Contrasting association of Leptin receptor polymorphisms and haplotypes with polycystic ovary syndrome in Bahraini and Tunisian women: a case-control study.

BACKGROUND: The present study examined the contribution of ethnicity to the association of leptin receptor gene (LEPR) gene variants with polycystic ovary syndrome (PCOS) in Tunisian and Bahraini Arabic-speaking women. METHODS: Subjects consisted of 320 women with PCOS, and 446 eumenorrhic women from Tunisia, and 242 women with PCOS and 238 controls from Bahrain. Genotyping of (exonic) rs1137100 and rs1137101 and (intronic) rs2025804 LEPR variants was done by allelic exclusion. RESULTS: The minor allele frequencies (MAFs) of rs1137100 and rs1137101 were significantly different between PCOS cases and control women from Bahrain but not Tunisia, and LEPR rs1137101 was associated with increased PCOS susceptibility only in Bahraini subjects. Furthermore, rs1137100 was associated with decreased PCOS risk among Bahrainis under codominant and recessive models; rs1137100 was negatively associated with PCOS in Tunisians after controlling for testosterone. In addition, rs2025804 was associated with increased PCOS risk among Tunisian but not Bahraini women, after adjusting for key covariates. Negative correlation was seen between rs1137101 and triglycerides in Tunisians, while homeostasis model assessment of insulin resistance (HOMA-IR) and insulin correlated with rs2025804 and rs1137101 among Bahraini subjects, and rs1137101 correlated with estradiol and prolactin. Taking TAG haplotype as common, positive association of TAA and negative association of TGG haplotype with PCOS was seen among Bahraini women; no three-locus PCOS-associated haplotypes were found in Tunisians. CONCLUSIONS: The present study is the first to demonstrate the contribution of ethnicity to the association of LEPR gene variants with PCOS, thereby highlighting the significance of controlling for ethnicity in gene association investigations.

Circulating leptin concentration, LEP gene variants and haplotypes, and polycystic ovary syndrome in Bahraini and Tunisian Arab women.

BACKGROUND AND AIM: Epidemiological studies suggested that ethnic/racial background influences the associations of altered leptin secretion and leptin gene (LEP) polymorphisms with polycystic ovary syndrome (PCOS). We investigated the association between LEP variants and plasma leptin levels with PCOS in Tunisian and Bahraini Arab women. SUBJECTS AND METHODS: Retrospective case-control study, involving 255 PCOS cases and 253 control subjects from Bahrain, and 320 women PCOS cases and 447 controls from Tunisia. LEP genotyping was done by allele exclusion on real-time PCR. RESULTS: Minor allele frequencies of rs10487506, rs7799039, rs2167270, rs12706832, and rs10954173 LEP variants were not significantly different between PCOS cases and control women among Bahraini and Tunisians, even before applying the Bonferroni correction. Similarly, the genotype distribution of the tested LEP variants was comparable between women with PCOS and control women among Bahraini and Tunisian subjects. None of the tested LEP variants was linked with altered leptin serum concentrations. However, five-locus haplotype analysis identified GGGGG and GAGGG haplotypes to be positively, and haplotype AAGGG to be negatively associated with PCOS in Bahraini women, after adjusting for HOMA-IR. No LEP haplotype associated with PCOS was identified in Tunisians. CONCLUSION: This is the first study to document differential contribution of LEP gene variants with PCOS according to ethnic/racial background of study subjects, highlighting the need for controlling for ethnicity in genetic association studies.

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

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.