Another possible explanation has to do with the discovery cohorts consisting only of men, whereas women made up 88% of the replication samples, with the one male replication set showing a borderline non-significant association ( P = 0.06).
rs1667255 did not reach statistical significance in the replication data set ( P = 0.08, Table 1 ), but did exhibit highly significant heterogeneity in the strength of association across studies ( P = 0.0005, Table 1 ), with similar magnitude of association in the ATBC and PLCO male cohorts, somewhat attenuated beta for two of the replication studies (NHS-CHD and InCH-males), and lack of association in the other replication studies of women.
The two highly significant SNPs from chromosome 10 were in the gene neighborhood of the RBP4 gene, which encodes retinol-binding protein 4 (RBP4), one of the two major carriers of retinol in serum.
The gender difference between the discovery and replication sets may also explain why rs1667255 failed to reach statistical significance in the NHS replication samples, despite having adequate power to detect an association (i.e. 99% power to detect a SNP explaining 1.7% of the variation in serum retinol at P = 0.05).