Summary Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

Aims: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Methods: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children ,13 years of age (median 3.8) with respiratory tuberculosis from INH concentrations determined 2-5 hours after a 10 mg/kg INH dose. The NAT2 genotype was determined; 25 children were classified as homozygous slow (SS), 24 as heterozygous fast (FS), and 15 as homozygous fast (FF) acetylators. Results: The mean (SD) k values of the genotypes differed significantly from one another: SS 0.254 (0.046), FS 0.513 (0.074), FF 0.653 (0.117). Within each genotype a median regression of k on age showed a significant decrease in k with age. The mean (SD) INH concentrations (mg/l) two hours after INH administration were SS 8.599 (1.974), FS 5.131 (1.864), and FF 3.938 (1.754). A within genotype regression of 2-hour INH concentrations on age showed a significant increase with age. A within genotype regression of 3-hour, 4-hour, and 5-hour concentrations on age also showed a significant increase with age in each instance. In ethnically similar adults, mean (SD) 2-hour INH concentrations (mg/l) for each genotype were significantly higher than the children's: SS 10.942 (1.740), FS 8.702 (1.841), and FF 6.031 (1.431). Conclusions: Younger children eliminate INH faster than older children and, as a group, faster than adults, and require a higher mg/kg body weight INH dose to achieve serum concentrations comparable to adults.

There was no difference in the t max values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.Isoniazid (INH), rifampin (RMP), and pyrazinamide (PZA) are routinely used to treat tuberculosis (TB) in children (23, 44). Recommendations for pediatric dosages are based on a small number of pharmacokinetic studies, few of which included children younger than 2 years of age. During early life, children experience significant changes in the relative sizes of their body compartments and their ability to absorb, metabolize, and excrete drugs (5, 17). These changes are greatest within the first 2 years of life (4). Most published studies on first-line anti-TB drugs in children have not analyzed differences between older and younger children or the effect of HIV coinfection. The pharmacokinetics of INH are further complicated by genetic polymorphisms of N-acetyltransferase type 2 (NAT2) in the metabolic pathway of INH, which influences INH concentrations (18,26,46).In the absence of pharmacodynamic data for children and therefore data that demonstrate an association between serum drug concentration and clinical outcome, optimal anti-TB therapy should aim to produce the targeted serum drug concentrations that have been determined in adult pharmacokinetic and pharmacodynamic studies. For INH, the proposed optimal maximum serum drug concentration (C max ) for therapy is 3 to 5 g/ml (15, 27). Target serum RMP concentrations in adults after a standard oral dose of 600 mg are in the range of 8 to 24 g/ml; serum RMP concentrations below 8 g/ml are considered low, and those below 4 g/ml are considered very low (28,29). There is more uncertainty regarding the optimal therapeutic serum PZA concentration. In adults, serum PZA concentrations are targeted at 20 to 60 g/ml (11, 28). However, in a recent study of adults, poor treatment outcome of pulmonary TB was associated with serum PZA concentrations of Ͻ35 g/ml (8).Optimal anti-TB therapy is important in all children but particularly in young children (Ͻ2 years of age) and those HIV infected, where there is a high risk of progression to severe