Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women

Abstract

BACKGROUND In this study, recurrent miscarriages (RMs) are defined as loss of two or more clinically detectable pregnancies before 20 weeks of gestation. HLA has been thought to play a role in RM. However, the results of earlier studies on the role of different human leucocyte antigen (HLA) genes were conflicting and inconclusive. In the present study, we investigate HLA genes (HLA-DRA, HLA-DRB1, HLA-DQA1 and HLA-DQB1) in RM couples with unknown etiology and normal couples. METHODS Blood samples from 143 RM couples and 150 control couples were analyzed, firstly to validate previously reported association studies and secondly to explore whether any novel alleles or haplotypes specific to Indian populations can be observed to be associated with RM. HLA typing was carried out by DNA sequencing. RESULTS Results suggest an association of the DQB1*03:03:02 allele with RM (odd ratio = 2.66; p(c) = 0.02; confidence interval = 1.47-4.84). Haplotypes of the DQA1 and DQB1 risk alleles also showed a significant association with RM, albeit not after Bonferroni correction for multiple comparisons. CONCLUSIONS HLA-DQB1 appears to have a strong involvement in the manifestation of RM in this population from South India. The current genetic analysis of RM and control couples not only highlights the genes exhibiting a strong etiological role but also reflects the protective nature of some HLA genes against RM. Nevertheless, most of these alleles/haplotypes were not those that are implicated in RM in other ethnic backgrounds, and hence require further validation in other populations of India, from different ethnic and/or geographic backgrounds.

Genetic factors influencing recurrent pregnancy loss: lessons learnt from recent studies

“…They found that a significantly increased risk of pregnancy failure was related to the frequency of HLA-DQB5 and the lowest risk quotient in the patient couples was associated with the HLA-DQ 03:02/03:03 allele. Hviid [27]. These alleles were not implicated in RM earlier in other populations, hence completely new alleles that have been reported at these loci tend to be associated with RM in this south Indian population [27].…”

“…Few studies have looked into the role of DQA1 in RM individually, and hence there have not been many reports on the nature of its association. Christiansen et al reported the involvement of DQA1 by the presence of DQA1*01:01 or DQA1*01:05 or DQA1*05:01 [26], whereas in a more recent study by Aruna et al, none of these alleles were found to be associated with RM in this Indian sample [27], albeit two other alleles -DQA1*03:01:01 and DQA1*01:05 -were significantly associated; while DQA1*03:01:01 appeared For personal use only.…”

“…Hviid [27]. These alleles were not implicated in RM earlier in other populations, hence completely new alleles that have been reported at these loci tend to be associated with RM in this south Indian population [27]. Furthermore, the DQB1*03:03:02 allele uniquely confers a very high risk for RM in this Indian population [27], thus highlighting the significance of the DQB1 gene in the etiology of RM.…”

“…www.expert-reviews.com Review to be a risk factor, DQA1*01:05 seems to play a protective role [27]. However, the results were not significant after correction for multiple testing.…”

The Role of CD16+, CD56+, NK (CD16+/CD56+) and B CD20+ Cells in the Outcome of Pregnancy in Women with Recurrent Spontaneous Abortion

“…Some of these hypotheses suggest increased cytotoxicity of decidua NK cells or peripheral blood against fetal antigens (7,31). Some antigens are associated with HLA (32,33) and others suggest a role of autoimmune disorders in RSA (34,35). During pregnancy, the maternal immune system faces a double dilemma: tolerance against growing semi-allogeneic fetus and protection of the mother and the progeny vs. pathogens at the same time.…”