FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome

Abstract

Background: Human homologs (FEM1A, FEM1B, FEM1C) of nematode sex determination genes are candidate genes for polycystic ovary syndrome (PCOS). We previously identified a FEM1A mutation (H500Y) in a woman with PCOS; FEM1B has been implicated in insulin secretion.

Methods: Women with and without PCOS (287 cases, 187 controls) were genotyped for H500Y and six FEM1A single nucleotide polymorphisms (SNPs), five FEM1B SNPs and five FEM1C SNPs. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes.

Results: No subject carried the FEM1A H500Y mutation. FEM1A SNPs rs8111933 (P = 0.001) and rs12460989 (P = 0.046) were associated with an increased likelihood of PCOS whereas FEM1A SNP rs1044386 was associated with a reduced probability of PCOS (P = 0.013). FEM1B SNP rs10152450 and a linked SNP were associated with a reduced likelihood of PCOS (P = 0.005), and lower homeostasis model assessment (HOMA) for beta-cell function (HOMA-%B, P = 0.011) and lower HOMA for insulin resistance (HOMA-IR, P = 0.018). FEM1B SNP rs12909277 was associated with lower HOMA-%B (P = 0.008) and lower HOMA-IR (P = 0.037). Haplotype associations were consistent with SNP results, and also revealed association of FEM1B haplotype TGAGG with increased HOMA-%B (P = 0.007) and HOMA-IR (P = 0.024). FEM1C variants were not associated with PCOS.

Conclusions: This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of PCOS. Only FEM1B variants were associated with insulin-related traits in PCOS women, consistent with prior evidence linking this gene to insulin secretion. Replication of these associations and mechanistic studies will be necessary to establish the role of these genes in PCOS.

Figure 1:

Gene structure and linkage disequilibrium plot for FEM1A. The gene structure of FEM1A is shown at top; the gene has one exon and no introns. The coding region is indicated by the black box; untranslated regions by white boxes. The locations of the genotyped SNPs relative to the gene are indicated. H500Y was not present in this cohort. The linkage disequilibrium plot at the bottom displays D’ values for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The solid blocks indicate D’ = 1 for the corresponding pair of variants. The haplotype block 1 is composed of three SNPs, and haplotype block 2 of two SNPs, as indicated.

Figure 2:

Gene structure and linkage disequilibrium plot for FEM1B. The gene structure of FEM1B is shown at top; the gene has two exons and one intron. The coding regions are indicated by the black boxes; untranslated regions by white boxes. The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium plot at the bottom displays D’ values for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The darker solid blocks indicate D’ = 1 for the corresponding pair of variants; lighter solid blocks also indicate D’ = 1, but with a wide confidence interval. The haplotype block comprising all five SNPs is indicated.

Figure 3:

Median levels of insulin resistance and insulin secretion indices by FEM1B rs10152450 genotype. The black bars indicate homeostasis model assessment of insulin resistance (HOMA-IR), the white bars homeostasis model assessment of beta-cell function (HOMA-%B). The HOMA-IR values have been multiplied by 100. The levels are significantly different under both dominant (HOMA-%B, P = 0.011; HOMA-IR, P = 0.018) and additive models (HOMA-%B, P = 0.020; HOMA-IR, P = 0.011).