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Background: The pathogenesis of recurrent pregnancy loss (RPL) is multifactorial and not completely elucidated. Dysregulated immunity was implicated with RPL, in which regulatory T cells (Tregs) are key. As Tregs development and function are regulated by forkhead box P3 (FOXP3) transcription factor, and as FOXP3 expression is genetically determined, a role for FOXP3 polymorphisms in RPL pathogenesis was suggested. Aim: To investigate the association of rs2294021, rs2232365, rs3761548, and rs141704699 FOXP3 variants with idiopathic RPL in Lebanese women. Methods: This retrospective case‐control study included 386 RPL cases and 398 age‐matched control women. Logistic odds ratios (OR) were estimated with 95% confidence interval after adjustment; a significance value of P<.05 was set. Results: Significantly lower rs22944021 and rs2232365 minor allele frequency (MAF) was found in patients with idiopathic RPL in comparison with the control group. Furthermore, statistically significantly lower frequency of heterozygous and homozygous rs2294021 and rs2232365 genotypes was seen in controls, while significantly lower rs3761548 heterozygous genotype frequencies were found in the patient group. Obesity, antihypertension treatment, smoking, positive RPL family history, abortion state, and infertility treatment correlated negatively with rs2294021, while rs2232365 negatively correlated with obesity, and rs3761548 negatively correlated with infertility treatment. Marked linkage disequilibrium (LD) was noted among FOXP3 SNPs, with TGCC and CGAC haplotypes being positive, while CAAC, CACC, and TGAC haplotypes being negatively associated with RPL risk. Except for CGAC, the association of these haplotypes with RPL persisted after adjustment. Conclusion: FOXP3 gene variants and haplotypes are associated with altered incidence of RPL, proposing the role of Treg in RPL pathogenesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• A study to investigate the role of ADIPOQ variants in altering the risk of PCOS. • ADIPOQ rs182052, rs822393, rs822396, rs7649121, rs3774261, and rs6773957 were linked to PCOS. • Specific ADIPOQ haplotypes were positively and negatively associated with PCOS. • An ethnic contribution to ADIPOQ association with PCOS was established. What role do ADIPOQ variants play in controlling adiponectin concentrations and altered risk of polycystic ovary syndrome (PCOS)? Study subjects comprised 583 women with PCOS and 713 age-matched controls. Genotyping of rs182052, rs822393, rs822396, rs7649121, rs3774271, rs266729, rs3774261 and rs6773957 ADIPOQ polymorphisms was done by real-time polymerase chain reaction (PCR). Of the 16 ADIPOQ variants, the minor allele frequencies of rs182052, rs822393, rs822396, rs7649121, rs3774261 and rs6773957 were significantly different between PCOS cases and controls. Significant differences in rs266729 (P = 0.02), rs822396 (P = 0.02), rs3774261 (P < 0.001) and rs6773957 (P < 0.001) genotypes were also noted between PCOS cases and controls. Reduced PCOS risk was found with heterozygous rs266729, while increased risk was linked to heterozygous rs822396 and homozygous minor allele rs3774361, and in heterozygous and homozygous minor allele rs6773957 genotype carriers. Haplotype analysis identified two blocks based on linkage disequilibrium pattern; alleles coded as '1' (major) and '2' (minor). Within Block 1 (rs4632532, rs16861194, rs266729, rs182052, rs16861209, rs822393, rs822395, rs822396, rs7649121), haplotypes 111111111 and 212211221 were positively, while haplotypes 212212112 and 212211211 were negatively associated with PCOS. Within Block 2 (rs2241766, rs1501299, rs2241767, rs3774261, rs6773957, rs1063539) haplotypes 111221 and 112221 were positively, while haplotype 111111 was negatively associated with PCOS. This is the first study to confirm the association of rs182052, rs822393, rs7649121 and rs6773957 ADIPOQ variants with altered risk of PCOS. The varied association of ADIPOQ variants with PCOS in relation to earlier reports indicate there is an ethnic contribution to ADIPOQ association with PCOS. [ABSTRACT FROM AUTHOR]

Problem: We investigated the association between idiopathic recurrent pregnancy loss (RPL) and HLA‐DPB1, HLA‐DQB1, and HLA‐DRB1 alleles and DPB1‐DQB1‐DRB1 haplotypes. Method of study: Case‐control retrospective study involved 93 Lebanese women with unexplained RPL, and 113 multiparous Lebanese women with two or more successful pregnancies, and no miscarriages who served as controls. DPB1, DQB1, and DRB1 genotyping was performed by PCR‐SSP. Results: Expected and observed DRB1, DQB1, and DPB1 frequencies were comparable, and HLA genotype frequencies were in Hardy‐Weinberg equilibrium. Significantly higher frequencies of DRB1*04:01:01 and DRB1*08:01:01, and decreased DRB1*07:01:01 frequency were seen in RPL cases than in controls. On the other hand, the distribution of DQB1 alleles was comparable between cases and control groups. Significantly lower frequencies of DPB1*04:01:01 and DPB1*14:01:01 were seen in women with RPL than control subjects. While the frequency DPB1*02:01:01 was markedly higher in RPL cases than in controls, the difference was not significant. DPB1‐DQB1‐DRB1 haplotype analysis identified haplotype DPB1*04:01:01‐DQB1*03:02:01‐DRB1*04:01:01 to be positively associated, while haplotype DPB1*04:01:01‐DQB1*02:01:01‐DRB1*07:01:01 to be negatively associated with RPL. Of these two haplotypes, only DPB1*04:01:01‐DQB1*02:01:01‐DRB1*07:01:01 remained significant after correction for multiple tests (Pc = .0008). Conclusion: Our results confirm an association of select DRB1 and DPB1 alleles with RPL in Lebanese women, and the first to identify DPB1‐DQB1‐DRB1 linked with altered RPL susceptibility, further highlighting the immunological/inflammatory nature of RPL. [ABSTRACT FROM AUTHOR]

Background: This study addresses whether the association of adiponectin gene (ADIPOQ) variants with idiopathic recurrent pregnancy loss (RPL) is influenced by obesity.Methods: Retrospective case-control study performed in outpatient obstetrics/gynecology clinics. Study subjects comprised 308 women with RPL, defined as ≥ 3 consecutive miscarriages of unknown etiology, and 310 control women. ADIPOQ genotyping was done by allele exclusion method on real-time PCR.Results: Of the 14 ADIPOQ variants tested, the minor allele frequency (MAF) of rs4632532, rs17300539, rs266729, rs182052, rs16861209, and rs7649121 were significantly higher, while rs2241767, and rs1063539 MAF were lower in RPL cases, hence assigning RPL-susceptibility and protection to these variants, respectively. Higher frequencies of heterozygous rs17300539 and rs16861209, and homozygous rs4632532, rs266729, and rs182052 genotypes, and reduced frequencies of heterozygous rs1063539 and rs2241767, homozygous rs2241766 genotypes were seen in RPL cases. ADIPOQ rs4632532, and rs2241766 were associated with RPL in obese, while rs1063539 and rs16861209 were associated with RPL in non-obese women; rs182052 and rs7649121 associated with RPL independently of BMI changes. Based on LD pattern, two haplotype blocks were identified. Within Block 1 containing rs4632532, rs16861194, rs17300539, rs266729, rs182052, rs16861209, rs822396, and rs7649121, increased frequency of CAGGACAT and TAACGAAA, and reduced frequency of TAGCGCAA haplotypes were seen in RPL cases when compared to controls, thereby assigning RPL susceptibility and protection, respectively.Conclusion: This is the first study to document contribution of ADIPOQ variants and haplotypes with RPL, and also to underscore the contribution of obesity to genetic association studies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the contribution of the −238G/A and −308G/A tumor necrosis factor (TNF) α, and +252A/G lymphotoxin (LT) α gene polymorphisms to idiopathic recurrent miscarriage (RM). Design: A retrospective case-control study. Setting: Outpatient maternity center. Patient(s): Study subjects comprised 372 RM women and 274 age-matched parous control women. Intervention(s): None. Main Outcome Measure(s): The TNFα and LTα gene variants and idiopathic RM. Result(s): Higher prevalence of TNFα −238A and LTα +252G alleles and LTα +252G/G genotype and lower frequencies of TNFα −308G/A were seen in RM cases. Three-loci haplotype analysis (TNFα −308GA/TNFα −238GA/LTα +252AG) demonstrated significant association between TNFα-LTα gene variants and RM. Both protective [−308A/−238G/+252A], and susceptible [−308G/−238A/+252G] haplotypes were identified. Mutlivariate regression analysis confirmed the association of −308G/−238A/+252G haplotype with exclusively early RM, after controlling for a number of covariates; no specific TNFα and LTα genotypes or haplotypes were linked with either late or combined early and late RM. Conclusion(s): The TNFα −238G/A and LTα +252A/G, but not TNFα −308G/A, polymorphic variants are associated with exclusively early idiopathic RM. [Copyright &y& Elsevier]