A new Androgenetic Alopecia genetic predisposing factor

Androgenetic alopecia (AGA) is a common disorder which affects mostly men. Despite a clear genetic predisposition, the aetiopathogenesis remains still unknown. An epidemiological survey of 7 genetic isolates in the secluted region of Ogliastra (Sardinia) demonstrates high prevalence of AGA (47.7%). It also clusters very well within families and has usually an early age of onset (70%? 35 yrs). Candidate gene approach has been carried out analyzing several polymorphisms (CAG and GGN repeats and StuI RFLP rs6152) in the X-linked androgen receptor gene which have been previously associated with AGA in different populations, although these results are still controversial. For our study we selected 500 cases (age of onset ?30,IV degree of AGA Norwood scale) and 500 controls (age>40 and no sign of AGA). For statistical analysis we used CC-QLS which can correct association values based on the kinship coefficient. When tested on the whole sample, StuI gave a pvalue of 2x10-19 (OR=4.2) while the repeats gave a weaker association (GGN pval=0.007,CAG =2.2x10-4). StuI showed the strong association in all the villages separately but one (Triei). LD pattern revealed that AR is in strong LD with a gene 900kb centromeric:EDA2R. We chose to test the only validated EDA2R nsSNP rs1385699 in our samples. This SNP reached an even stronger association than StuI (pval=8.9 x 10-31; OR=5.5) and gave a positive result on all populations including Triei. EDA2R, through TRAF3-6, activates JNK which can stimulate c-juns' expression which is important for AR trans-activation. The absence of the predisposing allele in the African HapMap samples may justify the low prevalence of AGA in men of African descent. However, the AR and EDAR2R genes do not explain all the genetic susceptibility to AGA. In order to find other genetic factors involved we selected 25 families coming from the village of Talana for linkage analysis both with 1000 microsatellites and 16k SNP genomewide. This way we found 3 loci on Chr 1, 6 and 7 which contain candidate genes related to the same pathway as both AR and EDA2R.