The HLA-G gene is primarily expressed in placental cells that invade the maternal decidua during pregnancy. This gene encodes multiple isoforms that fulfill a variety of functions at the maternal-fetal interface throughout gestation. Recently, a null allele for the most abundant HLA-G isoform was associated with recurrent miscarriage in two independent studies, suggesting that reduced levels of the HLA-G1 protein may compromise successful pregnancy. We initiated the present study to determine whether other polymorphisms that could affect expression levels of HLA-G were associated with fetal loss in women participating in a 15-year prospective study of pregnancy outcome. We genotyped these subjects for 18 single-nucleotide polymorphisms in the 1,300 bp upstream of exon 1, 13 of which were identified as part of this study, as well as for an insertion/deletion (in/del) polymorphism in the 3' untranslated region. The 18 SNPs defined eight unique haplotypes. One polymorphism, -725C/G, was associated with fetal loss, with an increased risk for miscarriage in couples in which both partners carried the -725G allele, compared with couples not carrying this allele (odds ratio 2.76, 95% confidence interval 1.08-7.09; P=.035). Further, the G at nucleotide -725 creates a CpG dinucleotide, and we demonstrate that this CpG site is methylated on -725G alleles. Overall, this study identified extraordinary levels of variation in the 5'-upstream regulatory region of HLA-G and provides evidence for an association between a promoter-region SNP and fetal loss rates, further attesting to the novel features and critical role of this gene in pregnancy.
Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.
The semiallogenic fetus is tolerated by the maternal immune system through control of innate and adaptive immune responses. Trophoblast cells secrete nanometer scale membranous particles called exosomes, which have been implicated in modulation of the local and systemic maternal immune system. Here we investigate the possibility that exosomes secreted from the first trimester and term placenta carry HLA-G and B7 family immunomodulators. Confocal microscopy of placental sections revealed intracellular colocalization of B7-H1 with CD63, suggesting that B7-H1 associates with subcellular vesicles that give rise to exosomes. First trimester and term placental explants were then cultured for 24 hours. B7H-1 (CD274), B7-H3 (CD276) and HLA-G5 were abundant in pelleted supernatants of these cultures that contained microparticles and exosomes; the latter, however, was observed only in first trimester pellets and was nearly undetectable in term explant-derived pellets. Further purification of exosomes by sucrose density fractionation confirmed the association of these proteins specifically with exosomes. Finally, culture of purified trophoblast cells in the presence or absence of EGF suggested that despite the absence of HLA-G5 association with term explant-derived exosomes, it is present in exosomes secreted from mononuclear cytotrophoblast cells. Further, differentiation of cytotrophoblast cells reduced the presence of HLA-G5 in secreted exosomes. Together, the results suggest that the immunomodulatory proteins HLA-G5, B7-H1 and B7-H3, are secreted from early and term placenta, and have important implications in the mechanisms by which trophoblast immunomodulators modify the maternal immunological environment.
Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P # 1.3 3 10 27 ) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P 5 7.3 3 10 212 and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27. Lipoprotein (a) [Lp(a)] is recognized as an independent risk factor for atherosclerotic cardiovascular disease (1, 2). The mechanisms underlying this pathogenesis are poorly understood, although proatherogenic, prothrombotic, and inflammatory pathways contribute. Moreover, plasma Lp(a) levels are not responsive to statins and other cholesterol-lowering drugs, except for niacin, for which the long-term efficacy and safety is not yet established (3). Lp(a) is produced in the liver (4) and circulates in the plasma as an LDL particle having as a protein moiety apolipoprotein(a) [apo(a)], encoded by the LPA gene, linked by a disulfide bond to an apolipoprotein B-100 particle, on a 1:1 molecular basis (5). While apolipoprotein B-100 remains relatively constant in size, apo(a) varies in size due to polymorphism in the number of tandemly repeated kringle IV type 2 domains encoded by sequences in exons 1 and 2 of the LPA gene (6).The human LPA gene arose as a duplication of the PLG gene in the primate lineage and retains 80% sequence identity to PLG (7), which has only a single kringle IV structure. The number of kringle IV repeats in Lp(a) is under genetic control and inversely correlates with plasma levels of Lp(a), likely as result of the lower secretion rate in hepatocytes of apo(a) isoforms with larger numbers of kringle IV repeats (8, 9). The LPA locus accounts for 70-90% of the variability in Lp(a) levels in worldwide Abbreviations: apo(a), apolipoprotein(a); BMI, body mass index; LD, linkage disequilibrium; Lp(a), lipoprotein (a); SNP, single nucleotide polymorphism; RSS, residual sum of squares.
Variation in the HLA-G promoter region influences transcription rates. Contrary to expectations, increased expression of HLA-G may be disadvantageous in some pregnancies.
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