evidence base for genomic medicine in such diverse populations is lacking and lags far behind that of European ancestry populations. For such populations, the advantages of genomic medicine may remain largely theoretical and out of reach until the necessary research is done to improve the evidence base applicable to them.

The need for more genomic research in diverse populations is obvious.


Why do they need "more genomic research in diverse populations"? Because genomic race matters. We just can't call it race -- because race can't exist for us.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907917/
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#23
Bidil seems pretty dodgy. Did they test it in anyone other than African Americans?
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#24
I read a toxicology textbook (download) some months ago. I'm fairly certain that under pharmacogenomics, it covered that the fact that different populations may react differently.

I looked it up briefly on Wikipedia. https://en.wikipedia.org/wiki/Pharmacoge...troversies

There are two more drugs with known race-interactions listed there.

The section of the textbook is 2.6:

Quote:Idiosyncratic sensitivity sometimes occurs because individuals express mutated or polymorphic versions of enzymes that cannot properly metabolise toxicants to facilitate their bodily elimination. In some ethnic populations, mutant xenobiotic- metabolising genes are so prevalent that they influence prescribing decisions by physicians. A famous example of this phenomenon involves the tuberculosis drug isoniazid, which causes liver damage in ~1 % of patients. The conjugative enzyme N-acetyl transferase 2 (NAT2) plays an important role in isoniazid metabolism, and studies in a variety of ethnic groups have associated a genetic deficiency in NAT2 (known as ‘slow acetylators’ due to their reduced ability to metabolise isoniazid and other xenobiotics) with an increased susceptibility to liver injury.

...

Another example of this phenomenon involves an aldehyde dehydrogenase gene (ALDH2) variant that confers a low tolerance of alcohol upon some Asian populations. The ALDH2 enzyme is located within hepatic mitochondria and is responsible for converting the acetaldehyde that forms during alcohol metabolism into acetic acid (Fig. 2.6a). In some Asian populations, a dominant mutation in the ALDH2 gene renders the enzyme largely inactive, ensuring affected individuals metabolise acetaldehyde poorly after consuming alcohol (Fig. 2.6b). Due to impaired clearance, blood concentrations of acetaldehyde remain above a toxic threshold for an extended timeframe following alcohol ingestion (Fig. 2.6c). Since acetaldehyde causes many unwanted ‘hangover’ symptoms in heavy drinkers, ALDH2 deficiency diminishes tolerance for wine, beer and other alcoholic beverages. Even consumption of low quantities of alcohol by ALDH2-defi cient individuals triggers symptoms of acetaldehyde intoxication that include dizziness, nausea, hypotension and palpitations. These subjects thus display a permanent phenotype that resembles the effects of disulfiram treatment in alcoholics (i.e. Antabuse, the ALDH2-blocking drug that is used with varying degrees of success to counteract alcohol dependence in heavy drinkers).

The second one is related to the generally known phenomena of Asian flush syndrome.

So this is the key word needed to find these studies. If you search Scholar for "pharmacogenomics + ethnic" you get lots of studies talking about and reporting these findings.

Some examples for the lazy:

Gumbo, T., Louie, A., Liu, W., Brown, D., Ambrose, P. G., Bhavnani, S. M., & Drusano, G. L. (2007). Isoniazid bactericidal activity and resistance emergence: integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations. Antimicrobial agents and chemotherapy, 51(7), 2329-2336.

Suarez-Kurtz, G. (2005). Pharmacogenomics in admixed populations. Trends in pharmacological sciences, 26(4), 196-201.

Takahashi, H., Wilkinson, G. R., Nutescu, E. A., Morita, T., Ritchie, M. D., Scordo, M. G., ... & Echizen, H. (2006). Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra-and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenetics and genomics, 16(2), 101-110.

Lee, S. S. J. (2005). Racializing drug design: implications of pharmacogenomics for health disparities. American Journal of Public Health, 95(12), 2133.

There is plenty of material here for you to make an ethical case for the use of race in medicine I think.
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#25
So there is as far as I know:

1: Crestor and East Asians frequency in absorbtion (All east Asians or just Chinese?)
2: Asian flush frequency aka metabolise acetaldehyde difference, common from 30-50% in Chinese and Japanese(what about other Asians?).
3: Warfarin dosage frequency in African Americans, American Europeans and East Asians.
4: leukemia and likely hood of finding bone marrow donors.

I don't think its good to consider Bidil because I cant get enough info on if they have been tested on others or not. Also seems very dodgy overall.

Anything else?
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#26
Did you look through studies on Google Scholar as linked to above? Surely there are more cases.

One can also find more cases by looking specific SNPs associated with drug sensitivity etc., and then look up the alleles for these in 1000genomes and ALFRED. Ask Piffer for help.
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#27
(2014-Dec-05, 14:46:49)Emil Wrote: Did you look through studies on Google Scholar as linked to above? Surely there are more cases.

One can also find more cases by looking specific SNPs associated with drug sensitivity etc., and then look up the alleles for these in 1000genomes and ALFRED. Ask Piffer for help.


I looked through your links and its hard to find anything substantial, though I haven't looked that hard yet. I see something with tuberculosis and side effects of some drug and bolivians, but most of its warfarin and simply speculation from decades ago. Also tiny samples.

The main thing is how effective are the predictions and how easy is it to simply find the trait causing the problem instead. If race beats those two, it would be ethical, otherwise not. The genomics is irrelevant here unlike the IQ debate. You only need the trait, like bigger heart valve, enzyme activity or lower amounts of blood sugar or something like that. All that information should be taken at checkup before you get the prescription for any drug. I simply don't see any racial difference thats big enough you can use to argue against this.

Bolivians: http://www.ncbi.nlm.nih.gov/pubmed/23190413

Also how many do you expect to find? Humans have around the same fst as Waterbuck. I cant really find much medication differences in dogs either(or disease differences, its a lot less than I thought). Most of the medical needs that are there has to do with body size.

The leukemia thing for example is a simple matter of time until they get more blood types and bone marrow in storage. It shouldn't take that long.

http://www.livescience.com/42770-artific...kemia.html
http://www.the-scientist.com/?articles.v...ent-Ready/
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#28
"Also how many do you expect to find? Humans have around the same fst as Waterbuck."

Zoidberg,

Fst is not a reliable measure of functional differences between populations. Or species. Genetic variation across a population boundary is qualitatively different from genetic variation within a population. You're comparing apples and oranges.

I've cut and pasted information on this point from one of my publications:

In the deer family, we see more genetic variability within some species than between some genera [7]. Some masked shrew populations are genetically closer to prairie shrews than they are to other masked shrews [8]. Only a minority of mallards cluster together on an mtDNA tree, the rest being scattered among black ducks [9]. All six species of Darwin’s ground finches seem to form a genetically homogeneous genus with very little concordance between mtDNA, nuclear DNA, and morphology [10]. In terms of genetic distance, redpoll finches from one species are not significantly closer to each other than are redpolls from different species [11]. Among the haplochromine cichlids of Lake Victoria, it is extremely difficult to find interspecies differences in either nuclear or mitochondrial genes, even though these fishes are well differentiated morphologically and behaviorally [12]. Neither mtDNA nor allozyme alleles distinguish the various species of Lycaedis butterflies, despite clear differences in morphology [13]. An extreme example is a dog tumor that spreads to other dogs through sexual contact: canine transmissible venereal sarcoma(CTVS). It looks and acts like an infectious microbe, yet its genes would reveal a canid and conceivably some beagles may be genetically closer to it than to Great Danes [14].

In sum, total genetic variation poorly mirrors genetic variation in adaptive traits, be they morphological, behavioral, or physiological. Keep in mind that a new species typically arises when a founder group buds off from a parent population and enters a new environment with new selection pressures. The new selection pressures, however, will leave most of its genome unchanged. In some cases, this is because the gene itself has little adaptive value (e.g., most genetic markers), often being no more than ‘junk DNA’. In other cases, the gene’s variants are equally adaptive in a variety of organisms. Many blood polymorphisms span not only different species but even different genera. In terms of the ABO system, for instance, a person may have more in common with some apes than with other people [12].

Of course, once the two populations have become reproductively isolated, they no longer accumulate the same mutations and will drift apart at all gene loci, including the many that weakly respond to natural selection. But this process is slow. For example, redpoll finches diverged into two species some fifty thousand years ago and have distinct phenotypes, yet their mitochondrial DNA shows a single undifferentiated gene pool [11]. The past ten thousand years have seen dogs diverge into distinct breeds, which nonetheless cannot be told apart by genetic markers. In fact, greater mtDNA differences exist within the single breeds of Doberman pinschers or poodles than between dogs and wolves [6].

Frost, P. (2011). Human nature or human natures? Futures, 43, 740–748. http://dx.doi.org/10.1016/j.futures.2011.05.017
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#29
(2014-Dec-06, 18:52:25)Peter Frost Wrote: "The past ten thousand years have seen dogs diverge into distinct breeds, which nonetheless cannot be told apart by genetic markers."


Most of them(if not all) can be very accurately identified using much fewer loci than when determining within humans.


(2014-Dec-06, 18:52:25)Peter Frost Wrote: "greater mtDNA differences exist within the single breeds of Doberman pinschers or poodles than between dogs and wolves [6]."

"in sum, total genetic variation poorly mirrors genetic variation in adaptive traits, be they morphological, behavioral, or physiological"


You are nitpicking extremes and some genetic material instead of the whole between species to say you cant compare within species groups. Stop giving me nonsense arguments. You have a measurable amount of genetic difference when you consider everything and its there between dogs, ants whatever and also between human populations, it simply is very little as a whole for humans. Unless the snps are of high effect, which is disproved, most of them are literally undetectable in effect.

You also seem to think that because a species can be different between groups within its species that the differences are automatically mostly(all?) hardwired fixed genetic differences that come via natural selection. Organisms with the same genes can adapt without fixed natural selection of mutations, but rather dynamic adaptations of the same genes to environment aka epigenetics.

Some of the animals you mentioned.

Butterflies:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277265/
Fish:
http://www.whoi.edu/page.do?pid=96466&ti...cid=142749
http://genome.cshlp.org/content/early/20...162172.113
http://rspb.royalsocietypublishing.org/c...4/20141146 (This one has behavioral effects).

Darwins Finches:
http://gbe.oxfordjournals.org/content/ea...gbe.evu158

Other:
http://yoichiishida.com/papers/Zeh_2009_BioEssays.pdf


So what is the big genetic difference between human groups then, did they miss something? In what genetic material? One thing is little fst difference. Then what else is there? I am honestly asking, because when you have a look at the differences in say diseases its rather little. Nobody is giving me a straight answer about this issue except Chuck.

Here is a list of most of what I have found with regards to diseases. Some of them are pretty rare and some don't have that much variation as you think. Maybe a 50% at most, mostly around 10% though. Some of these are not confirmed to be genetic, they have some associations only. First two are confirmed though I am sure.

1: Tay sachs(rare common in Jews and some small groups in Canada and America)
2: Sickle cell(common to Sub Saharan Africans)
3: Myocardial infarction(Don't know how big the risk factors really are, could be environmental because its cardiovascular, higher risk for African Americans)
4: Metabolic Syndrome(also could be mostly environmental because its got to do with metabolism, higher risk for all Asians(not sure)).
5:Celiac disease(more common in Northern Europeans).
6:Wilson’s disease(more common in Southern Europeans).

There are other risk factors for more cardiovascular and metabolic diseases but they change way too fast per generation to be likely to be genetic.

Still its hard to find that many illnesses that differ significantly between populations.
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#30
Psoriasis (which I have), may differ in rates. Evidence pretty scanty so far. The one study in Taiwan found 0 incidents.

Parisi R, Symmons DP, Griffiths CE, Ashcroft DM; Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team (February 2013). "Global epidemiology of psoriasis: a systematic review of incidence and prevalence". J Invest Dermatol 133 (2): 377–85. doi:10.1038/jid.2012.339. PMID 23014338

My girlfriend has https://en.wikipedia.org/wiki/Rosacea, another disease common in Northern Europeans.

Some results of a large UK survey here: http://www.patient.co.uk/doctor/Diseases...Groups.htm

There are so many thousands of rare genetic diseases, that hundreds of them if not thousands of them will differ in rates between populations for genetic reasons. For those where we know the SNPs (i.e. not the super-rare ones), one can just look up these SNPs in 1000Genomes to see if they differ markedly. For the more rare ones, we will have to wait until full genome sequencing and their GWAS become the norm. Perhaps another 5-15 years.
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