Plasma immunological markers in pregnancy and cord blood: A possible link between macrophage chemo‐attractants and risk of childhood type 1 diabetes

Background Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis. Methods Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non‐inherited, non‐shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort. Results We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68‐2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann‐Whitney P = .46). There was a possible association in the NIMA HLA‐DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05‐14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis. Conclusions Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort.

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“…At the biobank repository, DNA was extracted and stored at −20°C until analysis. For details of sample handling, see …”

Section: Methodsmentioning

confidence: 99%

Maternal microchimerism in cord blood and risk of childhood‐onset type 1 diabetes

Tapia

Mortimer

et al. 2019

Pediatr Diabetes

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“…Participants were genotyped for established type 1 diabetes susceptibilty SNPs including HLA tagSNPs using a custom Illumina Golden Gate assay (Illumina, San Diego, CA), as described earlier [31]. We calculated a 51 SNP non-HLA type 1 diabetes genetic risk score (GRS), weighted by the natural log-odds ratio of type 1 diabetes per risk allele reported from large GWAS studies (ESM Table 2, with further details given in the online supplement to [32]). Human leukocyte antigen (HLA) class II alleles were imputed using the HLA*IMP:02 web service [33] (details given in [31]) and all HLA genotypes were subsequently confirmed by allele specific PCR [34].…”

Section: Genotyping Assays and Genetic Risk Scoresmentioning

confidence: 99%

Prediction of type 1 diabetes at birth: cord blood metabolites versus genetic risk score in the MoBa cohort

Tapia

Suvitaival

Ahonen

et al. 2021

Preprint

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Background and aim Genetic markers are established as predictive of type 1 diabetes, but unknown early life environment is believed to be involved. Umbilical cord blood may reflect perinatal metabolism and exposures. We studied whether selected polar metabolites in cord blood contribute to prediction of type 1 diabetes. Methods Using a targeted UHPLC-QQQ-MS platform, we quantified 27 low molecular weight metabolites (including amino acids, small organic acids and bile acids) in 166 children, who later developed type 1 diabetes, and 177 random control children in the Norwegian Mother, Father and Child (MoBa) cohort. We analysed the data using logistic regression (estimating odds ratios per standard deviation [aOR]), area under the receiver operating characteristic curve (AUC) and k-means clustering. Metabolites were compared to a genetic risk score based on 51 established non-HLA SNPs, and a four-category HLA risk group. Results The strongest associations for metabolites were aminoadipic acid (aOR=1.23,95%CI:0.97-1.55), indoxyl sulfate (aOR=1.15,95%CI:0.87-1.51), and tryptophan (aOR=0.84,95%CI:0.65-1.10), with other aORs close to 1.0, and none significantly associated with type 1 diabetes. K-means clustering identified six clusters, none of which were associated with type 1 diabetes. Cross-validated AUC showed no predictive value of metabolites (AUC 0.49), while the non-HLA genetic risk score AUC was 0.56 and the HLA risk group AUC was 0.78. Conclusions In this large study, we found no support of a predictive role of cord blood concentrations of selected bile acids and other small polar metabolites in the development of type 1 diabetes.

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“…A non-HLA T1D genetic risk score (GRS), weighted by the increased risk reported per risk allele, was calculated on the basis of 51 non-HLA SNPs associated with T1D (details given in the online supplement to ref. 23).…”

Section: Genotyping Assays and Genetic Risk Scoresmentioning

confidence: 99%

Maternal and Newborn Vitamin D–Binding Protein, Vitamin D Levels, Vitamin D Receptor Genotype, and Childhood Type 1 Diabetes

et al. 2019

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OBJECTIVECircumstantial evidence links 25-hydroxy vitamin D [25(OH)D], vitamin D-binding protein (DBP), vitamin D-associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D. RESEARCH DESIGN AND METHODSFrom a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography-tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, and VDR). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders. RESULTSHigher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 [95% CI 0.74-0.98] per mmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 [95% CI 0.77-0.98] per 10 nmol/L increase) in children carrying the VDR rs11568820 G/G genotype (P interaction = 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions. CONCLUSIONSHigher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on VDR genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include VDR genotype and DBP levels.Type 1 diabetes (T1D) often presents in childhood and is associated with increased mortality (1). Vitamin D, vitamin D receptor (VDR), vitamin D-binding protein (DBP), and genetic polymorphisms associated with vitamin D metabolism have separately been suggested to influence the risk of T1D development (2). No studies have jointly

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Plasma immunological markers in pregnancy and cord blood: A possible link between macrophage chemo‐attractants and risk of childhood type 1 diabetes

Abstract: Increased mid-pregnancy CCL4 levels showed borderline associations with increased offspring T1D risk, which may indicate a link between environmental factors in pregnancy and offspring T1D risk.

Cited by 13 publications

References 63 publications

Maternal microchimerism in cord blood and risk of childhood‐onset type 1 diabetes

Maternal microchimerism in cord blood and risk of childhood‐onset type 1 diabetes

Prediction of type 1 diabetes at birth: cord blood metabolites versus genetic risk score in the MoBa cohort

Maternal and Newborn Vitamin D–Binding Protein, Vitamin D Levels, Vitamin D Receptor Genotype, and Childhood Type 1 Diabetes

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