Epistemology & Endocrinology

     How does one really know anything? As I have been researching genetic racial differences, I have frequently reencountered the dilemmas of scientific knowledge, such as the meanings of certainty and consensus. The skeptic Marcello Truzzi has been credited with originating the phrase "extraordinary claims require extraordinary proof." He actually defined extraordinary claims as being "revolutionary in their implications for established scientific generalizations already accumulated and verified." In that sense, skeptical claims also bear a burden of proof.
     Currently, the so-called Climategate scandal is receiving substantial attention from race realist bloggers. Skepticism can serve science well, but this particular movement has a clear political and financial constituency, and the climate science debate in the decades ahead could reach such an obvious conclusion that a veil of shame might extend to movements associated with global warming skepticism. Race realism science should stand on its own without its reception depending on unrelated causes. After all, race realism owes most of its taboo nature to World War II and Hitler rather than empirical disfavor.
     Therefore, I would like to briefly offer my own assessment of climate science before I detail the science of racial endocrinology, which could ultimately serve as the focal point of scientific understanding of racial differences. Though I must confess to the limitations of my knowledge of global warming research, I am cynical about global warming skeptics latching onto phenomena like El Niño or sun activity to repeatedly prophesy that the end is not nigh, as if they are Jehovah's Witnesses in reverse. In fact, I distinctly recall (though I cannot find a transcript) that Rush Limbaugh on his old television show interpreted the albedo effect of cooling caused by Mount Pinatubo's eruption as "Mother Nature" reversing global warming. How ironic that a conservative would employ the Gaia hypothesis to suggest that a living Earth would take it upon herself to negate human environmental impact. Even as skeptics attribute warming to a myriad of causes other than human activity, they refuse to accept that a temperature trend could have noise. Instead, they consider the record temperatures of 1998 as marking the year of complete reversal of global warming, which is not apparent from this graph:


     Even if all of that data is scientific fraud, no one seems to be disputing the rise of greenhouse gases or the greenhouse effect, itself. Therefore, even if anthropogenic global warming has not happened thus far, the greenhouse effect would presumably eventually overtake other influences on the climate.


     The fickleness of American public opinion on the matter seems to be contingent on gradients, much like support for the wars in Iraq and Afghanistan. How do things seem to be going? How soon and how bad will things get? What can be accomplished and at what cost? I, myself, felt relief when Archer et al placed radical positive feedback on global temperature escalations from a potential oceanic methane "belch" on the time scale of "millennia or longer." Then, Jain and Juanes detailed a mechanism by which methane could rise from the ocean much faster than previously thought. Methane is a more potent greenhouse gas than carbon dioxide.
     The Climategate scandal demonstrates politically correct liberals, who happen to be climate scientists, behaving like politically correct liberals. I consider it a greater scandal that the right wing has allowed the left wing to steal the cause of ecology. Even the Nazis had a green wing.

Polyglutamine Expansion Size Matters
     One link between race realism and environmentalism has been the alternative moniker "human biodiversity." As imperfect or imprecise as race realism may seem, I consider it superior to this pretentious ingratiation. It reminds me of atheists who demand that they be called "brights." Besides, every Seinfeld fan knows that one may not choose one's own nickname. As far as liberals are concerned, anyone who thinks independently about diversity is just a fascist white supremacist, anyway. Even worse, "human biodiversity" sounds prescriptive. I think it is fine if race realism informs one's views of interracial mixing—or global warming, for that matter. However, race realism science neither cares whom one marries nor what one drives. It just is.
     Author Steve Sailer explored the topic of interracial marriage in his 1997 National Review essay "Is Love Colorblind?" In particular, he offered his thoughts about the startling gender disparities of interracial marriage, pointing out that "on average, black men tend to appear slightly more and Asian men slightly less masculine than white men, while Asian women are typically seen as slightly more and black women as slightly less feminine than white women." Readers welcomed his insights by calling him "racist," "white supremacist," and a "typical white male" for peddling "age-old racial stereotypes," "prejudice," and "ignorance." If the media had reported the latest science on racial differences, Mr. Sailer would not have needed to postulate so modestly, and his oppugners could have skipped a self-induced hypertensive episode.
     Masculinity, of course, owes much to male hormones collectively called androgens. The level of expression of those androgens depends not only on the concentration of those hormones in the blood but also on the nature of the androgen receptor. At one end of the androgen receptor gene, which is alternatively labeled AR or NR3C4, there are varying amounts of the trinucleotide repeats CAG and GGC. The 1994 in vitro study by Chamberlain et al found that fewer CAG repeats caused increased transactivation of the receptor (meaning that the receptor became more activated to increase gene expression). Choong et al uncovered an association between fewer CAG repeats and higher amounts of receptors. In 1995, Irvine et al identified a 2.1-fold increased prostate cancer risk from having both fewer than 22 CAG repeats and not having the protective 16-repeat GGC allele. They surmised that the increased transactivation increased prostate cell proliferation, which "is known to promote tumorigenesis." They also produced the two tables below, showing African Americans to be the possessors of the alleles with the highest transactivation.



     Thus, African Americans average 18.5 CAG repeats, whites average 21, and Asians average 21.9. These results parallel both the prevalence of prostate cancer by population and Rushton's Rule, in which whites tend to be between the extremes of blacks and Asians. Sartor et al and Sasaki et al replicated these results. Edwards et al found such racial differences and also determined that the high rate of homozygosity in African Americans likely resulted from selection pressure.
     Genetic racial differences in the androgen receptor can give rise to disease susceptibility and trait disparities in the absence of racial differences in hormone levels. Research seems divided on the effects of CAG and GGC repeats on the actual baseline testosterone levels. Likewise, not all studies have found significantly higher baseline testosterone levels in African Americans, but Roney et al elicited transient salivary testosterone spikes that those other studies overlooked by developing an ingenious laboratory technique: expose men to young, attractive, and flirtatious women. Although the men scored the average of these women’s beauty a 5.83 on a scale from one to seven, the study failed to publish photographs. Nevertheless, men with fewer CAG repeats produced stronger testosterone responses to these ladies.
     This study also found that higher baseline cortisol suppressed testosterone increases with a beta coefficient equal to that of having more CAG repeats. Cortisol suppresses testosterone production, per Sapolsky and Dong et al.

Just How Nice is Sugar & Spice?
     Cortisol research has actually become a Holy Grail for politically correct liberals and people who make "alternative" or "integrative" medicine their hobby. The "central dogma," as one study put it, of cortisol research has been that stress is bad, and cortisol is a bad stress hormone. However, some research suggests that low cortisol or flattening of the daily circadian cycle of cortisol levels may be worse than high cortisol levels. DeSantis et al and Ukkola et al have found that African Americans have lower cortisol than whites. Liberals want to link this stress hormone to racism, which they presume is detrimental to the African-American psyche and physical well-being. Some research suggests that glucocorticoid hormones like cortisol affect memory processing and, therefore, cognition. Liberals also hope that cortisol stress response to discrimination will explain the higher rate of preterm births among African Americans. Two studies gave equivocal but arguably supportive results for this hypothesis. However, Lu and Chen failed to link preterm birth to stressful events other than "traumatic" events like becoming homeless or physical fights. Cohen et al also failed to link a higher level of evening cortisol to reported discrimination. DeSantis et al made much of the new evidence linking poor health outcomes to lower cortisol and the African Americans' considerably lower morning cortisol levels shown on the graph below. However, they also acknowledged the twin study by Bartels et al, showing a 60% heritability to morning cortisol levels. Hence, they turned their focus to a modestly higher evening cortisol level in African Americans, since this is apparently not heritable.


     This flip-flopping on the cortisol "central dogma" reminds me of the black-white suicide paradox. As an undergraduate, I came across some speculation as to why the universal oppressors, white males, have much higher suicide rates than the universal victims, black men. As author David Lester wrote, "The low rates of suicide in Africans in general, and African Americans in particular, may represent an African worldview which accepts suicide only in the very last resort in the face of extreme stress, an attitude consistent with the Afrocentric optimal psychology proposed by Myers and others." White men commit suicide more because they are prisoners to their own privileged status, which they must escape through suicide or bungee jumping. By the time I matriculated into medical school, the African-American male suicide rate was accelerating. The professors cited those startling statistics as further evidence of the oppression of the black man, while neglecting to mention that white men still had a higher suicide rate.


     Beginning with the 2004 Wust et al study on the effects of glucocorticoid receptor alleles on cortisol levels, progress in understanding cortisol heritability at the molecular level is slowly coming to fruition. Now, a new study by Way and Taylor has found that the short allele of 5-HTTLPR causes increased cortisol responses to a perceived social threat provided by the Trier Social Stress Test. As I previously mentioned, about 70-80% of East Asians, 40-50% of Europeans, and just 10-30% of Africans and African Americans possess this short allele. Also, a new study by Armbruster et al found that the 7R allele of DRD4 causes lower cortisol responses and that this allele interacted with the long allele of 5-HTTLPR to lower cortisol response to social stress. Beaver et al determined that African-Americans have significantly more 7R alleles than whites. The possibility that low cortisol levels in African Americans could be partly genetic has important implications for research on the genetics of violence. As I previously pointed out, the violence gene MAOA has a glucocorticoid and androgen response element, through which cortisol can up-regulate and testosterone can down-regulate MAOA enzyme levels. Sjoberg et al proved that higher testosterone levels increased aggressive tendencies in males with the 3R allele that is the most common MAOA allele in black people but did not increase aggression in males with the 4R allele that is the most common MAOA allele in whites.
     To summarize, African Americans have fewer CAG repeats in the androgen receptor gene, which somehow increases testosterone spikes. Higher testosterone decreases MAOA enzyme levels in those with the 3-repeat allele. Plus, androgen receptor alleles with fewer CAG repeats beget more androgen receptor activity. These receptors translocate to the cell nucleus and down-regulate the MAOA gene. African Americans likely have a significant genetic component to their lower baseline cortisol levels and lower cortisol spikes in response to threats. This further allows higher testosterone levels and decreases MAOA levels directly. Lower MAOA enzyme levels increase aggressive behavior, as my previous blog posts explain. These racial hormonal differences help to answer the black-Asian MAOA paradox: somehow Asians are much less inclined towards delinquent violence despite possessing about the same proportion of the 3R allele of MAOA. Greater prevalence of the 2R allele in black people cannot entirely explain the difference.
     The puzzle pieces are fitting together. One might predict based on this synthesis that fewer CAG repeats would correlate with aggression. Indeed, in 2008 Rajender et al determined that male control subjects average 21.19 repeats, rapists average 18.44 repeats, murderers average 17.59 repeats, and men who murder after they finish raping average 17.31 repeats. The shortest repeat lengths are associated with a higher degree of violence, earlier criminal records, verbal aggression, assertive personalities, extraversion, neuroticism, and self-transcendence (mystical tendencies), according to Cheng et al, Jonsson et al, and Westberg et al. Fewer GGC repeats are associated with aggression, impulsivity, promiscuity, and early menarche, according to Comings et al. A new study by Manuck et al localized the neural effects of shorter CAG repeat polymorphisms to the ventral amygdala, and previous research by Buckholtz et al found that the 3-repeat allele of MAOA is associated with increased amygdala activation.

Estrogen Poisoning
     Endocrinology studies a fascinating and complex web of hormonal interactions. Testosterone and cortisol decrease sex hormone-binding globulin (SHBG). SHBG, in turn, binds testosterone, which stimulates the hypothalamus to produce gonadotropin-releasing hormone, which acts on the pituitary gland to release follicle-stimulating hormone and luteinizing hormone. These hormones cause testicular aromatase to convert testosterone to estradiol. Studies show that young black men have higher SHBG than young white men. Specifically, I am referring to Abdelrahaman et al, Winters et al, Ross et al, Wright et al, and Gapstur et al (revealed only in a personal communication to Abdelrahaman et al). Black men have higher estradiol levels than white men, according to Morrison et al, Wright et al, and Rohrmann et al. The higher estradiol levels in black men have implications for bone mass, cardiovascular health, and, yes, violent behavior. Since estradiol decreases MAOA enzyme levels, one would expect higher estradiol levels to increase aggressive tendencies.
     By studying the plasma content of 214 twin pairs, Meikle et al calculated a 38% heritability for estradiol and a 62% heritability for SHBG. When Ahn et al published "the first comprehensive characterization of genetic variation in the sex steroid pathway" this past summer, I became somewhat disappointed that it could not definitively explain racial hormone disparities. Their supplement offered a list of 874 single nucleotide polymorphisms (SNPs) from 37 genes with p-values and beta coefficients for their effects on SHBG, testosterone, estradiol, and androstanediol-glucuronide (which converts testosterone to the more potent androgen dihydrotestosterone). To get a rough idea of how this data might relate to racial differences in hormones, I created graphs with p-values as the independent variable (making the graph most trustworthy towards the left side) and with the accumulative sums of beta coefficients multiplied by the allele prevalences for each population the dependent variable. In other words, the amount the graph rises with increasing uncertainty depends on both how common the more active alleles are in that group and how much effect that allele has on the hormone (or SHBG) concentration in blood. I calculated prevalences for whites, blacks, Chinese people, and Japanese people by combining all relevant populations in the HapMap database. Since the study population consisted entirely of white men, I expected a bias towards higher levels in whites, for whom these SNPs were selected and the beta coefficients were determined. In fact, each graph produced exactly that result with the exception of estradiol, shown below. The line for black people jumps above that of whites due to the adenine (A) allele of rs2687105 in the gene CYP3A4. The significance of this is questionable, as I have found no studies of breast or prostate cancer that found any correlation for this SNP. CYP3A4 produces an enzyme that mostly metabolizes testosterone but can also metabolize estrogen. Other variants of this gene may play a role in racial disparities in prostate and breast cancer.



Sweet and Noble It is to Die for One’s Meme
     Surely, everyone can comprehend that they will not wake up tomorrow and read the morning paper headline, "Cancer Cured!" The fight against cancer is incremental with multiple simultaneous strategies. One strategy would be to individually customize pharmacology based on decoded DNA. Every day you take the pill that is perfect just for you. Unfortunately, this approach is in its infancy. A superior approach to just waiting for this science to mature would be ethnopharmacology, in which drug approval is categorized for specific populations based on probability of benefit for individuals. Since different populations tend to have different medically-relevant allele frequencies, doctors could prescribe drugs based on the probability that the patient is like others in his or her ethnic group.
     The US Food and Drug Administration has already done this for BiDil, which was just a combination of existing approved generic drugs. It might not surprise that a drug created for improved compliance would help African Americans more given the new study by Roth et al, showing that African Americans had worse medical literacy (29% had adequate short test of functional health literacy in adults [S-TOFHLA] scores versus 58% of whites) and more medication-related problems, despite taking fewer medications. After poor sales, NitroMed stopped marketing BiDil and sold it to JHB Pharmaceuticals.


     In July, the Journal of the National Cancer Institute published a nearly 20,000-subject study, which sought to determine whether race affects cancer mortality independent of socioeconomic status. The "provocative aspect" of the study's conclusion was that the only cancers that have higher mortality for black people are the "sex-specific cancers (breast, ovarian, and prostate)." Apparently not knowing where they were supposed to stop, the authors continued that "one explanation for our findings might be that there are hormonal factors . . . that differ by race." Kathy Albain led the study. An accompanying editorial by Otis Brawley of the American Cancer Society decried "racial medical profiling," reminding the reader that race "is not a scientific categorization and is a construct rejected by anthropologists." Then, Catherine Elton wrote a tract in Time magazine that would have seemed like a slander that Dr. Albain is racist had it not included the disclaimer "no one is accusing authors like Albain of racism." Elton is a recipient of an exclusively female fellowship "to focus exclusively on human rights journalism and social justice issues."
     Progress in racial endocrinology may require braving (and possibly proving) a muck of the most offensive and sexualized stereotypes in order to better treat some of the most common and deadly cancers, (not to mention the disease of violence). I am hopeful in that I expect that we shall accomplish this before the methane belch ends our pitiful existence.