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To explore the association of leukemia inhibitory factor receptor (LIFR) gene variant rs3099124, ovarian steroids, and leukemia inhibitory factor with unexplained infertility in Pakistani females. A case–control investigation in which eighty-one (81) females with unexplained infertility and one hundred and sixty-two (162) fertile counterparts (age and body mass index compared) were recruited between October 2016 and 2018. Ten milliliters of venous blood was collected from all participants. “Genomic DNA” was taken out from lymphocytes in peripheral blood samples. “Tetra Amplification Refractory Mutation System Polymerase Chain Reaction (T-ARMS-PCR)” was constructed through software “Primer-I”. Amplification was carried out by “T-ARMS-PCR” followed by subsequent sequencing for confirmation and extensive consonance. Estradiol, Progesterone and Leukemia Inhibitory Factor (LIF) were measured in serum by ELISA. Statistically significant difference was noticed in genotype frequency in “LIFR-gene variant; rs3099124” (χ 2  = 28.222,  P  value &lt; 0.01) between research participants. Although, rs “3099124” “AA” (OR = 0.000; 95%CI = 0–0) and “GA” genotypes (OR = 0.525; 95%CI = 0.226–1.22) showed non-significant safety/protection against unexplained infertility yet minor/risk allele “A” frequency was greater in women with unexplained infertility suggesting a possible explanation of implantation failure. LIF concentration varied between fertile and infertile groups (χ 2  = 9.857,  P  &lt; 0.05) revealing significant threat of unexplained infertility in women with decreased LIF concentration (OR = 2.316, 95%CI = 1.214–4.416). Progesterone was significantly related to unexplained infertility in both study groups (χ 2  = 20.347,  P  &lt; 0.05). High progesterone reduced the possibility of unexplained infertility (OR = 0.306; 95% CI = 0.166–0.567). LIFR gene variation (rs3099124) and reduced LIF secretion may cause implantation failure in women with unexplained infertility.

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Interplay of “leukemia inhibitory factor receptor gene” (rs3099124) polymorphism, leukemia inhibitory factor and ovarian steroids with unexplained infertility