BACKGROUND

The ABCC11 gene encodes the multidrug resistance protein 8 (MRP8) (Kruh et al., 2007). This protein is involved in transport of many small molecules in normal physiology, in a variety of cellular and biological contexts. There is strong evidence suggesting that genetic variation at ABCC11 has pleiotropic effects. In particular, a functional non-synonymous SNP (rs17822931), also known as 538G-A or G180R, determines human earwax type (Yoshiura et al., 2006) and axillary osmidrosis (Nakano et al., 2009;Martin et al., 2010) and is associated with apocrine colostrum secretion from the mammary gland (Miura et al., 2007). It has also been related to breast cancer risk, although this is more controversial [(Toyoda and Ishikawa, 2010) and references therein].

rs17822931 genotype AA determines dry earwax type, while the presence of at least one G allele (GA or GG) determines wet earwax type. There are marked differences in rs17822931 allele frequencies across ethnic groups (Yoshiura et al., 2006;Toyoda et al., 2009;Toyoda and Ishikawa, 2010). There is a higher frequency of the A allele in East Asians and therefore higher prevalence of dry earwax type. In contrast, the wet earwax type is more prevalent in European and African populations due to higher frequencies of the G allele.

There is a close histological and functional relationship between ceruminous and apocrine sweat glands. This relationship is believed to explain the connection between earwax and axillary odor (Martin et al., 2010). AA homozygous individuals for rs17822931 display little of the characteristic axillary odorants (Preti and Leyden, 2010;Martin et al., 2010). In contrast, a study of Japanese individuals showed that essentially all individuals with axillary osmidrosis were GG or AG for rs17822931 (Nakano et al., 2009). This indicates that the G allele is necessary and sufficient to cause axillary odor, whereas AA genotype effectively marks non-odorous individuals.

In a recent study (Rodriguez et al., 2013) we have shown for the first time that there is a strongly significant (P=3.7x10^-20) differential usage of deodorant according to rs17822931 genotype. This represents the first evidence of a behavioural effect associated with rs17822931, that is directly relevant to the pharmacogenetics of body odour (Brown, 2013).

Two remarkable findings in relation to the behaviour of axillary deodorant use were that nearly 80% of European genetically non-odorous still use deodorant, whereas one in 20 individuals genetically odorous did not use it. This opens the possibility of a more complex scenario to explain the genetic basis of this human behaviour. To explore this possibility, an analysis of association at the whole genome level would therefore be required. However, a genome-wide analysis of genetic factors associated with deodorant usage has not been performed to date.

In addition, the potential role of ABCC11 genetic variation on other traits has not been studied yet. An interesting field is audition. One of the causes of hearing loss, pain and dizziness is cerumen impactation (McCarter et al., 2007). Ear wax impacts on audition and therefore, the involvement of rs17822931 on ear wax determination makes ABCC11 a good candidate for audition variation among individuals. A more controversial role of earwax is its potential involvement on earache. A common idea among GPs is that earwax does not cause earache and that one of effects of ear infection is the melting of earwax. However, in a pilot study in ALSPAC (approved by the executive, B586) we have found a significant association between earache at age 6-30 months and rs17822931. Muc more detailed analyses are required to understand this novel association and with the great depth of phenotypes involved, this needs an RA for at least a few months, it is not "an afternoon's work.". Similarly, the known role of rs17822931 in apocrine glands opens the possibility that ABCC11 could exert another pleiotropic effect, also acting on breast size. An interplay between breast size, breastfeeding and body odour should also be analysed.

HYPOTHESIS

That the functional SNP rs17822931 in ABCC11 has pleiotropic effects on earache and hearing, additional to its known effects on earwax, deodorant use and colostrum secretion.

AIMS

1.- To perform a phenome scan of all earache and hearing related phenotypes in ALSPAC in relation to rs17822931

2.- To conduct Genome-wide Association Studies on all reported and candidate pleiotropic effects associated with rs17822931, with special reference to deodorant use, earache and hearing.

3.- To access to record linkage data in order to gain more information from GP records to be added to the existing variables already available in ALSPAC

REFERENCES

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McCarter DF, Courtney AU, Pollart SM. Cerumen impaction. Am Fam Physician 2007; 75: 1523-1528.

Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J Invest Dermatol 2010; 130: 529-540.

Miura K, Yoshiura K, Miura S et al. A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland. Hum Genet 2007; 121: 631-633.

Nakano M, Miwa N, Hirano A, Yoshiura K, Niikawa N. A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene. BMC Genet 2009; 10: 42.

Preti G, Leyden JJ. Genetic influences on human body odor: from genes to the axillae. J Invest Dermatol 2010; 130: 344-346.

Rodriguez S, Steer CD, Farrow A, Golding J, Day IN. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol 2013; 133: 1760-1767.

Toyoda Y, Ishikawa T. Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure. Anticancer Agents Med Chem 2010; 10: 617-624.

Toyoda Y, Sakurai A, Mitani Y et al. Earwax, osmidrosis, and breast cancer: why does one SNP (538Ggreater than A) in the human ABC transporter ABCC11 gene determine earwax type?FASEB J 2009; 23: 2001-2013.

Yoshiura K, Kinoshita A, Ishida T et al.A SNP in the ABCC11 gene is the determinant of human earwax type. Nat Genet 2006; 38: 324-330.