Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Background: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objectives: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity. Methods: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults. Replication of signals was determined in a cohort of 116 cases and 68 controls obtained from Malawi, Uganda and Mozambique. Interaction with ERAP genes was determined in patients positive for HLA-C*04:01 . In silico docking studies were also performed for HLA-C*04:01 . Results: Fifteen SNPs demonstrated nominal significance ( P < 1 × 10 -5 ) with one or more of the hypersensitivity phenotypes. The most promising signal was seen in SJS/TEN, where rs5010528 ( HLA-C locus) approached genome-wide significance ( P < 8.5 × 10 -8 ) and was below HLA -wide significance ( P < 2.5 × 10 -4 ) in the meta-analysis of discovery and replication cohorts [OR 4.84 (95% CI 2.71-8.61)]. rs5010528 is a strong proxy for HLA-C*04:01 carriage: in silico docking showed that two residues (33 and 123) in the B pocket were the most likely nevirapine interactors. There was no interaction between HLA-C*04:01 and ERAP1 , but there is a potential protective effect with ERAP2 [ P = 0.019, OR 0.43 (95% CI 0.21-0.87)]. Conclusions: HLA-C*04:01 predisposes to nevirapine-induced SJS/TEN in sub-Saharan Africans, but not to other hypersensitivity phenotypes. This is likely to be mediated via binding to the B pocket of the HLA-C peptide. Whether this risk is modulated by ERAP2 variants requires further study.

PBDE levels in breast milk are decreasing in California.

To assess the efficacy of the bans in reducing PBDE levels, we recruited 67 California first time mothers (sampled during 2009-2012) and collected cord blood at birth (n = 31), breast milk (n = 66) and maternal blood (n = 65) at 3-8 weeks postpartum. Using the same sample extraction procedures and analytical instrumentation method (GC-HRMS), we compared PBDE as well as PCB levels in these breast milk samples to those from our previous study (n = 82, sampled during 2003-2005) and found that the sum of PBDEs over the ∼7 year course declined by 39% (GeoMean = 67.8 ng/g lipid in 2003-2005; 41.5 ng/g lipid in 2009-2012) and that the sum of PCBs declined by 36% (GeoMean = 71.6 ng/g lipid in 2003-2005; 45.7 ng/g lipid in 2009-2012). This supports our earlier finding of a PBDE decline (39%) in blood. We also found that the PBDE concentrations and congener profiles were similar in breast milk and their matched maternal/cord blood: BDE-47 was the dominant congener, followed by BDE-153, -99, and -100. Similar levels and congener profiles of PBDEs in these matrices suggest that they are at equilibrium. Therefore, we propose that maternal serum levels may be used to predict an infant's daily dose of PBDE exposure from breastfeeding when breast milk levels are not available. In addition, our study confirmed that breastfeeding babies are still exposed to high levels of PBDEs, even though PBDE levels are decreasing.

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study.

INTRODUCTION: Nephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD. METHODS: A total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event. RESULTS: Data are currently being analyzed. Results are pending. DISCUSSION: The Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm.

Phenotype standardization for drug-induced kidney disease.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition.

The international serious adverse events consortium.

The International Serious Adverse Events Consortium is generating novel insights into the genetics and biology of drug-induced serious adverse events, and thereby improving pharmaceutical product development and decision-making.

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

High postnatal exposures to polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) via breast milk in California: does BDE-209 transfer to breast milk?

Breast milk samples collected during 2003-2005 from 82 first-time mothers in 24 communities located throughout California contained levels of polybrominated diphenyl ethers (∑(tri-hexa (8))PBDEs; median = 53.3 ng/g lw, range = 9.60-1291) and polychlorinated biphenyls (∑(12)PCBs; median = 73.4 ng/g lw, range = 22.2-433) that are among the highest in the world. PBDE levels varied 100-fold. BDE-47 was the dominant PBDE congener, with levels exceeding the U.S.EPA Reference Dose (RfD) for neurodevelopmental toxicity (100 ng/kg/day) in most (60%) breast milk samples. In some samples, BDE-209 (2/82) and/or BDE-153 (5/82) were the dominant congeners, suggesting that BDE-209 can transfer to breast milk and/or break down in the mother and transfer to the nursing infant as the lower-brominated PBDEs associated with adverse effects. PBDE levels in California breast milk are approaching those of PCBs, and the trend PBDEs > PCBs may continue as PBDEs migrate from products to the indoor and outdoor environments.

Prey species as possible sources of PBDE exposures for peregrine falcons (Falco peregrinus) nesting in major California cities.

Our earlier findings indicate that (1) peregrine falcons (Falco peregrinus anatum Bonaparte) nesting in major California cities have among the highest polybrominated diphenyl ether (PBDE) levels in the world (max ∑PBDEs=100 ppm), and (2) Big City peregrines have higher levels and proportions of the higher-brominated congeners (hepta- to deca-BDEs) than do their Coastal counterparts. In this study we classified the prey species (n =185) from the remains of prey (feathers) at 38 peregrine nest sites over 25 years (1974-1998). We grouped the prey species into 15 categories based on diet and found distinctly different prey patterns for Big City vs. Coastal peregrines. Big City peregrines had a higher (almost three times) weight percentage intake of food waste-eating birds (e.g., rock pigeons, Columba livia) than Coastal peregrines. These differing prey patterns suggest diet as a potential source of the unusually high levels and proportions of higher-brominated PBDEs in Big City peregrines. The relative contributions of diet and dust (e.g., preening) exposure to PBDE patterns in Big City peregrines will be explored in future investigations.

Polybrominated diphenyl ether (PBDE) levels in peregrine falcon (Falco peregrinus) eggs from California correlate with diet and human population density.

Peregrine falcons are now considered a conservation success story due in part to the phasing out of harmful contaminants that adversely affected reproduction. Recent studies have shown that peregrine eggs collected from California cities, however, have high levels of the higher-brominated polybrominated diphenyl ethers (SigmaPBDE(183-209)), a class of industrial flame retardants, in comparison to published data for other wildlife. Sources of these high PBDE levels and unusual PBDE profiles are unknown. Here we analyzed the stable carbon (delta(13)C), hydrogen (deltaD), and nitrogen (delta(15)N) isotope composition of peregrine eggs collected from urban and nonurban habitats. We found that delta(13)C values were significantly higher in urban versus nonurban eggs, suggesting that urban peregrines indirectly receive anthropogenic subsidies via their consumption of prey reliant on corn-based anthropogenic foods. delta(15)N and deltaD values were significantly lower in urban versus nonurban eggs, reflecting differences in dietary diversity and food/water sources available to peregrines in each habitat. These patterns suggest a link between an anthropogenic diet and high levels of SigmaPBDE(183-209) in California peregrines, and identify anthropogenic food as a potentially important PBDE exposure pathway for urban wildlife. If diet is an important PBDE exposure pathway for peregrines, continued high body burdens of SigmaPBDE(183-209) may be a potential risk to ongoing peregrine conservation efforts in California.

Time-trends and congener profiles of PBDEs and PCBs in California peregrine falcons (Falco peregrinus).

High levels (microg/g lw) of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in peregrine falcon eggs from California (n = 90 eggs from 52 birds, 38 nest sites, collected 1986-2007, SigmaPBDEs median = 4.53, range = 0.08-53.1). Over the past 22 years, PBDE levels more than tripled each decade in the eggs, whereas PCB levels had no significant changes. PBDE levels were highest in eggs from major California cities ("Big Cities"), whereas PCBs showed no difference across the regions. For PBDEs, Big City eggs had markedly different patterns from Coastal eggs: BDE-209 and the higher brominated PBDEs (hexa-nona) were dominant congeners in Big City eggs, while BDE-47 and -99 were dominant in Coastal eggs. In many of the birds that gave multiple eggs over time ("time series"), PBDE patterns changed over time: the high proportions of BDE-209 and higher brominated PBDEs (short half-lives) in young birds contrasted with increasingly higher proportions of BDE-153 (long half-life) and other lower brominated PBDEs as the birds aged. These data are consistent with metabolic debromination of BDE-209 (t(1/2) = 1-2 weeks) to the lower brominated PBDEs, with accumulation over time of BDE-153 (t(1/2) = 3-4 years). In contrast, PCB patterns showed no differences by locations, and did not change over time. Diet (prey birds) may explain the urban PBDE pattern, as the patterns in urban pigeons and peregrines were similar, with high proportions of BDE-209 and the higher-brominated PBDEs. Also, our prey data (feathers from peregrine nests) showed urban peregrines having a higher proportion (>2 fold) of granivorous/opportunistic birds (e.g., "introduced feral" pigeons, mourning doves, starlings) in their diet than coastal peregrines. In summary, these data indicate that BDE-209 exits consumer products as an environmental contaminant to be taken up by wildlife (particularly in urban locations), and undergoes metabolic debromination to the banned lower-brominated PBDEs. High levels of the higher-brominated PBDE congeners, especially in urban locations, permitted accurate measures of relative proportions of homologues in each of the hexa-nona congener classes. Using the major hexa-nona homologues in each of these classes, we propose a pathway for the stepwise, metabolic debromination of BDE-209.

Unusual hepta- and octabrominated diphenyl ethers and nonabrominated diphenyl ether profile in California, USA, peregrine falcons (Falco peregrinus): more evidence for brominated diphenyl ether-209 debromination.

High (maximum of 4.1 ppm lipid weight) levels of BDE-209 and other higher brominated diphenyl ethers (BDEs) found in California, USA, peregrine falcon (Falco peregrinus) eggs (n = 95) provided an opportunity to examine homolog profiles of nona-, octa-, and hepta-BDEs as possible evidence for biological debromination of BDE-209. We found two congeners in eggs, an unidentified hepta-BDE (BDE-heptaUNK) and BDE-202 (octa-BDE) that are not present in commercial mixtures. In addition, BDE-208 (nona-BDE) was present at much higher (10-fold) proportions in eggs than in commercial mixtures. To examine whether these unusual homolog patterns arose from assimilation of environmentally degraded BDE commercial mixtures, we compared nona-hepta-BDE homolog profiles of peregrine falcon eggs with those of weathered BDEs present in various abiotic matrices (sludge, sediment, and dusts). We found the profiles differed significantly: BDE-207 was the major nona-BDE in eggs, whereas BDE-206 was the major nona-BDE in abiotic matrices. Thus, the evidence for the biological debromination of BDE-209 in peregrine falcons is twofold: Eggs have two congeners (BDE-202 and -heptaUNK) that are not reported for any commercial mixtures nor in the abiotic matrices examined thus far, and eggs have higher-brominated BDE homolog patterns that are different from those found in commercial mixtures or environmental matrices.

Concentrations and time trends of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in aquatic bird eggs from San Francisco Bay, CA 2000-2003.

Concentrations of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in 169 avian eggs. We analyzed randomly collected eggs of two species of piscivorous birds: Caspian tern (Sterna caspia) (n=78) and Forster's tern (Sterna forsteri) (n=76). We also analyzed fail-to-hatch eggs from two species protected under the Federal Endangered Species Act of 1973, that breed in the San Francisco Bay region: the piscivorous California Least tern (Sterna antillarum brownii) (n=11) and the omnivorous California Clapper rail (Rallus longirostris obsoletus) (n=4). San Francisco Bay eggs were collected annually for four years (2000-2003), and additional 20 eggs were collected and analyzed from Gray's Harbor, Washington in 2001. Geometric mean PBDE concentrations did not significantly differ in the three tern species, but concentrations in eggs from the fail to hatch California Clapper rail eggs were significantly lower than those found in the randomly collected tern eggs. Median concentrations of SigmaPBDEs in Caspian tern eggs for 2000-2003 were 2410, 4730, 3720 and 2880 ng/g lipid weight (lw), respectively, in Forster's terns 1820, 4380, 5460 and 3600 ng/g lw, respectively, and in California Least terns for 2001 and 2002 were 5060 and 5170 ng/g lw, respectively. In contrast, median SigmaPBDEs concentration in California Clapper rail eggs for 2001 was 379 ng/g lw. Five PBDEs were the major congeners found and decreased in the order BDE-47, -99, -100, -153, and -154. BDE-32, -28, -71, -66, -85, -183 were less prevalent, minor congeners, as was BDE-209, which was measured in a subset of samples. PBDE concentrations in bird eggs from San Francisco Bay were site related. There was no significant difference in PBDE concentrations in Caspian tern eggs from San Francisco Bay and Gray's Harbor, WA. Average PBDE concentrations in eggs did not significantly increase over the period 2000-2003.

Depuration of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from California first-time mothers (primiparae).

BACKGROUND: Little is known about the rates of loss (depuration) of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) from mothers during lactation. Depuration rates affect infant exposure to chemicals during breast-feeding, and fetal and lactational transfers during subsequent pregnancies. OBJECTIVE: Our objective in this study was to estimate depuration rates of PBDEs and PCBs using serial samples of breast milk. METHOD: Nine first-time mothers (primiparae) each collected samples at 4, 6, 8, 12, 16, 20, and 24 weeks after birth. Nine additional primiparae each collected two samples at varying time intervals (18 to > 85 weeks after birth). Analytical precision was assessed to evaluate the accuracy of measured monthly percentage declines in PBDEs and PCBs. RESULTS: The four major PBDE congeners decreased 2 or 3% +/- 1% per month over the 6-month period. These decreases were consistent over a 50-fold range (21-1,330 ng/g lipid weight) of initial PBDE concentrations in breast milk. The change in PCB-153 ranged from + 0.3% to -0.6% per month, with heterogeneous slopes and greater intraindividual variability. PBDE and PCB concentrations declined 1% per month over longer periods (up to 136 weeks). CONCLUSIONS: Our data indicate that PBDEs and PCBs are not substantially (4-18%) reduced in primiparae after 6 months of breast-feeding. Consequently, the fetal and lactational exposures for a second child may not be markedly lower than those for the first. Participants were volunteers from a larger study population (n = 82), and were typical in their PBDE/PCB levels and in many demographic and lifestyle factors. These similarities suggest that our results may have broader applicability.

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from the Pacific Northwest.

Breast milk samples from 40 first-time mothers from the Pacific Northwest of the US and Canada were analyzed for polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs). Total PBDEs (summation operator PBDEs), calculated by summing values for the 12 PBDEs congeners analyzed, ranged from 6 to 321 ppb (lipid weight) (mean=96 ppb; median=50 ppb). In approximately 40% of the women (15/40), summation operator PBDEs>100 ppb lw in their milk, and four samples had levels >250 ppb lw. PBDE 47 was the dominant congener in most samples, whereas PBDE 153 was predominant in a few (3/40). summation operator PCBs were calculated by summing values for the 82 PCB congeners analyzed, and ranged from 49 to 415 ppb (lipid weight) (mean=147 ppb; median=126 ppb). approximately 30% of the mothers (13/40) have summation operator PBDEs> summation operator PCBs in their milk samples, and approximately 65% (25/40) have BDE 47>PCB 153 in breast milk samples, with BDE 47 averaging 3-fold greater levels than PCB 153. Clearly, the lower brominated PBDEs are surpassing PCBs as a major environmental concern in North America, and are likely affecting significant portions of the populations in these regions. PBDEs have become a major persistent organic pollutant. However, there are no positive correlations between levels of summation operator PBDEs and summation operator PCBs, or between levels of PBDE 47 and PCB 153, suggesting there may be some differences in exposure pathways for PBDEs and PCBs in humans.

The innovative use of a large-scale industry biomedical consortium to research the genetic basis of drug induced serious adverse events.

The International Serious Adverse Event Consortium (SAEC) is a pharmaceutical industry and FDA led international (501 c3 non-profit) consortium, focused on identifying and validating DNA-variants useful in predicting the risk of drug induced, rare serious adverse events (SAEs). As such, it functions with the explicit purpose of enhancing the 'public good'. Its members are (i) organizations engaged principally in the business of discovering, developing and marketing pharmaceutical products, or (ii) a charitable, governmental, or other non-profit organization with an interest in researching the molecular basis of drug response.Drug-induced, rare SAEs present significant health issues for patients; and pose challenges for the safe use of approved drugs and the development of new drugs. Examples of drug-induced, rare SAEs include hepatotoxicity, QT prolongation, rhabdomyolosis, serious skin rashes (e.g. SJS), edema, acute renal failure, acute hypersensitivity, anemias/neutropenias, excessive weigh gain, retinopathy, vasculitis, among others. The rarity of such drug induced SAEs and the absence of effective government surveillance/research networks, makes it extremely difficult for any one company or research entity to accrue enough SAE cases and controls to conduct effective whole genome studies. Central to the notion of the SAEC is industry, government and health care providers can join forces to make use of a variety of sample and data resources in researching the genetic basis of these events.The purpose of the SAEC is threefold:•To carry out research directed toward the discovery of DNA-variants clinically useful in understanding and predicting the risk of drug induced serious adverse events and similar scientific research.•To ensure the widespread availability of the results of such research to the scientific research community and the public at large for no charge through publication and web-based methods; and•To educate the scientific research and medical communities about issues related to severe adverse drug reactions and about issues related to the Consortium's research.The SAEC was launched in late September of 2007 with the scientific, technical and financial support of eight founding industrial research-funding members (i.e. Abbott, GSK, J & J, Novartis, Pfizer, Roche, Sanofi-Aventis and Wyeth). Additional members are being added as the consortium executes its phase one research program and develops its future plans.The Consortium's will focus initially on two research projects. It will attempt to identify DNA variants associated with drug-induced liver-disease and serious skin rashes [e.g. Stevens-Johnson syndrome ('SJS') and toxic epidermal necrolysis ('TEN')]. These two projects, while important in their own right, will also allow the SAEC to generate initial results in a reasonable time frame (owing to the availability of established case-control DNA sample collections) and build its core operations. Simultaneous with the Phase 1 research activities, the SAEC will plan follow on, hypothesis driven studies (post whole genome association studies) for DILI and SJS and explore the feasibility of whole genome research on additional SAEs. Our long term goal is to discover and validate genetic markers predictive of the major drug induced, rare SAEs and make these available at no cost at the same time, unencumbered by any intellectual property constraints, to all researchers and developers of clinical diagnostics.

A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set.

Linkage disequilibrium and inference of ancestral recombination in 538 single-nucleotide polymorphism clusters across the human genome.

The prospect of using linkage disequilibrium (LD) for fine-scale mapping in humans has attracted considerable attention, and, during the validation of a set of single-nucleotide polymorphisms (SNPs) for linkage analysis, a set of data for 4,833 SNPs in 538 clusters was produced that provides a rich picture of local attributes of LD across the genome. LD estimates may be biased depending on the means by which SNPs are first identified, and a particular problem of ascertainment bias arises when SNPs identified in small heterogeneous panels are subsequently typed in larger population samples. Understanding and correcting ascertainment bias is essential for a useful quantitative assessment of the landscape of LD across the human genome. Heterogeneity in the population recombination rate, rho=4Nr, along the genome reflects how variable the density of markers will have to be for optimal coverage. We find that ascertainment-corrected rho varies along the genome by more than two orders of magnitude, implying great differences in the recombinational history of different portions of our genome. The distribution of rho is unimodal, and we show that this is compatible with a wide range of mixtures of hotspots in a background of variable recombination rate. Although rho is significantly correlated across the three population samples, some regions of the genome exhibit population-specific spikes or troughs in rho that are too large to be explained by sampling. This result is consistent with differences in the genealogical depth of local genomic regions, a finding that has direct bearing on the design and utility of LD mapping and on the National Institutes of Health HapMap project.