Richard S. Cooper

Detecting recent positive selection in the human genome from haplotype structure

The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.

Hypertension Treatment and Control in Five European Countries, Canada, and the United States

Abstract—Levels of hypertension treatment and control have been noted to vary between Europe and North America, although direct comparisons with similar methods have not been undertaken. In this study, we sought to estimate the relative impact of hypertension treatment strategies in Germany, Sweden, England, Spain, Italy, Canada, and the United States by using sample surveys conducted in the 1990s. Hypertension was defined as a blood pressure of 160/95 mm Hg or 140/90 mm Hg, plus persons taking antihypertensive medication. “Controlled hypertension” was defined as a blood pressure less than threshold among persons taking antihypertensive medications. Among persons 35 to 64 years, 66% of hypertensives in the United States had their blood pressure controlled at 160/95 mm Hg, compared with 49% in Canada and 23% to 38% in Europe. Similar discrepancies were apparent at the 140/90 mm Hg threshold, at which 29% of hypertensives in the United States, 17% in Canada, and ≤10% in European countries had their blood pressure controlled. At the 140/90 mm Hg cutpoint, two thirds to three quarters of the hypertensives in Canada and Europe were untreated compared with slightly less than half in the United States. Although guidelines vary among countries, resulting in different case definitions, this does not account entirely for the varying success of different national control efforts. Low treatment and control rates in Europe, combined with a higher prevalence of hypertension, could contribute to a higher burden of cardiovascular disease risk attributable to elevated blood pressure compared with that in North America.

Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis

Sequence variation in human genes is largely confined to single-nucleotide polymorphisms (SNPs) and is valuable in tests of association with common diseases and pharmacogenetic traits. We performed a systematic and comprehensive survey of molecular variation to assess the nature, pattern and frequency of SNPs in 75 candidate human genes for blood-pressure homeostasis and hypertension. We assayed 28 Mb (190 kb in 148 alleles) of genomic sequence, comprising the 5´ and 3´ untranslated regions (UTRs), introns and coding sequence of these genes, for sequence differences in individuals of African and Northern European descent using high-density variant detection arrays (VDAs). We identified 874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to reveal a discordancy rate of 21% for VDA detection. The SNPs detected have an average minor allele frequency of 11%, and 387 are within the coding sequence (cSNPs). Of all cSNPs, 54% lead to a predicted change in the protein sequence, implying a high level of human protein diversity. These protein-altering SNPs are 38% of the total number of such SNPs expected, are more likely to be population-specific and are rarer in the human population, directly demonstrating the effects of natural selection on human genes. Overall, the degree of nucleotide polymorphism across these human genes, and orthologous great ape sequences, is highly variable and is correlated with the effects of functional conservation on gene sequences.

Trends and Disparities in Coronary Heart Disease, Stroke, and Other Cardiovascular Diseases in the United States Findings of the National Conference on Cardiovascular Disease Prevention

A workshop was held September 27 through 29, 1999, to address issues relating to national trends in mortality and morbidity from cardiovascular diseases; the apparent slowing of declines in mortality from cardiovascular diseases; levels and trends in risk factors for cardiovascular diseases; disparities in cardiovascular diseases by race/ethnicity, socioeconomic status, and geography; trends in cardiovascular disease preventive and treatment services; and strategies for efforts to reduce cardiovascular diseases overall and to reduce disparities among subpopulations. The conference concluded that coronary heart disease mortality is still declining in the United States as a whole, although perhaps at a slower rate than in the 1980s; that stroke mortality rates have declined little, if at all, since 1990; and that there are striking differences in cardiovascular death rates by race/ethnicity, socioeconomic status, and geography. Trends in risk factors are consistent with a slowing of the decline in mortality; there has been little recent progress in risk factors such as smoking, physical inactivity, and hypertension control. There are increasing levels of obesity and type 2 diabetes, with major differences among subpopulations. There is considerable activity in population-wide prevention, primary prevention for higher risk people, and secondary prevention, but wide disparities exist among groups on the basis of socioeconomic status and geography, pointing to major gaps in efforts to use available, proven approaches to control cardiovascular diseases. Recommendations for strategies to attain the year 2010 health objectives were made.

Estimating African American Admixture Proportions by Use of Population-Specific Alleles

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.

The prevalence of hypertension in seven populations of west African origin.

OBJECTIVES This study was undertaken to describe the distribution of blood pressures, hypertension prevalence, and associated risk factors among seven populations of West African origin. METHODS The rates of hypertension in West Africa (Nigeria and Cameroon), the Caribbean (Jamaica, St. Lucia, Barbados), and the United States (metropolitan Chicago, Illinois) were compared on the basis of a highly standardized collaborative protocol. After researchers were given central training in survey methods, population-based samples of 800 to 2500 adults over the age of 25 were examined in seven sites, yielding a total sample of 10014. RESULTS A consistent gradient of hypertension prevalence was observed, rising from 16% in West Africa to 26% in the Caribbean and 33% in the United States. Mean blood pressures were similar among persons aged 25 to 34, while the increase in hypertension prevalence with age was twice as steep in the United States as in Africa. Environmental factors, most notably obesity and the intake of sodium and potassium, varied consistently with disease prevalence across regions. CONCLUSION The findings demonstrate the determining role of social conditions in the evolution of hypertension risk in these populations.

Socioeconomic status and health in blacks and whites : The problem of residual confounding and the resiliency of race

A large number of epidemiologic studies have focused on racial/ethnic differences, particularly between blacks and whites. Because health endpoints and racial categorizations are associated with socioeconomic status, investigators generally adjust for socioeconomic indicators. The intention is usually to control for confounding, thereby making groups comparable and excluding socioeconomic status as an alternative explanation to hypotheses of innate physiologic differences. A threat to the validity of these analyses is therefore the presence of residual confounding. We identify four potential sources of residual confounding in this analytical design: categorization of socioeconomic status variables, measurement error in socioeconomic indicators, use of aggregated socioeconomic status measures, and incommensurate socioeconomic indicators. Using simulations and examples from the literature, we demonstrate that the effect of residual confounding is to bias interpretation of data toward the conclusion of independent racial/ethnic group effects. Investigators often refer to possible “genetic” differences on the basis of models that control for socioeconomic status. We propose that such conclusions on the basis of this analytical strategy are generally unwarranted. Racial/ethnic differences in disease are a pressing public health concern, but the current approach does not often provide a basis for inference about putative biological factors in the etiology of this disparity.

The Prognostic Role of Left Ventricular Hypertrophy in Patients with or without Coronary Artery Disease

OBJECTIVE To examine the association between echocardiographically determined left ventricular hypertrophy and mortality in patients with and without coronary artery disease. DESIGN Cohort study with a mean follow-up period of 4 years. SETTING An inner-city public hospital in Chicago. PATIENTS A cohort of 785 patients, most of whom were black and had hypertension. INTERVENTIONS Coronary arteriography for presumed coronary artery disease and echocardiography. MAIN OUTCOME MEASURE All-cause and cardiac mortality. RESULTS Left ventricular hypertrophy, based on left ventricular mass corrected for body surface area, was present in 194 of 381 patients (51%) with coronary artery disease and in 162 of 404 patients (40%) without coronary artery disease. Patients with left ventricular hypertrophy had worse survival than those without hypertrophy in both the group with coronary artery disease and the group without coronary artery disease. After adjustment was made for age at baseline, sex, and hypertension, the relative risk for death from any cause in patients with hypertrophy compared with patients without hypertrophy was 2.14 (95% CI, 1.24 to 3.68) among those with coronary artery disease and 4.14 (CI, 1.77 to 9.71) among those without coronary artery disease. CONCLUSIONS Echocardiographically determined left ventricular hypertrophy is an important prognostic marker in patients with or without coronary artery disease. The effect of reversing ventricular hypertrophy in patients with and without coronary disease deserves further study.

Left Ventricular Hypertrophy Is More Prevalent in Blacks Than Whites in the General Population The Dallas Heart Study

Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (P<0.001), fat-free mass (P=0.002), or height2.7 (P<0.001) was 2- to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (P<0.001 when left ventricular hypertrophy was indexed to body surface area or height2.7 and P=0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2- to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10−6). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na+ excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.