Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
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ABSTRACT:
SUBMITTER: Hiby SE
PROVIDER: S-EPMC4028203 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
Hiby Susan E SE Apps Richard R Chazara Olympe O Farrell Lydia E LE Magnus Per P Trogstad Lill L Gjessing Håkon K HK Carrington Mary M Moffett Ashley A
Journal of immunology (Baltimore, Md. : 1950) 20140428 11
Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤ 5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 131 ...[more]
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Project description:Maternal and offspring cell contact at the site of placentation presents a plausible setting for maternal-fetal genotype (MFG) interactions affecting fetal growth. We test hypotheses regarding killer cell immunoglobulin-like receptor (KIR) and HLA-C MFG effects on human birth weight by extending the quantitative MFG (QMFG) test.Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these interactions, we developed the extended QMFG test, a linear mixed-effect model that can use multi-locus genotype data from families.We demonstrate the extended QMFG test's statistical properties. We also show that if an offspring-only model is fit when MFG effects exist, associations can be missed or misattributed. Furthermore, imprecisely modeling the effects of both KIR and HLA-C could result in a failure to replicate if these loci's allele frequencies differ among populations. To further illustrate the extended QMFG test's advantages, we apply the extended QMFG test to a UK cohort study and the Norwegian Mother and Child Cohort (MoBa) study.We find a significant KIR-HLA-C interaction effect on birth weight. More generally, the QMFG test can detect genetic associations that may be missed by standard genome-wide association studies for quantitative traits.
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Project description:Study questionAre maternal and paternal preconception urinary bisphenol A (BPA) or bisphenol S (BPS) concentrations associated with offspring birth size?Summary answerMaternal-but not paternal-preconception urinary BPA concentrations were associated with lower birth size among couples seeking fertility evaluation.What is known alreadyPrenatal BPA exposure has been previously associated with reduced birth size in some but not all epidemiologic studies. However, the potential effect of BPA exposure before conception in either parent is unknown. Data on BPS is practically absent.Study design, size, durationOngoing prospective preconception cohort of women and men seeking fertility evaluation between 2005 and 2016 in a large fertility center in an academic hospital in Boston, MA, USA.Participants/materials, setting, methodsWe examined the association between maternal and paternal preconception, as well as maternal prenatal urinary BPA and BPS concentrations, and size at birth among 346 singletons from couples recruited in the Environment and Reproductive Health (EARTH) Study using multivariable linear regression. Infant birth weight and head circumference were abstracted from delivery records. Mean preconception and prenatal exposures were estimated by averaging urinary ln-BPA and ln-BPS concentrations in multiple maternal and paternal urine samples collected before pregnancy, and maternal pregnancy samples collected in each trimester.Main results and the role of chanceMaternal preconception urinary BPA concentrations were inversely associated with birth weight and head circumference in adjusted models: each ln-unit increase was associated with a decrease in birth weight of 119 g (95% CI: -212, -27), and a head circumference decrease of 0.72 cm (95% CI: -1.3, -0.1). Additional adjustment by gestational age or prenatal BPA exposure modestly attenuated results. Women with higher prenatal BPA concentrations had infants with lower mean birth weight (-75 g, 95% CI: -153, 2) although this did not achieve statistical significance. Paternal preconception urinary BPA concentrations were not associated with either birth weight or head circumference. No consistent patterns emerged for BPS concentrations measured in either parent.Limitations, reasons for cautionWe observed a strong negative association between maternal-but not paternal-preconception BPA concentrations and offspring birth size among a subfertile population. Although these results are overall consistent with prior studies on prenatal BPA exposure, these findings may not be generalizable to women without fertility concerns.Wider implications of the findingsThis study suggests that the unexplored maternal preconception period may be a sensitive window for BPA effects on birth outcomes.Study funding/competing interest(s)Work supported by Grants (ES R01 009718, ES 022955 and ES 000002) from the National Institute of Environmental Health Sciences (NIEHS). C.M. was supported by a post-doctoral fellowship award from the Canadian Institutes of Health Research. There are no competing interests to declare.
| S-EPMC6070117 | biostudies-literature
Project description:BACKGROUNDThere is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo.METHODSWe used stable isotope labeling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections.RESULTSWe showed that an individual's iKIR-ligand genotype was a significant determinant of CD8+ T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8+ T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8+ T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8+ and CD4+ T cell immune aging phenotype.CONCLUSIONSTogether, these data reveal an unexpectedly large effect of iKIR genotype on T cell survival.FUNDINGWellcome Trust; Medical Research Council; EU Horizon 2020; EU FP7; Leukemia and Lymphoma Research; National Institute of Health Research (NIHR) Imperial Biomedical Research Centre; Imperial College Research Fellowship; National Institutes of Health; Jefferiss Trust.
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Project description:Killer cell immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and subsets of T cells. The KIR genes are polymorphic and the KIR gene complex is polygenic with varying numbers of inhibitory and activating receptors. HLA class I molecules serve as ligands for the KIR. Interactions of the independently segregating KIR and HLA loci are important for recognition of targets by NK cells as well as NK cell 'licensing'. Several disease association studies indicate a role for interactions between these loci in infectious diseases, autoimmune/inflammatory disorders, cancer and reproduction. Emerging functional data supports a mechanism based on a continuum of inhibition to activation through various compound KIR-HLA genotypes in diseases.
| S-EPMC3501819 | biostudies-literature