Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women
HUMAN REPRODUCTION
Authors: Aruna, Meka; Nagaraja, Theeya; Bhaskar, Sadaranga Andal; Tarakeswari, Surapaneni; Reddy, Alla Govardhan; Thangaraj, Kumarasamy; Singh, Lalji; Reddy, B. Mohan
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.
YB-1 DNA-BINDING PROTEIN REPRESSES INTERFERON-GAMMA ACTIVATION OF CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX GENES
JOURNAL OF EXPERIMENTAL MEDICINE
Authors: TING, JPY; PAINTER, A; ZELEZNIKLE, NJ; MACDONALD, G; MOORE, TM; BROWN, A; SCHWARTZ, BD
Abstract
Interferon gamma (IFN-gamma) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a lambda t11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-gamma induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an efficient transient transfection system was developed which resulted in a >70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-gamma induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.