Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa.

As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations. Here, we examine Africa's large burden of infectious disease, discuss key examples of known genetic variation modulating disease risk, and provide examples of clinically relevant variants critical for establishing dosing guidelines. We propose that a more systematic characterization of the genetic diversity of African ancestry populations is required if the current benefits of precision medicine are to be extended to these populations.

Pharmacogenomics, ancestry and clinical decision making for global populations.

Pharmacogenomically relevant markers of drug response and adverse drug reactions are known to vary in frequency across populations. We examined minor allele frequencies (MAFs), genetic diversity (FST) and population structure of 1156 genetic variants (including 42 clinically actionable variants) in 212 genes involved in drug absorption, distribution, metabolism and excretion (ADME) in 19 populations (n=1478). There was wide population differentiation in these ADME variants, reflected in the range of mean MAF (ΔMAF) and FST. The largest mean ΔMAF was observed in African ancestry populations (0.10) and the smallest mean ΔMAF in East Asian ancestry populations (0.04). MAFs ranged widely, for example, from 0.93 for single-nucleotide polymorphism (SNP) rs9923231, which influences warfarin dosing to 0.01 for SNP rs3918290 associated with capecitabine metabolism. ADME genetic variants show marked variation between and within continental groupings of populations. Enlarging the scope of pharmacogenomics research to include multiple global populations can improve the evidence base for clinical translation to benefit all peoples.

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. METHODS: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs. RESULTS: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci. CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

Replication of genome-wide association studies (GWAS) loci for fasting plasma glucose in African-Americans.

AIMS/HYPOTHESIS: Chronically elevated blood glucose (hyperglycaemia) is the primary indicator of type 2 diabetes, which has a prevalence that varies considerably by ethnicity in the USA, with African-Americans disproportionately affected. Genome-wide association studies (GWASs) have significantly enhanced our understanding of the genetic basis of diabetes and related traits, including fasting plasma glucose (FPG). However, the majority of GWASs have been conducted in populations of European ancestry. Thus, it is important to conduct replication analyses in populations with non-European ancestry to identify shared loci associated with FPG across populations. METHODS: We used data collected from non-diabetic unrelated African-American individuals (n = 927) who participated in the Howard University Family Study to attempt to replicate previously published GWASs of FPG. Of the 29 single nucleotide polymorphisms (SNPs) previously reported, we directly tested 20 in this study. In addition to the direct test, we queried a 500 kb window centred on all 29 reported SNPs for local replication of additional markers in linkage disequilibrium (LD). RESULTS: Using direct SNP and LD-based comparisons, we replicated multiple SNPs previously associated with FPG and strongly associated with type 2 diabetes in populations with European ancestry. The replicated SNPs included those in or near TCF7L2, SLC30A8, G6PC2, MTNR1B, DGKB-TMEM195 and GCKR. We also replicated additional variants in LD with the reported SNPs in ZMAT4 and adjacent to IRS1. CONCLUSIONS/INTERPRETATION: We identified multiple GWAS variants for FPG in our cohort of African-Americans. Using an LD-based strategy we also identified SNPs not previously reported, demonstrating the utility of using diverse populations for replication analysis.

Investigating population stratification and admixture using eigenanalysis of dense genotypes.

Principal components analysis of genetic data is used to avoid inflation in type I error rates in association testing due to population stratification by covariate adjustment using the top eigenvectors and to estimate cluster or group membership independent of self-reported or ethnic identities. Eigendecomposition transforms correlated variables into an equal number of uncorrelated variables. Numerous stopping rules have been developed to identify which principal components should be retained. Recent developments in random matrix theory have led to a formal hypothesis test of the top eigenvalue, providing another way to achieve dimension reduction. In this study, I compare Velicer's minimum average partial test to a test on the basis of Tracy-Widom distribution as implemented in EIGENSOFT, the most widely used implementation of principal components analysis in genome-wide association analysis. By computer simulation of vicariance on the basis of coalescent theory, EIGENSOFT systematically overestimates the number of significant principal components. Furthermore, this overestimation is larger for samples of admixed individuals than for samples of unadmixed individuals. Overestimating the number of significant principal components can potentially lead to a loss of power in association testing by adjusting for unnecessary covariates and may lead to incorrect inferences about group differentiation. Velicer's minimum average partial test is shown to have both smaller bias and smaller variance, often with a mean squared error of 0, in estimating the number of principal components to retain. Velicer's minimum average partial test is implemented in R code and is suitable for genome-wide genotype data with or without population labels.

Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19.

We identified a family in Mali with two sisters affected by spastic paraplegia. In addition to spasticity and weakness of the lower limbs, the patients had marked atrophy of the distal upper extremities. Homozygosity mapping using single nucleotide polymorphism arrays showed that the sisters shared a region of extended homozygosity at chromosome 19p13.11-q12 that was not shared by controls. These findings indicate a clinically and genetically distinct form of hereditary spastic paraplegia with amyotrophy, designated SPG43.

Genetic influences on growth and body composition in mice: multilocus interactions.

BACKGROUND: The genetic architecture of body weight and body composition is complex because these traits are normally influenced by multiple genes and their interactions, even after controlling for the environment. Bayesian methodology provides an efficient way of estimating these interactions. SUBJECTS AND MEASUREMENTS: We used Bayesian model selection techniques to simultaneously estimate the main effects, epistasis and gene-sex interactions on age-related body weight (at 3, 6 and 10 weeks, denoted as WT3wk, WT6wk and WT10wk) and body composition (organ weights and fat-related traits) in an F(2) sample obtained from a cross between high-growth (M16i) mice and low-growth (L6) mice. RESULTS: We observed epistatic and main-effect quantitative trait loci (QTL) that controlled both body weight and body composition. Epistatic effects were generally more significant for WT6wk than WT10wk. Chromosomes 5 and 13 interacted strongly to control body weight at 3 weeks. A pleiotropic QTL on chromosome 2 was associated with body weight and some body composition phenotypes. Testis weight was regulated by a QTL on chromosome 13 with a significantly large main effect (2log(e)BF approximately 15). CONCLUSION: By analyzing epistatic interactions, we detected QTL not found in a previous analysis of this mouse population. Hence, the detection of gene-gene interactions may provide new information about the genetic architecture of complex obesity-related traits and may lead to the detection of additional obesity genes.

Advances in Bayesian multiple quantitative trait loci mapping in experimental crosses.

Many complex human diseases and traits of biological and/or economic importance are determined by interacting networks of multiple quantitative trait loci (QTL) and environmental factors. Mapping QTL is critical for understanding the genetic basis of complex traits, and for ultimate identification of genes responsible. A variety of sophisticated statistical methods for QTL mapping have been developed. Among these developments, the evolution of Bayesian approaches for multiple QTL mapping over the past decade has been remarkable. Bayesian methods can jointly infer the number of QTL, their genomic positions and their genetic effects. Here, we review recently developed and still developing Bayesian methods and associated computer software for mapping multiple QTL in experimental crosses. We compare and contrast these methods to clearly describe the relationships among different Bayesian methods. We conclude this review by highlighting some areas of future research.

Effect of organic solvents on in vitro human skin water barrier function.

Skin barrier disruption caused by organic solvents to human cadaver dermatomed skin was evaluated using an in vitro model system. Resultant changes in transepidermal water loss (TEWL), as measured with an evaporimeter, were recorded after topical application of either acetone, chloroform:methanol 2:1, hexane, hexane:methanol 2:3, or the control, water, for exposure times of 1, 3, 6, and 12 min. The resultant lipid/solvent mixture was removed and analyzed for its lipid content. The ability of the different solvents to induce changes in the skin's barrier function was assessed by comparing pre- to post-solvent exposure TEWL (delta TEWL). When compared to the controls, water and unexposed skin, chloroform:methanol 2:1 caused the greatest significant increase in TEWL, followed by hexane:methanol 2:3. Acetone and hexane showed no difference in TEWL from the controls. Besides solvent, exposure time was a significant independent variable for predicting delta TEWL, and the interaction of the two (exposure time and solvent type together) was the strongest predictor. Lipid analysis of the extracts revealed that all the solvents removed comparable quantities of the surface lipids (triglycerides, wax esters, squalene, cholesterol esters). Stratum lipids--ceramides, free fatty acids, and cholesterol--extracted by chloroform:methanol 2:1 and hexane:methanol 2:3 were comparable and significantly greater than those extracted by acetone and hexane. These two solvents failed, however, to induce comparable changes in TEWL, as chloroform:methanol 2:1 induced a significantly greater delta TEWL than hexane:methanol 2:3. Additionally, no individual lipid class extracted by either chloroform:methanol 2:1 or hexane:methanol 2:3 proved to be a significant or accurate variable for predicting delta TEWL. This suggests that the mechanism by which topical chloroform:methanol 2:1 and hexane:methanol 2:3 exposure induce a delta TEWL involves more than pure lipid extraction.

Cycling of organic and inorganic sulphur in a chestnut oak forest.

Sulfur (S) cycling in a chestnut oak forest on Walker Branch Watershed, Tennessee, was dominated by geochemical processes involving sulfate. Even though available SO 42- was present far in excess of forest nutritional requirements, the ecosystem as a whole accumulated ∼60% of incoming SO4-S. Most (90%) of this accumulation occurred by SO 42- adsorption in sesquioxide-rich subsurface soils, with a relatively minor amount accumulating and cycling as SO 42- within vegetative components. Organic sulfates are thought to constitute a large proportion of total S in surface soils, also, and to provide a pool of readily mineralized available S within the ecosystem.

Photography for the early diagnosis of malignant melanoma in patients with atypical moles.

Several articles have been published that carefully describe techniques for obtaining reliable photographic series of patients with the atypical mole syndrome. Four common methods of total body photography are described. Follow-up studies of the effectiveness of photodocumentation for patients with the atypical mole syndrome are reviewed.

Photographic utilization in dermatology clinics in the United States: a survey of university-based dermatology residency programs.

BACKGROUND: Photography has recently been introduced as an adjunct to the clinical management of patients with the dysplastic nevus syndrome (DNS). OBJECTIVE: Our purpose was to evaluate the methods used and the extent of clinical photography in dermatology residency programs in the United States. METHODS: Nonmilitary accredited dermatology residency programs in the United States were surveyed (73% response rate) regarding utilization and technical aspects of clinical photography. RESULTS: Forty-one percent of respondents used photography for the clinical management of 90% or more of patients with DNS. Twenty-four percent of respondents used photography for the clinical management of all patients with DNS. Eighty-one percent of respondents used slides, and 62% utilized total body photographs. The median number of photographs taken for a patient with DNS was 20. CONCLUSION: Dermatologic photography has been widely adopted for the clinical management of patients with DNS. Failure of the health insurance industry to recognize the value of this procedure may result in its underutilization.

Regional variation of nonimmunologic contact urticaria. Functional map of the human face.

BACKGROUND AND DESIGN: Benzoic acid (BA) was used to induce nonimmunologic contact irritation in 10 younger (23-47 years old) and 5 older (72-90 years old) healthy volunteers. BA 2.5% in petrolatum was applied to 8 locations on the face, neck and volar forearm. Changes in the skin blood flow were monitored using a laser Doppler flowmeter. Also measured at each location were baseline measurements of skin blood flow, transepidermal water loss, stratum corneum hydration, skin surface temperature and skin surface pH. RESULTS: The neck area exhibited the greatest reaction in both age groups while the forearm exhibited the least. At each site tested, the younger group consistently demonstrated greater reactivity to BA. A significant correlation was noted between stratum corneum hydration and irritation. CONCLUSIONS: This information provides a basis to further study the frequent poorly understood intolerance of the face to topical formulation.

The mechanism of retroviral recombination: the role of sequences proximal to the point of strand transfer.

Transfer of nascent DNA from an RNA template (donor) to the homologous region of a second RNA template (acceptor) was studied. The templates were designed to assess the roles of the sequences proximal (3' relative to the transferring DNA) to the point of transfer. The donor template was primed with a specific 18 nucleotide DNA such that extension by reverse transcriptase to the end of the template produced a 79 nucleotide product. Homologous strand transfer and subsequent extension on the acceptors produced longer products allowing distinction between strand transfer and donor-directed synthesis. The donor and one particular acceptor shared a region of homology which included 8 tandem 5'-CAGU-3' repeats followed at the 3' end by a 17 nucleotide region of random homologous sequence. Derivatives of the acceptor either completely lacked the 17 nucleotide region or were progressively truncated resulting in a shorter region. With the acceptor lacking this region, prominent transfer products differing in length by 4 nucleotides were observed. Presumably this occurs because the transferring DNA can base-pair with several copies of the repeat elements of the acceptor. Addition of 5 or more of the 17 random nucleotides to the 3' end of the acceptor resulted in transfer products of essentially one length, and consistent with the transferring DNA correctly base-pairing with the 3' nucleotides. Results suggest that the transferring DNA interacts with the acceptor over several bases to form the most energetically stable hybrid duplex prior to extension on the acceptor. Hybrids formed from shorter interactions between the 3' end of the DNA and acceptor are either realinged prior to extension or precluded due to the mechanism of transfer.

Optical illusions in clinical dermatology: the Mach band phenomenon and afterimages.

A survey of dermatologists was conducted to determine whether the perceptions of afterimages and Mach bands impacted on clinical dermatology practice. 26.5% (13/49) of respondents indicated that they perceived one or both of these optical illusions. No false-positive potassium hydroxide interpretations of skin scrapings for hyphae were reported due to perceived afterimages, and no skin biopsies were reportedly performed as a result of Mach bands.

Mohs micrographic surgery.

Mohs micrographic surgery (MMS) is a specialized type of minimal marginal surgery that offers cure rates superior to other options in the treatment of contiguous skin cancers in selected settings. Developed by Dr. Frederic E. Mohs, the technique originally required in situ tissue fixation before excision. Most Mohs micrographic surgeons now use the fresh tissue technique exclusively. Horizontal frozen histologic sections of the excised tumor permit more complete microscopic examination of the surgical margin than traditional methods. Residual tumor is graphically mapped and malignant extensions are pursued with staged excisions until the tumor is removed. Maximum sparing of tumor-free adjacent tissue is achieved with histologic mapping of the tumor boundaries, thus optimizing subsequent wound reconstruction. The history, techniques, indications, cure rates, and current controversies of MMS are reviewed.

Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses.

The rate of progression to AIDS in human immunodeficiency virus type 1 (HIV-1)-infected individuals is determined by a complex series of interactions between the host and virus. Here we evaluate virologic properties and host responses in two men near-simultaneously infected with HIV-1 from the same sexual partner--one individual progressed to AIDS in less than 2 years, and the other remains asymptomatic 3 years postinfection. Distinct neutralizing antibody and cellular immune responses were evident, with the slower progressor exhibiting generally stronger and broader responses, except for cytotoxic T-lymphocyte responses early in infection. Virtually identical, homogeneous virus populations were found in both patients in the first sample obtained; however, a second unrelated HIV-1 virus population was also found in the fast progressor. Whether the second population emanated from an additional source of infection or the two were transmitted from the original source could not be determined. The virus population in the slower progressor turned over and diversified rapidly, whereas both virus populations in the rapid progressor evolved at a much slower rate. In addition, the character of mutational changes underlying these diversities appeared to be distinct, with a bias for diversifying selection developing in the slower progressor and a reciprocal bias towards purifying selection maintained in both populations in the fast progressor. Thus, the rapid evolution that is a hallmark of HIV replication may be a reflection of strong host resistance against emerging virus variants and a longer period of asymptomatic infection. Furthermore, rapid progression was not linked to a collapse of any appreciable immune response following attainment of some threshold of antigenic diversity but rather to a failure to drive this diversification and a condition of relatively unimpeded expansion of variants with optimized replicative capacity within the host.