Differential association of DENND1A genetic variants with polycystic ovary syndrome in Tunisian but not Bahraini Arab women

摘要

Abstract Background and aim Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and results from interaction between modifiable and non-modifiable factors, including genetic predisposition. Previous genome-wide association studies and meta-analysis identified DENND1A as PCOS susceptibility locus in some, but not all populations. We investigated whether the association of DENND1A gene variants with PCOS was similar between Tunisian and Bahraini Arab women. Subjects and methods This was retrospective case-control study. Study subjects comprised 320 women with PCOS, and 446 age-and ethnically-matched control women. Genotyping of DENND1A rs10818854, rs2479106, and rs10986105 variants was done by real-time PCR. Results Minor allele frequency of rs10818854 and rs10986105 DENND1A variants were significantly higher among women with PCOS. Setting homozygous wild-type genotype carrier as reference, rs10818854 and rs10986105 were associated with increased risk of PCOS, which persisted after controlling for key covariates, while reduced PCOS risk was seen with only rs2479106 under the additive model. This assigned PCOS susceptibility and protective nature to these genotypes, respectively. Both rs10818854 and rs10986105 were positively associated with HOMA-IR and AMH in women with PCOS. Haploview analysis revealed limited linkage disequilibrium between the tested DENND1A variants. Extensive diversity in haplotypes assignment was seen, with most haplotypes (99.5%) captured by 5 haplotypes. Taking GAT haplotype as reference, AAG, and GAG haplotypes were positively, while GAT haplotype was negatively associated with PCOS. Conclusion The association of DENND1A rs10818854 and rs10986105 variants with PCOS in Tunisian but not Bahraini women confirms the dependence of this association on the ethnic/racial origin of study subjects. Highlights ? rs10818854 and rs10986105 DENND1A SNP were associated with increased risk of PCOS. ? DENND1A rs2479106 was linked with reduced PCOS risk only under the additive model. ? rs10818854 and rs10986105 were associated with HOMA-IR and serum AMH in PCOS cases. ? Positively (AAG, GAG) and negatively (GAT) associated DENND1A haplotypes identified.