Polymorphisms of the TNF, LTA, and TNFRSF1B genes are associated with onsets of menarche and menopause in US women of European ancestry

Background: The TNF, LTA and TNFRSF1B genes have been implicated in various traits related to menarche and menopause.

Aim: To analyse the TNF, LTA and TNFRSF1B genes for their association with ages at menarche (AM) and natural menopause (ANM).

Subjects and methods: The study sample consisted of 314 unrelated females of European ancestry. Twenty SNPs located in and near the genes were analysed using various statistical methods. In addition, the functional significance of the loci associated with AM and ANM was analysed in silico.

Results: Locus rs2229094 of the LTA gene was associated with AM according to the additive (β = -0.295, p_perm = 0.016) and recessive (β = -0.940, p_perm = 0.016) genetic models. Haplotype GG rs1148459-rs590368 of the TNFRSF1B gene was associated with AM (β = 0.307, p_perm = 0.023). Haplotype GCA rs2844484-rs2229094-rs1799964 was associated with ANM after adjustment for covariates (β = -1.020, p_perm = 0.035). All studied loci were associated with ANM after adjustment for breastfeeding (raw p < 0.05). In addition, eight of the most significant models of interlocus interactions were associated with AM and five with ANM.

Conclusion: The results of the present study suggest that the TNF, LTA and TNFRSF1B genes are associated with AM and ANM.