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Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.

ABSTRACT: 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.

SUBMITTER: Clark MM

PROVIDER: S-EPMC5557278 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.

Clark Michelle M MM Chazara Olympe O Sobel Eric M EM Gjessing Håkon K HK Magnus Per P Moffett Ashley A Sinsheimer Janet S JS

Human heredity 20160101 4

<h4>Background/aims</h4>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.<h4>Methods</h4>Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these intera ...[more]

PMID: 28214848

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Project description:ImportanceMaternal obesity, pregestational type 1 diabetes, and gestational diabetes have been reported to increase the risks for large birth weight and preterm birth in offspring. However, the associations for insulin-treated diabetes and non-insulin-treated type 2 diabetes, as well as the associations for joint diabetes disorders and maternal body mass index, with these outcomes are less well documented.ObjectiveTo examine associations of maternal diabetes disorders, separately and together with maternal underweight or obesity, with the offspring being large for gestational age and/or preterm at birth.Design, setting, and participantsThis population-based cohort study used nationwide registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014, in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.ExposuresMaternal prepregnancy body mass index, pregestational diabetes with insulin treatment, pregestational type 2 diabetes without insulin treatment, and gestational diabetes.Main outcomes and measuresOffspring large for gestational age (LGA) at birth and preterm delivery. Logistic regression models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status.ResultsOf the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Statistically significant interactions existed between maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3 [P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes, was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%]; adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Mothers who were moderately obese with type 2 diabetes were at increased risks of LGA (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes was associated with an increased risk also for very and extremely preterm births.Conclusions and relevanceMaternal insulin-treated diabetes appeared to be associated with markedly increased risks for LGA and preterm births, whereas obesity in mothers with type 2 diabetes had mild to moderately increased risks; these findings may have implications for counseling and managing pregnancies.

Project description:The aim of this study was to determine how maternal undernutrition during pregnancy and offspring birth-weight can affect the postnatal development of offspring under farm conditions, which may lead to consequences in its meat and carcass quality. The current study involved a total of 80 litters from Iberian sows fed a diet fulfilling daily requirements (n?=?47; control) or providing 70% daily requirements (n?=?33; underfed) from d 38 to d 90 of gestation when fetal tissue development begins. After birth, piglets born live were classified as low birth-weight (LBW; <?1 kg) and normal birth-weight (NBW; ?1 kg). During the growing phase, 240 control and 230 underfed pigs (50% males and females) distributed by BW category and sex were studied until the slaughter.At birth and weaning, there were significant differences in all morphological measures and weight between NBW and LBW piglets as expected (P?<?0.0005), but few effects of the gestational feed restriction. During the growing phase, NBW pigs continued with higher weight than LBW pigs on all the days of evaluation (P?<?0.05), even though control-LBW-females and LBW-males showed a catch-up growth. However, underfed pigs showed slower growth and higher feed conversion ratio than control pigs (P?<?0.0001) at 215 days old. Moreover, the average daily weight gain (ADWG) for the overall period was greater for NBW, male and control pigs than for their LBW, female and underfed pigs (P?<?0.0001, P<?0.0005 and P<?0.05, respectively) and NBW pigs were slaughtered at a younger age than LBW pigs (P?<?0.0001). After slaughtering, control pigs also had higher carcass yield and backfat depth than underfed pigs (P?<?0.0005) and the maternal nutritional effect caused main changes in the polar lipid fraction of liver and loin. The fatty acid composition of loin in control pigs had higher C18:1n-9 and n-3 FA concentrations, as well as lower ?n-6/?n-3 ratio, than in underfed pigs (P?<?0.005).In brief, results showed that the effects of maternal nutritional restriction appeared and increased with offspring age, causing worse developmental patterns for underfed pigs than for control pigs.

Dataset Information

Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.

Publications

Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.

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