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Keywords:

  • alopecia;
  • curly hair;
  • genetic polymorphisms in hair;
  • hair follicle;
  • hair pigmentation and greying

Synopsis

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

Hair diversity, its style, colour, shape and growth pattern is one of our most defining characteristics. The natural versus temporary style is influenced by what happens to our hair during our lifetime, such as genetic hair loss, sudden hair shedding, greying and pathological hair loss in the various forms of alopecia because of genetics, illness or medication. Despite the size and global value of the hair care market, our knowledge of what controls the innate and within-lifetime characteristics of hair diversity remains poorly understood. In the last decade, drivers of knowledge have moved into the arena of genetics where hair traits are obvious and measurable and genetic polymorphisms are being found that raise valuable questions about the biology of hair growth. The recent discovery that the gene for trichohyalin contributes to hair shape comes as no surprise to the hair biologists who have believed for 100 years that hair shape is linked to the structure and function of the inner root sheath. Further conundrums awaiting elucidation include the polymorphisms in the androgen receptor (AR) described in male pattern alopecia whose location on the X chromosome places this genetic contributor into the female line. The genetics of female hair loss is less clear with polymorphisms in the AR not associated with female pattern hair loss. Lifestyle choices are also implicated in hair diversity. Greying, which also has a strong genetic component, is often suggested to have a lifestyle (stress) influence and hair follicle melanocytes show declining antioxidant protection with age and lowered resistance to stress. It is likely that hair research will undergo a renaissance on the back of the rising information from genetic studies as well as the latest contributions from the field of epigenetics.

Résumé

La diversité des cheveux, leur style, leur couleur, leur forme et leur courbe de croissance sont parmi les caractéristiques qui nous déterminent les plus. Le style naturel comparé au style temporaire est influencé par ce qui arrive à nos cheveux au cours de notre vie, comme la perte génétique de cheveux, perte soudainede cheveux, le vieillissement et la perte pathologiquede cheveux dans les différentes formes d'alopécie due à la génétique, la maladie ou des médicaments. En dépit de la taille et de la valeur globale du marché des soins capillaires, notre connaissance de ce qui contrôle les caractéristiques innées et exogène de la diversité des cheveux reste limitée. Dans la dernière décennie, la recherches'est concentrée dans le domaine de la génétique où les caractéristiques des cheveux sont évidentes et mesurables et les polymorphismes génétiques sont trouvés qui soulèvent des questions intéressantes sur la biologie de la croissance des cheveux. La récente découverte que le gène de la trichohyaline contribue à la forme des cheveux n'est pas une surprise pour les biologistes du cheveux qui ont cru pendant 100 ans que la forme des cheveux est liée à la structure et la fonction de la gaine interne. D'autres énigmes qui attendent élucidation incluent les polymorphismes du récepteur des androgènes (AR) décrits dans le modèle de l'alopécie masculine,puisque l'emplacement de l'AR sur le chromosome X place ce contributeur génétique dans la lignée féminine. La génétique de la perte de cheveux féminine est moins claire puisque les polymorphismes dans l'AR ne sont pas associés à la perte de cheveux chez les femmes. Les choix de vie sont également impliqués dans la diversité des cheveux. La perte de pigmentation (cheveux gris), qui a aussi une forte composante génétique, est souvent suggéréed'être due à une influence du mode de vie (stress) et les mélanocytes du follicule pileux montrent une protection anti-oxydante qui diminue avec l'âge et réduit la résistance au stress. Il est probable que la recherche capillaire va subir une renaissance dans le sillon de l'information croissante venant des études génétiques ainsi que des dernières contributions du domaine de l'épigénétique.


Introduction

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

Hair is often referred to by static descriptors (thick/dry/straight) as if it is always fixed. However, a person's hair obviously can and does change dramatically during a lifetime, driven by more than just the continuous ageing of the intact hair fibre over time [1]. This provides the opportunity and desire to improve consumer awareness of their changing hair care needs over time, something that the skin care category has been very successful in doing because of the greater knowledge of diversity in skin type [2]. It is perhaps also worth thinking that one person's problem is another's solution (think of perming straight hair to curly or colouring brown hair to black or blonde). Thus, it could be said that the natural range of diversity equals the range of need at a global level. So understanding what genes give rise to variable hair shape or cause hair loss and how lifestyle influences gene expression may help point the way to new technologies. Two areas of understanding are required for this; firstly an understanding of how the hair growth cycle influences hair length and density; and secondly how the position and proliferative activity of the various cells within the follicle bulb control hair fibre size, shape and colour.

The role of the hair growth cycle

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

Hairs are of course replaced by the hair cycle and to appreciate hair diversity it is necessary to understand why a hair cycle is important and what features are key in its control. In animals and evolutionarily speaking, the cycle is needed to renew the protective covering of body hair [3]; it also enables the seasonal change in coat quality and colour [4] and the length of the phases of the cycle determines the length of the hair and its replacement rate (think of hair moulting/shedding). In man, the cycle determines the characteristics of hair across different body sites and also helps to explain what happens in hair loss and hirsuitism to change maximum hair fibre length, which has major consequences for an individual who is affected [5]. The cyclic nature of hair growth has a distinct purpose, however, biologists and technologists are very keen to understand the transitions between the phases of the cycle in order to manipulate hair growth. The latest appreciation of the hair follicle as a ‘bi-stable’ organ is very interesting in this regard. Bernard [6, 7] suggests that the stages of the cycle, anagen and telogen exist for stable periods, interspersed by short transitions, catagen and neogen. The stability can be thought of as ‘refractive’ or ‘permissive’, with tissue factors in the adjacent skin helping to retain the status, as suggested in mice by Plikus [8]. Thus movement between phases in the cycle may now be thought of as facilitating a more permissive state in the follicle and adjacent tissues, something suggested by the early study on role of proteoglycans in hair growth control [9, 10].

Hair fibre size and shape

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

The shape and size of the follicle have been shown to determine shape and size of the hair fibre [11], large hair follicles produce ‘terminal’ hairs such as those on the scalp. Curved follicles produce curly hair fibres in all ethnicities [12]. Small follicles produce fine ‘vellus’ hairs that are characteristic of body hair. Vellus hair follicles exist in body sites in children that later grow terminal hair such as beard area in boys and underarm and pubic regions in both genders [5]. Although scalp produces terminal large follicles, the vellus follicle is all that remains after miniaturization caused by genetic hair loss [13]. Thus factors controlling change in follicle size are part of normal physiology throughout a lifetime; controlling how the follicle changes has, however, become of greater significance to the development of new technologies for both increasing and decreasing hair growth.

Hair shape is defined in the follicle and not by the angle of emergence from the skin surface [12]. The hair follicle bulb consists of seven concentric layers of epithelial cells, all with unique differentiation pathways and properties (Fig. 1). It has been long thought that fibre shape was determined by the hardening of the inner root sheath layers inside the follicle [14], however, curvature, as in eyelash (one direction) or African curly hair (2 directions, retro-curvature), requires asymmetry in the processes involving cell proliferation and differentiation within the follicle bulb. Studies have shown that many proteins are expressed in an asymmetric pattern in the follicle bulb of a curly hair [15, 16]. The most notable is HHa8/K38, which is expressed much earlier on the concave side of the follicle. This maturation is what is thought to bestow the curvature ‘force’ on the follicle; however, even this elegant study does not really explain the retro-curvature of the human hair follicle in a person with very curly hair. This can be seen in Fig. 2a, where the bulb shows curvature and in addition, the hair shaft is curved in the skin as indicated by the double bisection in the image shown in Fig. 2b. Developmental aspects of hair follicle formation might shed light on this process, however, such studies present ethical issues whether embryonic or animal studies are proposed. One recent study [17] elegantly demonstrated the role of insulin like growth factor binding protein 5 (IGFBP5), in controlling hair shape both in vivo and in vitro using ex vivo human hair follicles. IFGBP5 is involved in the action of the growth promoter IGF1 that is known to be required for hair growth [18] and the increased expression of IGFBP5 on the convex side of the follicle was shown to impart asymmetric growth. This suggests that asymmetrical growth rate of cells forming the hair cortex influence curl degree as well as asymmetric expression of hair keratins. Growth rate per-se was shown by Saint Olive Baque et al. [19] to correlate well with hair characteristics such as inter-scale distance, diameter and medullation, suggesting that these features are independent of ethnicity and more a feature of the biology of the hair follicle itself.

image

Figure 1. A detailed drawing of the cellular compartments of the hair follicle bulb, with a key to describe the various cell types.

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image

Figure 2. Retro-curved hair follicles in African scalp skin (H&E, ×10 magnification). A) The lower follicle and bulb shows curvature with asymmetric outer root sheath thickness (arrows). The hair follicle above the bulb is also curving away from the plane of section which is further demonstrated in B) where the hair shaft within the follicle above the bulb is curved as indicated by the double bisection.

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Genetics of hair diversity

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

As mentioned earlier, genetic diversity accounts for a vast array of hair diversity within the human population and genetics is now being used for genome wide association and linkage studies in hair traits such as curl and hair loss. It is helpful if hair traits can be linked to specific hair follicle proteins that are polymorphic as it confirms the basis for their involvement in the trait. Just how the changes at the protein level actually lead to the phenotypic change often remains to be determined. However, understanding that they do will provide some clues as to how a change in hair texture might be produced through action in the follicle not through chemistry in the fibre. As perhaps might be predicted by the hair biologist and phylogenist [20] polymorphisms in proteins that are expressed in the follicle inner root sheath (IRS) would appear to be strongly linked to hair shape (Table 1). For example, Cadieu et al. [21] showed, using pure bred dogs that just three genes seem to control the major attributes of the coat (length, curliness and facial ‘furniture’ such as long eyebrows and beard), with mutations in the IRS gene KRT71 which codes for keratin 71, giving rise to wavy/curly coats. The putative change in protein synthesis suggests that interference in intermediate filament formation would result in a reduction in the ability of the IRS to harden. Another gene expressed in the IRS is KRT74 (the gene for IRS keratin 74), which is found in Huxleys layer (Fig. 1). Shimomura et al. studied autosomal dominant woolly hair and showed that a polymorphism in KRT74 was linked to the hair disorder [22]. Similarly, mutations in genes that signal intermediate filament formation and that are expressed in the IRS such as the gene for lipase H and the receptor for lysophosphatitidic acid, the product of action of lipase H on phospholipids, LPAR6/P2RY5, also cause hair growth defects in patients with hypotrichosis simplex [23, 24].

Table 1. Genes that are polymorphic with respect to diversity in hair shape
ProteinPathwayPhenotype changeReference
EDAREDAR signalling via NFkB in hair placode formation and in adult hair growth cycleStraighter, thicker hair in East Asian populations27. Mou C et al. [27] Fujimoto A et al., [29]
FGFR2Increase in FGFR2 mRNA in hair follicles of affected subjectsThicker hair in East Asian populations28. Fujimoto A et al. [28]
TrichohyalinTrichohyalin, Interaction with IRS keratins and hardening of the IRS in Huxleys layerStraighter hair in European populations. SNP increases chances of straighter hair by 6%25. Medland S et al. [25]
KRT71Intermediate filament formation in IRSCurly coat in dogs21. Cadieu et al. [21]
KRT74Intermediate filament formation in IRSWoolly hair with curl/wave22. Shimomura et al. [22]
LIPH/P2Y5Generates/binds bioactive lipids that affect hair growthWoolly hair with curl/wave23, 24. Shimomura et al. [23], [24]

The archetypal protein in the IRS is trichohyalin, so it was without surprise that a polymorphism in this unusual protein was found to associate with straighter hair within European ancestry [25]. Trichohyalin is expressed in the IRS in Huxleys layer and is responsible for organizing the intermediate filaments as they change and harden. It is a highly charged protein but is then modified by peptidyl arginine deiminase to reduce the overall charge and permit association with the IRS keratins, which are further stabilized by the action of transglutaminases. In terms of function, trichohyalin mechanically strengthens the hair follicle inner root sheath to contain and permit shape to be set into the hair fibre [26].

Another family of genes that seems to be providing clues to the diversity of hair shape is those of the ectodysplasin receptor family, EDAR, which is a cell surface receptor of the TNF family and expressed during hair follicle development and again at puberty. Functional significance in relation to control of hair thickness and straightness has been proposed by several genetic studies that suggest positive selection of a non-synonymous SNP in East Asian and Native American populations some 10,000 years ago. Follicle size and fibre thickness increase with the variant allelic form [27, 28] as do shovel-shaped incisor teeth and increased secretions of sebum and meiobian lipids in the eye and saliva [29]. The latter glandular changes may, in fact, have been the driving force behind the penetrance of the new gene in East Asians, with straighter hair being a non-selective consequence. Furthermore analysis between Asian and European populations for polymorphic explanations for hair traits include a single nucleotide polymorphism in fibroblast growth factor receptor 2 FGFR2 [30] with evidence of functional significance in the hair follicle.

Hair pigmentation and greying

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

It is not right to leave the subject of diversity in hair texture without mention of hair colour and greying. It is known that grey/white hairs grow faster, are thicker and more medullated and that unpigmented hairs exhibit some physical differences such as increased diameter and faster water sorbtion/desorbtion [31]. The loss of melanocytes from the area above the dermal papilla may, in some way, lead to a reprogramming of the keratinocytes of this part of the bulb as medullation is much more obvious in unpigmented hairs. However, as it is predicted that lack of hair pigmentation occurs as a result of failure of melanocytes to populate the bulb, this re-programming must occur during the earliest stages of anagen as part of the developmental processes of hair follicle regeneration [32]. Choi et al. [33] showed recently using microarray analyses that in unpigmented hair follicles several hair specific genes were expressed more strongly vs. pigmented hair follicles as well as increase in the ratio of the fibroblast growth factors FGF7:FGF5 which would also promote more hair bulb cell growth activity. Interestingly, the keratin associated protein (KAP) genes were markedly increased in expression in unpigmented hair follicles along with KRT14 and KRT16, which are expressed within the outer root sheath. The question remains whether failure to establish the melanocyte reservoir in the bulb facilitates greater cellular activity or whether greater cellular activity in early anagen lessens the chances of melanocytes establishing themselves in the bulb?

Hair colour can also exhibit marked age-related changes, particularly in those people of European origin. For example, there is often a switch from fair hair of intermediate calibre to more deeply pigmented and courser (terminal) hair during puberty. Furthermore, hair fibre heterochromia (mixed colour) may become more apparent with age, most strikingly seen for scalp and beard [34]. Hair follicular melanocytes appear to be more sensitive than skin or epidermal melanocytes to ageing [35], as shown by the often rapid onset of hair greying/canities compared with the much more gradual change in skin tone. Accumulation of oxidative damage is thought to be an important general determinant of the rate of cell ageing, and it is likely that the antioxidant systems within the hair follicle melanocyte become impaired with age. Recent studies by Kauser et al. [36] showed that in skin samples from older donors (late 50s and 60s), both the hair bulb and melanocytes isolated from the hair bulb express lower levels of catalase activity and protein. This suggests that the hair follicle bulb environment is more oxidizing with age and that the melanocytes are quite sensitive to this. Other studies have also suggested that the follicular–melanin unit of greying hair is associated with increased melanocyte apoptosis and oxidative stress [37]. Moreover, this study also reported that the ‘common’ deletion in mitochondrial DNA (associated with oxidative stress) occurred more prominently in greying compared with normally pigmented hair follicles. Greying hair follicles were also less well equipped to handle an exogenous oxidative stress, which is likely to be the result of impaired antioxidant mechanisms [37].

The onset and progression of hair greying correlates closely with chronological ageing and occurs to varying degrees in all individuals, regardless of gender or race. Greying is recognized as having a strong genetic component as found by Gunn et al. in twin studies [38], however, the genetic basis for greying inheritance is not yet known. Age of onset also appears to be genetically controlled and heritable. Although there appears to be no difference in the age of onset of greying in men or women, there may be some gender differences in the pattern of greying [39], first temporal in men and first frontal in women. It was also interesting to note that the age of onset appears not to be predictive of rate of progression, although the extent increases markedly in the 50s regardless of when it started.

It remains to be seen how this age-related change relates to the genetics of inheritance of greying and there may also be some value in looking closely at the genetic associations with premature greying (occurring in the teens), as well as in premature ageing syndromes like progeria and Werner's syndromes.

The average age of greying onset for Caucasians is the mid-30s; for Asians, late-30s; and for Africans, mid-40s. Similarly, hair is said to grey prematurely if it occurs before the age of 20 in whites, before 25 in Asians and before 30 in Africans. Greying is also a progressive condition in all races, however, dilution of pigment levels in hair with age can also be a concern to consumers with resulting loss of shine. Recent studies by Commo et al. on the chemical composition of melanin pigments in hair from different races and ages suggest that the production of eumelanin declines with age, possibly because of loss of function and or expression of dopachrome tautomerase (TRP2) in the hair follicle melanocytes [36].

Scattered throughout the literature are studies suggesting a link between greying and cardiovascular disease, and in some cases that the degree of premature hair greying may be independent risk marker for coronary artery disease. In the latter case, the authors suggested that this phenotypic change was a predictor of biological, rather than chronological age [40]. The increasing longevity of human life inevitably means we will spend an increasing proportion of our lives sporting (or attempting to hide) this grey sign of lost youth.

Loss of hair density and genetic influences

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

Perhaps the most important factor affecting our hair is loss of density (thinning and baldness). An obvious question for the biologist is why hair loss patterns are different in men and women and why in some cases the patterns are reversed? In combination with the levels of circulating hormones it is the responsiveness of the follicles to them that also differs between males and females. Hair loss occurs in men in well-defined scalp region (usually the frontal scalp and vertex), whereas other areas remain largely unaffected. This has been explained by these regions being either androgen responsive or non-androgen responsive, meaning that the expression of androgen receptors and steroid metabolizing enzymes is different [5]. The responsive areas are characterized by the presence of high density of androgen receptors, elevated 5a-reductase and decreased aromatase activity [41]. However, conclusive evidence for the role of androgens in female pattern hair loss has thus far been difficult, if not impossible to obtain [42]. So, the pattern and response of the hair follicle are variable and both age and gender influences this; the question remains how much of this is genetic?

Male pattern balding is generally considered to be a multi-gene disorder [43]. Baldness is very common with some variability between racial groups as to age of onset, but generally the frequency of balding in the population increases with age. This means studying inheritance of balding as a trait is difficult. This confounds the selection of populations for comparison as does the variability of the clinical pattern. Despite these apparent difficulties, there are now several studies that have detected genetic variability as a risk factor in developing pattern hair loss, especially in males. The benefit of identifying new targets is to develop new treatments, but with genetics it is also possible to develop genetic tests for risk and some of these are already commercially available.

The main hormone involved in male pattern hair loss is testosterone; in fact testosterone must be metabolized to dihydrotestosterone via the enzyme 5-alpha-reductase to be functional [5]. Evidence for the physiological involvement of possible genetic candidates has come from more conventional studies of expression and activity, for example a reduction in AR coactivator ARA70b/ELE1b expression in the dermal papilla and the hair bulbs from balding hairs was found [44] and the co activator Hic-5 ARA55 is more highly expressed in androgen sensitive follicle papilla cells [45]. Family studies, like the one by Birch and Messenger [46] looked at risk of male pattern balding in families and interestingly showed evidence that non-balding in males may have a strong genetic link. Selection on non-bald older men is likely to be easier suggesting that genetic comparison studies in older male subjects might be of value. Some genetic disorders also help explain the importance of intact hormonal metabolism and receptor expression with patterns of hair growth and loss acting as signals for the underlying condition [5]. As mentioned earlier, the androgen basis for female pattern hair loss is less clear and in a recent Twin study [38], Gunn et al. showed that frontal thinning (temples) had a strong genetic component but that general thinning on the crown had no genetic component. Frontal thinning has been described in women as male pattern type, suggesting some women may be pre-disposed to male type pattern hair loss [47].

So what are the likely genetic targets relating to pattern hair loss? It is clear that androgens are involved so the androgen receptor (AR) and the enzyme 5-a-Reductase (5aR) that generates its ligand, dihydrotestosterone were initial genes to be examined for polymorphisms linked to balding. No genetic links were found for the enzyme [48], however, several have been found for the androgen receptor. The androgen receptor gene lies on the X chromosome, which in itself presents a conundrum in relation to the inheritance of male pattern balding, as polymorphic variation in the AR cannot wholly explain the resemblance of fathers and sons with respect to the development of AGA. This suggests that the average phenotypic resemblance should be greater between affected males and their maternal male relations than between affected males and their fathers. Ellis et al. showed that the androgen receptor gene Stu1 restriction fragment length polymorphism was found in almost all (98.1%) young bald men, most older bald men (92.3%), but only in 77% of non-bald men [49]. This finding was highly significant. Hillmer et al. found that 46% of the inheritance susceptibility provided through a ‘23GGN’ haplotype of the AR in early onset AGA in males can be attributed to the maternal line showing that inheritance via the mother's X chromosome is important for, but not sufficient to explain hair loss in men [50]. Most recently, Redler et al. [51] have explored a new set of sex-steroid related protein gene variants for relationship to female pattern hair loss and have shown that none of steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex-steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) show any genetic link to hair loss in females. This again points to the genetic differences between male and female pattern hair loss.

So, although there is a clear physiological role of androgen sensitivity in hair loss, the heritability of this trait suggests that the mutations have, somehow, become fixed in the population. So what is the driving force and is it related to sexual selection? Recent findings [52] suggest that Linkage disequilibrium (LD) , that is, stable inheritance of the haplotype between AR gene and the Ectodysplasin A2 Receptor (EDA2R) on the X chromosome in European populations indicates positive selection of this entire haploytype in these populations. As the entire haplotype is stably inherited, either of these mutations could be driving selection. Given the extent of LD between the two genes, it is possible that the AGA risk alleles rose to high frequency because of a so-called ‘hitchhiking event’ that was driven by rapid selection for the mutant allele [53]. EDA2R is expressed in hair development and again at puberty, and functional significance in relation to control of hair thickness, follicle size and glandular development has already been proposed. However, a direct causative link to baldness is less likely as the 100% penetrance of the EDA2R haplotype in Asian populations does not completely tally with their having lower hair loss prevalence than Europeans.

The AR polymorphisms do not account for all genetic susceptibility to hair loss and the hunt is on for other susceptibility loci. Other recent findings suggest a non-androgen receptor locus on chromosome 20 that is polymorphic, is linked to balding [54]. Although this single nucleotide polymorphism is significantly linked with balding in males, the region is non-coding and clues as to a possible link with hair loss are being investigated [55]. Furthermore genome wide association studies have recently revealed a third gene with a susceptibility link to AGA; histone deacetylase 9 on Chromosome 7 [56]. So far functional evidence for this site is lacking. Thus the genetics of baldness is still very much a study in progress with many questions remaining and more genetic clues will emerge over the coming few years that may translate into solutions or at least good genetic testing strategies [57].

It is noteworthy that several conditions affecting general health have also been linked with hair loss; coronary heart disease [58], benign prostate hyperplasia [59] and insulin resistance [60, 61]. Although studies suggest an association between cardiovascular disease and MPB, the explanation remains unknown. It seems logical that androgens may be involved, given the androgen-dependent nature of AGA and the increased risk of cardiovascular disease in males when compared with females in whom CVD occurs on average 10 years later than males. Greater extent of hair loss in both men and women was found to be associated with insulin resistance, impaired glucose tolerance and central obesity, suggesting a possible lifestyle impact, although this link has not been examined genetically. In a large population study, Hawk, 2000 found that men with bald spots at the top of their heads (vertex baldness) were one and a half times more likely to have prostate cancer than those without bald spots. In contrast, there was no link between a receding hairline (frontal baldness) and cancer [59].

Future perspectives

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

The data emerging from the field of epigenetics is now pointing to the importance of this ‘instruction manual’ control of gene expression and cell behaviour. Epigenetics is a rapidly growing field that investigates the mechanisms that alter gene expression programmes without changing the DNA sequence. Epigenetic mechanisms of gene activation or silencing include DNA methylation, DNA and histone modifications, changing chromatin structure with involvement of chromatin modifiers and post-transcriptional regulation by small non-coding RNAs – called microRNAs (miRNA). Increasing evidence indicates that environmental factors, such as chemical pollutants, diet, temperature changes and other external stresses, are able to modulate the status of epigenetic modifications, and hence influence the gene expression programme [62]. Intriguingly, it was found that food-derived exogenous plant microRNAs (small non-coding RNAs negatively regulating expression of their target genes) are present in the sera and tissues of various animals. Rice-enriched miR-168a was found to be abundantly present in the sera of Chinese subjects. This miRNA can bind to the low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA, inhibits its expression in liver, and helps removing ‘bad’ LDL cholesterol from the bloodstream [63]. This demonstrates that dietary components could have an influence on gene expression programmes in our bodies and perhaps represents another real level of control of phenotype over genotype.

In skin, it was demonstrated that epigenetic mechanisms may be functionally important in driving the phenotypic changes associated with ageing and chronic sun exposure because of the significant changes in the DNA methylation patterns of human epidermis and dermis samples that have been observed comparing sun protected and sun exposed skin [64].

Epigenetic control at the level of DNA methylation and miRNAs play a significant role in hair biology too. One recent study demonstrated the importance of DNA methylation in hair follicle growth as the lack of DNA methyltransferase 1 in mutant mice resulted in the production of shorter and thinner hair fibres and the development of progressive hair loss because of the impaired maintenance of stem cell homoeostasis [65]. Furthermore, loss of chromatin regulators, histone methylases EZH1 or EZH2, severely compromises hair follicle formation and maintenance [66].

Hair follicle regeneration and regression are accompanied by marked changes in the expression levels of over 200 miRNAs [67]. This hair cycle-associated fluctuation in the expression of miRNAs suggests their active involvement in the activation and silencing of the distinct gene expression programmes during the hair cycle. It was identified that stem cells enriched for miR-125b act as a rheostat, providing the control of stem cell proliferation, their fate commitment and their differentiation by targeting the vitamin D receptor and transcriptional repressor Blimp1, a crucial regulator of the development of sebaceous glands [68]. miR-31 was identified as one of the miRNAs whose expression is strictly coupled to hair cycle progression by being exclusively and strongly expressed in the follicular epithelium during anagen. The loss of miR-31 functions in keratinocytes affects expression of several signalling pathways important in hair cycling, such as Fgf10, the Wnt and Bmp inhibitor Sost, and the Bmp antagonist Bambi and transcriptional factor Dlx3. Loss of miR-31 results in hyperplastic changes in the follicular outer root sheath and defects in the hair fibre [67].

Concluding remarks

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

Although genome mapping studies and identification of polymorphic variants associated with hair traits is becoming much easier and is being very successful, understanding the relationship between hair genetics, epigenetics and hair diversity remains a challenge. The new knowledge about genetic variation and potential for epigenetic control needs to be translated into solutions that are beneficial to consumers to be attractive for research funding. Genetic and epigenetic studies are revealing new clues about the character of hair and how the expression of our genes in the cells and compartments of the hair follicle influences this character throughout our lives. Within a lifetime, many things can impact hair growth and appearance, including the influence of a person's lifestyle on how their genes determine the character of their hair. The hair care industry depends on this diversity and seeks an ever-increasing range of ‘problems’ to provide solutions for which science is describing.

Acknowledgements

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References

We would like to thank Dr Claire Higgins for permission to use the diagram in Fig. 1 and Dr Martin Green for permission to use the images in Fig. 2a and 2b. The authors received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

References

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. The role of the hair growth cycle
  5. Hair fibre size and shape
  6. Genetics of hair diversity
  7. Hair pigmentation and greying
  8. Loss of hair density and genetic influences
  9. Future perspectives
  10. Concluding remarks
  11. Acknowledgements
  12. References