Publications

Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago.

BACKGROUND

Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.

OBJECTIVES

We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.

METHODS

We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis.

RESULTS

Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos.

CONCLUSIONS

This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

The importance of drug transporters as one of the determinants of pharmacokinetics has become increasingly evident. While much research has been conducted focusing the role of drug transporters in the liver and kidney less is known about the importance of uptake and efflux transporters identified in the intestine. Over the past years the effects of intestinal transporters have been studied using in vivo models, in situ organ perfusions, in vitro tissue preparations and cell lines. This review aims to describe up to date findings regarding the importance of intestinal transporters on drug absorption and bioavailability, highlighting areas in need of further research. Wu and Benet proposed a Biopharmaceutics Drug Disposition Classification System (BDDCS) that allows the prediction of transporter effects on the drug disposition of orally administered drugs. This review also discusses BDDCS predictions with respect to the role of intestinal transporters and intestinal transporter-metabolizing enzyme interplay on oral drug pharmacokinetics.

OBJECTIVES

To determine patterns of co-occurring diseases in older adults and the extent to which these patterns vary between the young-old and the old-old.

DESIGN

Observational study.

SETTING

Department of Veterans Affairs.

PARTICIPANTS

Veterans aged 65 years and older (1.9 million male, mean age 76 ± 7; 39,000 female, mean age 77 ± 8) with two or more visits to Department of Veterans Affairs (VA) or Medicare settings in 2007 and 2008.

MEASUREMENTS

The presence of 23 common conditions was assessed using hospital discharge diagnoses and outpatient encounter diagnoses from the VA and Medicare.

RESULTS

The mean number of chronic conditions (out of 23 possible) was 5.5 ± 2.6 for men and 5.1 ± 2.6 for women. The prevalence of most conditions increased with advancing age, although diabetes mellitus and hyperlipidemia were 11% to 13% less prevalent in men and women aged 85 and older than in those aged 65 to 74 (P < .001 for each). In men, the most common three-way combination of conditions was hypertension, hyperlipidemia, and coronary heart disease, which together were present in 37% of men. For women, the most common combination was hypertension, hyperlipidemia, and arthritis, which co-occurred in 25% of women. Reflecting their high population prevalence, hypertension and hyperlipidemia were both present in 9 of the 15 most common three-way disease combinations in men and in 11 of the 15 most common combinations in women. The prevalence of many disease combinations varied substantially between young-old and old-old adults.

CONCLUSIONS

Specific combinations of diseases are highly prevalent in older adults and inform the development of guidelines that account for the simultaneous presence of multiple chronic conditions.

Gastrointestinal histoplasmosis (GIH) is common in patients with disseminated disease but only rarely comes to clinical attention due to the lack of specific signs and symptoms. We report the unusual case of a 33-year-old Caucasian male with advanced AIDS who presented with upper GI bleeding from diffuse erosions throughout the duodenum. Biopsy of the lesions revealed small bowel mucosa with granulomatous inflammation and macrophages with small intracellular yeasts consistent with disseminated histoplasmosis. The patient demonstrated significant clinical improvement following a two-week course of liposomal amphotericin B. To our knowledge, this is the first case report of duodenal histoplasmosis leading to clinically significant bleeding, manifesting with worsening anemia and melanotic stools. Given our findings, we maintain that GIH should be considered on the differential diagnosis for GI bleeding in AIDS patients at risk, specifically those with advanced immunosuppression (i.e., CD4(+) cell counts <100 cells/mm(3)) who reside in endemic areas (Ohio or Mississippi river valleys) and/or have a prior history of histoplasmosis. For diagnostic evaluation, we recommend checking a urine Histoplasma quantitative antigen EIA as well as upper and/or lower endoscopy with biopsy. We recommend treatment with a two-week course of liposomal amphotericin B followed by indefinite itraconazole.

PURPOSE

Despite the extensive use of complementary and alternative medicine (CAM) among cancer patients, patient-physician communication regarding CAM therapies remains limited. This study quantified the extent of patient-physician communication about CAM and identified factors associated with its discussion in radiation therapy (RT) settings.

METHODS AND MATERIALS

We conducted a cross-sectional survey of 305 RT patients at an urban academic cancer center. Patients with different cancer types were recruited in their last week of RT. Participants self-reported their demographic characteristics, health status, CAM use, patient-physician communication regarding CAM, and rationale for/against discussing CAM therapies with physicians. Multivariate logistic regression was used to identify relationships between demographic/clinical variables and patients' discussion of CAM with radiation oncologists.

RESULTS

Among the 305 participants, 133 (43.6%) reported using CAM, and only 37 (12.1%) reported discussing CAM therapies with their radiation oncologists. In multivariate analyses, female patients (adjusted odds ratio [AOR] 0.45, 95% confidence interval [CI] 0.21-0.98) and patients with full-time employment (AOR 0.32, 95% CI 0.12-0.81) were less likely to discuss CAM with their radiation oncologists. CAM users (AOR 4.28, 95% CI 1.93-9.53) were more likely to discuss CAM with their radiation oncologists than were non-CAM users.

CONCLUSIONS

Despite the common use of CAM among oncology patients, discussions regarding these treatments occur rarely in the RT setting, particularly among female and full-time employed patients. Clinicians and patients should incorporate discussions of CAM to guide its appropriate use and to maximize possible benefit while minimizing potential harm.