Association of HLA-G alleles and 3′ UTR 14 bp haplotypes with recurrent miscarriage in Brazilian couples

Human leukocyte antigen (HLA)–G expression is restricted, expressed on trophoblast, with a major role in fetus acceptance. In addition to the 46 HLA-G alleles, the presence or absence of a 14 bp polymorphism located in the 3′ UTR contributes to gene polymorphism that may influence both HLA-G mRNA stability and HLA-G isoform's splicing and consequently could play an immunomodulatory function in pregnancy. To elucidate the role of HLA-G polymorphism in pregnancy, HLA-G allele frequencies and the 14 bp polymorphisms were analyzed and compared in 60 couples with recurrent miscarriage (RM) and 68 fertile control couples. Two haplotypes showed a significant elevated frequency in patients (HLA-G*01:01:08/+14, pc < 0.0001 and HLA-G*01:04:01/−14, pc < 0.0001). The haplotype HLA-G*01:01:A/+14 exhibited a significant protective effect against RM in women (pc = 0.0238). Remarkably, significant differences in linkage disequilibrium were observed between patient and control groups. Two alleles showed a positive association with the +14 bp segment in RM patients and a strong negative association with fertile controls (HLA-G*01:01:08 = patients D′ = 0.295–0.371; controls D′ = −0.715 to −1.000; HLAG* 01:05N = patients D′ = 0.728−1.000; controls D′ = −1.000). HLA-G*01:04:01 showed a negative association with the 14 bp segment in patients and a positive association in controls (patients D′ = −0.249 to − 0.674; controlss D′ = 0.688–1.000). Our results suggest that haplotypic combinations of HLA-G alleles and the 14 bp segment may be associated with RM.