We have conducted a multistage genomewide association study, using 1,620,742 single-nucleotide polymorphisms to systematically investigate the genetic factors influencing intrinsic skin pigmentation in a population of South Asian descent. Polymorphisms in three genes--SLC24A5, TYR, and SLC45A2--yielded highly significant replicated associations with skin-reflectance measurements, an indirect measure of melanin content in the skin. The associations detected in these three genes, in an additive manner, collectively account for a large fraction of the natural variation of skin pigmentation in a South Asian population. Our study is the first to interrogate polymorphisms across the genome, to find genetic determinants of the natural variation of skin pigmentation within a human population.

A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation. Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodium-calcium exchanger family denoted NCKX5. In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of approximately 43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network. Removal of the NCKX5 protein through small interfering RNA-mediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production. Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity. Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity. We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.

SummaryBackground Seborrhoeic dermatitis is a chronic relapsing inflammatory skin disease with unclear pathophysiological mechanisms. Objectives To establish which lifestyle and physiological determinants are associated with seborrhoeic dermatitis. Methods Seborrhoeic dermatitis was diagnosed by a trained physician during a full-body skin examination within the Rotterdam Study, a prospective population-based cohort study in middle-aged and elderly people. The current design is a comparative cross-sectional study embedded in the Rotterdam Study. Potential factors were identified from the literature and analysed in a multivariable logistic regression, including: age, sex, obesity, skin colour, stress, depression, education level, hypertension, climate, xerosis cutis, alcohol and tobacco use. Results Of the 5498 participants, 788 participants were diagnosed with seborrhoeic dermatitis (14Á3%). We found associations between seborrhoeic dermatitis and male sex [adjusted odds ratio (OR) 2Á09, 95% confidence interval (CI) 1Á77-2Á47], darker skin (adjusted OR 0Á39, 95% CI 0Á22-0Á69), season (summer vs. winter: adjusted OR 0Á63, 95% CI 0Á48-0Á82) and generalized xerosis cutis (adjusted OR 1Á41, 95% CI 1Á11-1Á80). Conclusions Seborrhoeic dermatitis is one of the most common inflammatory dermatoses in middle-aged and elderly individuals, especially during winter. Men, and people with a light and dry skin were most likely to have seborrhoeic dermatitis.

Hair fibres show wide diversity across and within all human populations, suggesting that hair fibre form and colour have been subject to much adaptive pressure over thousands of years. All human hair fibres typically have the same basic structure.However, the three-dimensional shape of the entire fibre varies considerably depending on ethnicity and geography, with examples from very straight hair with no rotational turn about the long axis, to the tightly sprung coils of African races. The creation of the highly complex biomaterials in hair follicle and how these confer mechanical functions on the fibre so formed is a topic that remains relatively unexplained thus far.We review the current understanding on how hair fibres are formed into a nonlinear coiled form and which genetic and biological factors are thought to be responsible for hair shape. We report on a new GWAS comparing low and high curl individuals in South Africa, revealing strong links to polymorphic variation in trichohyalin, a copper transporter protein CUTC and the inner root sheath component keratin 74. This builds onto the growing knowledge base describing the control of curly hair formation. K E Y W O R D Scurl, hair follicle, hair trait genetics, human hair | INTRODUCTIONThe basic structure of hair-a cuticle, cortex and medulla (in some)-does not reveal how these structures are built by the hair follicle or shaped into the curly fibre, suggesting there is a level of "fine control" on the process of hair fibre formation by the hair follicle.The distribution of forms of curly hair is shown in Figure 1 and a closer inspection reveals that curly hair fibres are rarely a true coil but exhibit heterogeneity in the direction of the curl in all but the mildest cases. Curly hairs have an elliptical or "D" shape in cross section.This enables bidirectional bending stiffness, bending most easily in the direction of the flattened axis. The relationship of the long and short diameter to the direction of hair growth also changes (unlike the eyelash where this relationship is maintained [1] ). Therefore, we need to understand how the arrangement of cells results in a fibre that is elliptical with the orientation of the ellipse changing with time during hair growth to form a coil.Hair fibres across all races and geographies show degrees of curl that are readily measurable.[2-4] Both Hrdy and de la Mettrie [2,5] studied various hair types sampled from countries and cultures across the world. The degree of curvature of a fibre in its natural state appears to account for most of the variation (87% [5] ), which is as expected. The presence of a medulla is chiefly correlated with hair diameter. The major curl forms are "twist" (with irregular natural constrictions in the fibre producing a discontinuity in curvature), "crimp" (change in direction of curvature), "wave" (number of oscillations/coils per unit length) and "kink" (sharp twist or bend).Hrdy 1973 [2] showed that kinking and crimp were not always correlated with curvature and irregular curvature ca...