Gender Differences in Treatment Response to Sertraline Versus Imipramine in Chronic Depression Susan G. Kornstein, M.D. Objective: The authors examined gender study. Gender differences in time to re- differences in treatment response to ser- sponse were seen with imipramine, with Alan F. Schatzberg, M.D. traline, a selective serotonin reuptake in-
Unl.eduRace and Medicine Genetic studies of population differences, although controversial, promise David Goldstein of University College in clues to disease as well as new drug targets, scientists believe London agrees: "If you say on average the difference between West Africans and Eu- Mention race and medicine in a group of racial identity biologically irrelevant. But ropeans is slight, that does not rule out a scientists, and you are likely to provoke a that is decades away. Meanwhile, some sci- great many variants that influence how range of heated opinions on whether it is entists maintain that race can serve as a use- people respond to drugs." useful, or even ethical, to consider how peo- ful, if crude, indicator in sorting out why Joel Buxbaum, who studies the molecu- ple of different ancestry respond to disease people experience diseases—and their treat- lar basis of disease at Scripps Research In- and treatments. No one disputes that some ments—differently and in finding new tar- stitute in La Jolla, California, is persuaded diseases strike disproportionately in some gets for drugs.
as well. "A call to ignore [race] in diagnosis racial or ethnic groups—thalassemia in peo- and treatment is a call to ignore biology," he ple whose ancestors came from the Mediter- The argument
says. "Research in the last 35 years has un- ranean area, sickle cell anemia in people of The chief argument against the notion that covered significant differences among racial African origins, for example. Less clear-cut biological race can be medically meaning- and ethnic groups in their rate of drug me- than these single gene disorders—but the ful is that there are far more genetic differ- tabolism, in clinical responses to drugs, and subject of increasing research—is the med- ences among individuals than there are be- in drug side effects." ical significance of a host of more subtle tween different ancestral groups. Neil The most definitive evidence is on differ- gene variants that appear in differing Risch of Stanford University says that ent levels of certain drug-metabolizing en- frequencies in various populations and comparison is misleading, however. He zymes found in whites, blacks, and Asians.
that seem to influ- Some of these differences are quite dramatic; for example, Genaissance Pharmaceuticals in New Haven, Connecticut, has found a mu- tation of a major metabolism-controlling en- zyme that occurs in 30% to 40% of Asians have been spotted, and less than 5% of members of other groups. Such findings help explain what is largely circum- many doctors have long observed—that stantial. Some sci- Image not
many people of East Asian ancestry need entists dismiss the smaller than average doses of a variety of available for
data as too prelim- heart, pain, and psychotropic drugs.
inary, or the differ- Less well documented—and more con- ences as insignifi- troversial—is emerging evidence on differ- ent patterns of cardiovascular disease among various populations. Researchers biological differ- are looking for bio- ences in how peo- logical roots not only of the well- racial and ethnic known differences groups respond to Sabotaged by thrifty gene? Indians around the
between blacks and disease and treat- world have higher heart disease risk.
whites, but also of another, much less fairly stigmatize some patients and lead to and others argue that publicized pattern inferior health care. Yet many scientists see if 30% of one popula- of heart disease that exploration of differences among ancestral tion can't metabolize Image not
groups as a way to learn more about com- a certain drug, com- affects Asian Indi- plex diseases and ultimately improve treat- pared with 10% of an- available for
ans. Although nei- ment for some groups of patients. other population, the ther of these groups online use.
Already, drug companies are hunting for between-group vari- seems more disease- genetic reasons behind commonly observed ability is low because prone in its ances- medical differences between groups. Scien- most people in both tral environment, tists are doing retrospective genetic analyses g roups lack this of data from drug trials. And 18 months ago a company called NitroMed launched a trial morphism. Nonethe- larly increased con- of a heart drug directed at compensating for less, this variation is what is believed to be a nitric oxide (NO) signif icant when it and fat, smoking, deficiency in many African Americans. comes to estimating and inactivity—hit Everyone's ultimate dream is to have evi- the probability of re- dence on individual genotypes to guide sponse to treatment, Vulnerable. Cardiovascular disease is a partic-
when investigators medicine, a development that would make he says. Geneticist ular scourge for African Americans.
try to control for en- vironmental factors that could explain group whites in genes that manipulate the response role of so-called NO subsensitivity in heart differences, says cardiologist Clyde Yancy of the sympathetic nervous system to hor- disease. McNamara, who calls the trial of the University of Texas Southwestern mones like adrenaline. Stephen Liggett and "very unique and very important," says he Medical Center in Dallas, "you can still see colleagues at the University of Cincinnati re- and colleagues will do a genetic substudy, excess expression of disease." Yancy and ported last fall that possessing a combination looking at a number of candidate markers others see this as strong evidence for some- of two particular versions of alpha and beta for correlations with treatment response. thing genetic at work. But teasing it apart adrenergic receptors raised heart failure risk Researchers are also combing through from other risk factors is proving daunting.
for blacks 10-fold. The high-risk version of data from earlier big heart trials. To get a fix the alpha receptor occurs almost exclusively on the nature of the suspected racial differ- in people of African ence in response to beta- Blacks don't have more heart attacks than origin and is present in blockers, Buxbaum and whites, but in the United States they die about 40% of U.S.
colleagues are looking at sooner from cardiovascular problems—both blacks, says Liggett.
data from BEST (the Beta- heart failure and strokes, says Yancy. They The researchers be- Blocker Evaluation of Sur- also have 10 times the rate of kidney failure, lieve that depressed re- vival Trial), which tested a three times the incidence of cardiac hyper- ceptor function leads trophy, and more than twice the rate of dia- to excess release of called Bucindilol. In 2700 betes, a destroyer of blood vessels. High norepinephrine, which people with congestive blood pressure, which afflicts almost one- is bad for the heart.
heart failure, black pa- third of the U.S. black population, is the en- The study is relevant tients as well as sicker gine that, in large part, drives these related for the use of beta- ones generally failed to conditions. It leads to excess stress on or- blockers, which inhibit benefit from the drug. So gans, which respond with hypertrophy, or the effects of adrena- the scientists are genotyp- abnormal cell growth. Intertwined with the line on beta receptors ing the 600 black patients problem is a shortage of nitric oxide and, in and which may be to see if they can spot a many cases, excess salt sensitivity that in less effective in black genetic marker that will turn leads to fluid retention. Heart failure in heart patients. Liggett's serve as a better indicator blacks often occurs from damage to the left team reported in the than race for whether the ventricle, which is responsible for sending September issue of drug is likely to work. The freshly oxygenated blood through the body.
Nature Medicine that results will be put in a Indeed, according to Yancy, in blacks, heart the high-risk beta DNA bank available for failure "may be a different disease with less receptor, which is NO booster. BiDil developer Jay Cohn.
other investigators. favorable outcomes" than in whites. also more common in Although these studies Scientists are looking for genes that blacks, raises the risk of heart failure in both are important, says Yancy, there is still no would explain these patterns, in particular for mice and people and forebodes a poor re- substitute for getting data from really big genes related to hypertension. Because NO, sponse to beta-blockers.
populations, not only to find vulnerability the chemical responsible for keeping blood genes but to sort out what's "normal"—that vessels fit and toned, is important in the ac- Drug trials
is, genetic patterns (in any race or ancestral tion of ACE (angiotensin-converting en- Clinical trials have not been particularly group) that do not predispose to heart dis- zyme) inhibitors, genes for NO synthase, the helpful in illuminating such differences, ease. He has high hopes for another initia- enzyme most important for vascular NO says McNamara, because usually at least tive, called UNITE-HF, led by the Universi- production, are prime candidates. Dennis 80% of participants are white, and the ty of North Carolina with support from the McNamara of the University of Pittsburgh pooling of data often obscures any racial drug company AstraZeneca, a U.K.-based Medical Center says the prevalence of certain company with U.S. headquarters in Wilm- versions of these genes is "much different in That is why many researchers are partic- ington, Delaware. UNITE-HF is collecting blacks and whites." The variant that ACE in- ularly excited about the first clinical trial of blood samples from the country's "stroke hibitors work best with is found in 60% of a heart failure treatment that exclusively tar- and heart attack belt" in the southern and whites but only 30% of blacks, he says.
gets African Americans. It was launched in southeastern United States. So far investiga- Also blood pressure–related is the gene March 2001 by NitroMed, a company in tors have samples from some 800 ambulato- for transforming growth factor–β (TGF-β).
Bedford, Massachusetts, to test a drug that ry heart patients, both black and white, A group led by Phyllis August at Weill Med- may be uniquely beneficial to heart patients which they will analyze for the prevalence ical College of Cornell University in New with NO deficiencies. The first-of-its-kind of suspect genes. York City reported in 2000 that TGF-β1 is trial, called A-HeFT (for African-American overexpressed in black patients with end- Heart Failure Trial), is testing a drug called stage renal disease or severe hypertension— BiDil that was originally developed in the The other population with a big heart dis- and more so than in white patients with the 1980s. BiDil combines vasodilators with an ease problem is South Asian Indians. "Until same diseases. This looks like a promising NO source and antioxidant properties to 50 years ago it was hardly ever heard that genetic candidate for hypertension, the au- help potentiate treatment by ACE inhibitors.
Indians had high heart attack risk," says car- thors say, because TGF-β1 regulates sub- All patients in the trial will get standard diologist Prakash Deedwania of the Univer- stances that act both as vasoconstrictors and medication; half will also get BiDil. Scien- sity of California, San Francisco, Fresno, as growth factors for vascular cells. tists believe that the trial, which has been School of Medicine. But as more Indians In addition to genes involved in high endorsed by an array of groups, including are becoming westernized, many now have blood pressure, researchers have found a sig- the Association of Black Cardiologists Inc., heart attacks as early as their mid-30s, and, nif icant difference between blacks and should produce some definitive data on the he says, "the risk is enormously high all over the world." A major risk factor is dia- Many Indian doctors believe that the In- ic data. "Our company was founded on the betes, which, according to figures collected dian vulnerability to heart disease is striking principle that human genetic variation is by F. P. Cappuccio of St. George's Hospital enough to justify more preventive vigilance.
critical to drug response," says Claiborne Medical School in London, is roughly four Cardiologist Enas Enas, director of the Coro- Stephens, vice president for genetics. The times as prevalent among Indians (in urban nary Artery Disease in Indians Foundation in obvious way to make a first cut at that varia- India and abroad) as in Londoners. Indians Lisle, Illinois, has stated that the goals of tion, he notes, is to look at how evolution also tend to have high levels of triglyc- treatment for high blood pressure and obesi- parceled out different versions of various erides and low levels of HDL, the "good" ty should be at least 10% lower, and choles- genes according to the environments in cholesterol. One evolutionary explanation is terol 20% lower, for Asian Indians than the which early human populations evolved. the "thrifty gene hypothesis": Over the mil- goals recommended for Caucasians.
One of its projects is a detailed data repos- lennia people in India en- itory of more than 7000 dured cyclical famines; Asian/African-American SNP Comparison (42,659 SNPs) genes from 93 whites, those who fared best blacks, and Asians, in- were those who could cluding information on conserve energy in ab- the origins of their par- dominal fat. Now, for ents and grandparents, those exposed to plenty, which companies can this ability has turned in- use as a reference in clin- to a disadvantage. ical trials. This is enough Some preliminary evi- to give "a reasonable dence for a genetic con- idea of what the gene fre- nection is emerging.
quencies are" in those Asian carrier frequency 20% Michael Miller, director groups, says Stephens of the Center for Preven- Fraction of SNPs with given (color) tive Cardiology at the Although everyone University of Maryland agrees that data are still African-American Carrier Frequency Medical Center, says his preliminary, there's been group has found a high enough talk to get peo- Biodiversity. More than 42,000 SNPs (genetic variations) found in African Americans are
prevalence of an alteration ple concerned over how divided into columns according to how frequently they appear in that population. Colors in the apolipoprotein C3 indicate the frequency with which these same groups of SNPs are found in East Asians.
these f indings could gene, which regulates For instance, in the second column, of the 7188 SNPs that are found in 15% to 30% of affect medical care. For triglyceride metabolism, African Americans, more than half show no variation in Asians.
example, Richard Coop- in Indians living in the er, a cardiologist at Loy- United States. The researchers found this Era of transition
ola University Medical Center in Chicago, polymorphism by taking blood samples from Increasing awareness of possible genetic worries that any new information on race dif- 99 attendees at an Indian festival in Northern contributions to ethnic differences is reflect- ferences will lead to inferior care for non- Virginia, as they describe in the January ed in a recommendation issued last January whites. He says that so far, the best data on 2001 American Journal of Cardiology. This by the U.S. Food and Drug Administration biological race differences are only "mixed," alteration is also associated with low HDL (FDA). Calling for more scrutiny of subpop- and even where differences do exist they are levels, says Miller, and possibly also insulin ulations, FDA wants drug testers to use never great enough to justify any race-based resistance. The group is now looking to see racial divisions specified by the Census Bu- generalizations in the absence of genetic if people in India show the same pattern.
reau "to ensure consistency in evaluating tests. He says there's no evidence that risk Investigators in New Delhi have already potential differences in drug response." factors don't operate the same way for all reported from a genetic analysis of 139 Drugmakers are already on the lookout groups. BiDil developer Jay Cohn of the Uni- healthy males in Northern India that almost for genetic subgroups that could divulge versity of Minnesota, Twin Cities, agrees that one-third carried a related variation in the new targets for therapeutic drugs. "I think the best treatment is the same for any race.
apolipoprotein gene, a rare mutation in Cau- we all believe there's a lot of potential But he wouldn't have a problem with, say, casians. Furthermore, it was twice as frequent there," says Gary Palmer, a Pfizer vice pres- prescribing a drug that will boost NO in a among those with elevated triglycerides—a ident in New York. Pfizer is particularly in- black heart patient. If a doctor knows that a risk factor for coronary artery disease. terested in hypertension-related genes in trait is "more common in one population than More clues on how genetic variation blacks and diabetes-related genes that could another," that could be enough to "consider could translate into different responses to account for the high rates of the disease in modifying one's treatment strategy," he says. medication should come from a new 6-week both Asian Indians and Native Americans.
Although scientists hope that the advent clinical trial, sponsored by AstraZeneca. It AstraZeneca is also looking for population of genomic medicine will obviate the need will compare Crestor (rosuvastatin), a new differences in drug response in its clinical to grapple with race issues, Goldstein warns cholesterol-lowering drug that won govern- trials. Spokesperson Gary Bruell says that if that the day of individually tailored treat- ment approval in August, with an older one the company found that a drug has a "pro- ments may be far away. Even after relevant (atorvastatin) in South Asian Americans.
found effect" on a particular group, it would genes are identified, it will be a chore to sort Deedwania says it will be the largest label and promote it accordingly. "If a popu- out what all the alleles do, he says. And so prospective trial ever done on Indians, with lation doesn't benefit, that could end up on far, only a handful of such genes have been some 800 subjects from 150 centers around the label too," he adds. identified. "Pharmacogenetic studies are in the country. Miller says Crestor may be bet- Companies will probably be getting their absolute infancy," he says. So "the big .STEPHENS/GENAISSANCE ter for Indians because it does a little better more help from outfits like Genaissance, set question is the interim strategy: how to use :C job at raising HDL. up 6 years ago to develop and market genet- –CONSTANCE HOLDEN CREDIT
Livestock Science 110 (2007) 214 – 220 Effect of photoperiod on milk yield and quality, and reproduction in dairy goats R. Garcia-Hernandez, G. Newton, S. Horner, Lou C. Nuti ⁎ International Goat Research Center, Prairie View A&M University, Prairie View, Texas, 77446, United States Received 2 May 2006; received in revised form 5 October 2006; accepted 2 November 2006