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This study aimed to explore associations of serum cluster of differentiation 44 (CD44) levels and its genetic variants in early pregnancy with gestational diabetes mellitus (GDM). We conducted a 1:1 case-control study (n = 414) nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in Tianjin, China. Blood samples were collected at the first antenatal care visit (at a median of 10 th gestational week). Binary conditional logistic regressions were performed to examine associations of serum CD44 levels and its genetic variants with increased risk of GDM. In this study, we found that serum CD44 levels in early pregnancy was associated with GDM risk in a U-shaped manner. High serum CD44 levels and its genetic risk score in early pregnancy were associated with markedly increased risk of GDM after adjustment for traditional confounders (OR: 1.95, 95%CI: 1.12-3.40 & 1.95, 1.05-3.61). Furthermore, after adjustment for serum CD44 levels, the OR of CD44 genetic risk score for GDM was slightly attenuated but not significant (1.84, 0.98-3.48). In conclusion, serum CD44 levels and its genetic variants in early pregnancy were associated with GDM risk in Chinese pregnant women, with the effect of CD44 genetic variants being accounted for by serum CD44. SIGNIFICANCE: Recent studies suggested that pregnant women with GDM may have abnormal levels of CD44 and abnormal expression of CD44 gene, but it is uncertain whether abnormal CD44 plays a causal role in occurrence of GDM. Specifically, it remains unknown whether serum CD44 levels in early pregnancy and its genetic variants can predict the later occurrence of GDM. In this study, we found that high serum CD44 levels in early pregnancy and its genetic variants were associated with markedly increased risk of GDM in Chinese pregnant women, with the effect of CD44 genetic variants being largely accounted for by serum CD44 levels. Our study is the first reporting that serum CD44 levels and its genetic variants were associated with markedly increased risk of GDM. These multi-omics risk markers may be useful for identification of women at high risk of GDM in early pregnancy. Our findings also provide new insights into the disease mechanisms., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To examine long-term risk of overweight in offspring of women with gestational diabetes mellitus (GDM) defined by the International Association of Diabetes and Pregnancy Study Group (IADPSG)'s criteria but not by the 1999 World Health Organization (WHO)'s criteria., Methods: We followed up 1681 mother-child pairs for 8 years in Tianjin, China. Overweight in children aged 1-5 and 6-8 were respectively defined as body mass index-for-age and -sex above the 2 z-score and 1 z-score curves of the WHO's child growth standards. Logistic regression was performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of hyperglycemia indices at oral glucose tolerance test and GDMs defined by different criteria for offspring overweight at different ages., Results: Offspring of women with fasting plasma glucose ≥5.1 mmol/L were at increased risk of overweight at 6-8 years old (OR:1.45, 95% CI: 1.09-1.93). GDM defined by the IADPSG's criteria only was associated with increased risk of childhood overweight at 6-8 years old (1.65, 1.13-2.40), as compared with non-GDM by either of the two sets of criteria., Conclusions: Newly defined GDM by the IADPSG's criteria increased the risk of offspring overweight aged 6-8 years., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2024 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

The cases were a pair of siblings with a carnitine palmitoyltransferase (CPT2) deficiency detected by tandem mass spectrometry. Their C16 and C18:1 levels were both within the normal range, while C0 was low, and the (C16+C18:1)/C2 ratio was high. Following genetic testing, a novel CPT2 gene mutation was identified in both patients. The male patient had a normal growth rate during 5 years of follow-up after treatment. By contrast, the female patient did not take l-carnitine supplements and died after an infectious disease-associated illness when she was 1 year old. These data emphasize the need to raise awareness about CPT2 deficiency so as to correctly diagnose and accurately manage the disease., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Aims: To explore association of serum hyaluronidase 1 (HYAL1) level in early pregnancy with gestational diabetes mellitus (GDM), and to examine interactive effects of HYAL1 with ceramides species on GDM risk., Materials and Methods: We conducted a 1:1 matched case-control study (n = 414) of pregnant women from 2010 to 2012 in Tianjin, China. Blood samples were collected at the first antenatal care visit (at a median of 10 th gestational weeks). Binary conditional logistic regression and restricted cubic spline (RCS) analysis were used to examine full-range risk association between HYAL1 and GDM. Additive interactions and multiplicative interactions were employed to test interactive effects of HYAL1 with ceramides species on GDM risk., Results: Ln HYAL1 was linearly associated with GDM risk and the adjusted OR of HYAL1 ≥ vs. < its median for GDM was significant (1.65, 95%CI: 1.08-2.52). High HYAL1 markedly enhanced the ORs of high ceramide 18:0 for GDM from 2.31 (1.06-5.01) to 6.74 (2.85-16.0), and low ceramide 24:0 from 3.08 (1.33-7.11) to 8.15 (3.03-21.9), with significant additive interactions., Conclusions: High HYAL1 in early pregnancy may increase the risk of GDM in Chinese women, possibly via enhancing the effects of high ceramide 18:0 and low ceramide 24:0 on GDM risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To examine the associations of parental obesity prior to pregnancy with offspring overweight before two years of age among children of Chinese women with gestational diabetes mellitus (GDM)., Methods: Offspring of women with GDM (n = 774) who were diagnosed in 2010-2012 were followed up to two years of age in Tianjin, China. Multinomial logistic regression was used to obtain odds ratios (ORs) and 95% confidence interval (CI) of maternal and paternal prepregnancy obesity with offspring overweight at < 1, 1-1.5, and 1.5-2 years of age., Results: Among 774 offspring of women with GDM, 457 (59.0%) of the offspring developed overweight before two years of age. Maternal prepregnancy obesity was associated with increased risk of offspring overweight at 1-1.5 years of age and 1.5-2 years of age (ORs: 1.98, 95%CI: 1.09-3.59 & 2.14, 1.10-4.15, respectively). Paternal prepregnancy obesity was only associated with elevated risk of offspring overweight at 1.5-2 years of age (1.82, 1.08-3.06). Furthermore, copresence of both maternal and paternal obesity prior to pregnancy had an additive effect on the risk of offspring overweight at 1.5-2 years of age (3.73, 1.50-9.27)., Conclusions: Parental prepregnancy obesity predicted offspring overweight before two years of age among children of Chinese women with GDM., Competing Interests: Declaration of Competing Interest All authors declared no conflict of interest., (Copyright © 2022 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Interactions between genetic and nutritional factors can contribute to the risk of gestational diabetes mellitus (GDM)., Objectives: We aimed to explore the associations of cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) single-nucleotide polymorphism (SNP) rs7747752 and serum concentrations of SFAs with the risk of GDM in Chinese women., Methods: We conducted a 1:1 case-control study in a prospective cohort of pregnant women in Tianjin, China. Serum SFA data were collected from a total of 243 women with GDM and their controls matched by maternal age (±1 y). Among them, 207 case-control pairs had high-quality sequencing data. P/L and S/P ratios were defined as palmitic acid (16:0)/lauric acid (12:0) and stearic acid (18:0)/palmitic acid, respectively. Conditional logistic regression analysis was performed to estimate associations of CDKAL1 SNP rs7747752 and serum concentrations of SFAs with the risk of GDM. An additive interaction between rs7747752 and palmitic acid was analyzed to test the contribution of their interaction to the risk of GDM., Results: Among the 5 tested SFAs, palmitic acid was positively whereas lauric acid was negatively associated with the risk of GDM. A P/L ratio ≥12.2 and an S/P ratio ≤0.71 were independently and synergistically associated with an increased risk of GDM. The CDKAL1 rs7747752 G > C variant was significantly associated with an increased risk of GDM (P < 0.05). Furthermore, the presence of the rs7747752 G > C variant increased the OR (95% CI) of high palmitic acid concentration from 1.55 (0.61, 3.97) to 4.34 (2.04, 9.23), with a significant additive interaction., Conclusions: The interaction between high serum palmitic acid concentration and the CDKAL1 rs7747752 G > C variant played a critical role in GDM. Given that a hypocaloric low-carbohydrate diet can lower palmitic acid concentrations, it is worthwhile to test whether such a diet is effective in reducing the risk of GDM, especially among women who have both risk factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Aims: This study aimed to examine impacts of gestational diabetes mellitus (GDM) on quality of life (QoL) domains in Chinese pregnant women., Methods: We recruited 13,358 pregnant women in Tianjin, China. GDM was diagnosed using the criteria of International Association of Diabetes and Pregnancy Study Group. QoL was measured using the 36-Item Short-Form Health Survey. General linear model was used to obtain β-coefficient and 95% confidence intervals (CI) of GDM for QoL domain and summary scores., Results: 7.25% of the pregnant women developed GDM. Among the QoL domain and summary scores, only general health (GH) score was lower in the GDM group than in the non-GDM group. GDM and advanced maternal age (i.e., ≥ versus <30 years) were negatively associated with GH in multivariable analyses (β-coefficient: -1.17, 95%CI: -2.17 to -0.17 & -0.79, -1.40 to -0.18, respectively). In subgroup analyses, the β-coefficient of GDM for GH among women with maternal age ≥30 years was enhanced to -2.17 (-3.94 to -0.40) in multivariable analysis while the β-coefficient of GDM for GH among women aged <30 years was attenuated to non-significance., Conclusions: GDM and advanced maternal age were associated with reducing GH, and presence of advanced maternal age markedly increased the effect of GDM on GH., (Copyright © 2019 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Aims: Women with prior gestational diabetes mellitus (GDM) or high genetic susceptibility are prone to development of type 2 diabetes. We examined whether a lifestyle intervention modified the genetic effect on changes in glycemic markers among women with prior GDM., Research Design and Methods: This study included 560 women with prior GDM from a randomized controlled trial, the Tianjin Gestational Diabetes Mellitus Prevention Program, who were assigned into an intervention arm (improved physical activity and healthy dietary intakes) or a control arm. We assessed associations of GDM related genetic variants in/near the CDKAL1 (rs7754840) and MTNR1B (rs10830962) genes with changes in fasting levels of glucose and insulin, β-cell function (HOMA-B) and insulin resistance (HOMA-IR) at 1 year and 2 years after the baseline., Results: We found significant interactions between CDKAL1 variant rs7754840 and lifestyle intervention on changes in fasting insulin and HOMA-IR at 1 year (P for interactions = 0.008 and 0.006, respectively). The GDM-increasing C allele was associated with a 0.07-unit greater increase in fasting insulin (P = 0.048) and HOMA-IR (P = 0.045) in the control group, while opposite-directional associations were observed in the intervention group; women with the C allele seemed to decrease more in these glycemic markers than the non-C-carriers (both P ≤ 0.06). The interactions between the CDKAL1 genetic variant and lifestyle intervention on changes in fasting insulin (P = 0.035) and HOMA-IR (P = 0.024) remained significant over the 2-year period, even though the effects of lifestyle intervention were attenuated at 2-year. The MTNR1B variant rs10830962 did not show interaction with lifestyle intervention on changes in the glycemic markers., Conclusions: Healthy lifestyle intervention may be beneficial for women with the GDM predisposing CDKAL1 genetic variant in improvement of insulin resistance., Trial Registration Number: ClinicalTrials.gov NCT01554358. URL OF REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01554358., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Maternal metabolic abnormalities have been related to offspring obesity especially during childhood., Objectives: We analyzed whether the gestational diabetes mellitus (GDM)-associated melatonin receptor 1B (MTNR1B) genotype of mothers modified the relation between maternal gestational weight gain and childhood obesity., Methods: A total of 1114 Chinese mother-child pairs (mothers with or without prior GDM) were included. Mothers' MTNR1B rs10830962 genotype and gestational weight gain were assessed. Indicators of childhood obesity included BMI-for-age z-score, weight-for-age z-score, waist circumference, and body fat. Childhood overweight and obesity were also analyzed., Results: We found that the maternal MTNR1B genotype significantly interacted with gestational weight gain on indicators of offspring's obesity (all P for interaction < 0.05). After multivariable adjustment, BMI-for-age z-scores associated with 1-kg gestational weight gain were 0.009 (SE 0.018), 0.026 (SE 0.010), and 0.061 (SE 0.010) in children with the maternal MTNR1B genotype CC, CG, and GG, respectively (P-interaction = 0.012). Similar interactions were observed for weight-for-age z-score, waist circumference, and body fat (P-interaction = 0.001, 0.003, and 0.012, respectively). The associations remained consistently significant in women with and without GDM. We also found significant interactions between the maternal MTNR1B genotype and gestational weight gain on the offspring's childhood overweight and obesity (P-interaction = 0.005 and 0.026, respectively)., Conclusions: The maternal MTNR1B genotype might interact with gestational weight gain on offspring's obesity risk during childhood., (Copyright © The Author(s) 2019.)

Purpose: The benefits of concurrent newborn hearing and genetic screening have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of newborns with genetic screening results., Methods: Newborns in China were screened for 20 hearing-loss-related genetic variants from 2012 to 2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed up via phone interviews., Results: Following up 12,778 of 1.2 million genetically screened newborns revealed a higher rate of hearing loss by three months of age among referrals from the initial hearing screening (60% vs. 5.0%, P < 0.001) and a lower rate of lost-to-follow-up/documentation (5% vs. 22%, P < 0.001) in the positive group than in the inconclusive group. Importantly, genetic screening detected 13% more hearing-impaired infants than hearing screening alone and identified 2,638 (0.23% of total) newborns predisposed to preventable ototoxicity undetectable by hearing screening., Conclusion: Incorporating genetic screening improves the effectiveness of newborn hearing screening programs by elucidating etiologies, discerning high-risk subgroups for vigilant management, identifying additional children who may benefit from early intervention, and informing at-risk newborns and their maternal relatives of increased susceptibility to ototoxicity.

Background: A history of gestational diabetes mellitus (GDM) has been related to an elevated risk of type 2 diabetes. The melanocortin-4 receptor (MC4R) genotype has been related to glycemic changes in women with prior GDM., Objective: The objective of this study was to analyze whether lifestyle intervention modified the association between the MC4R genotype and changes in insulin sensitivity among women with prior GDM., Methods: We genotyped MC4R rs6567160 and measured glucose and insulin in fasting plasma samples at baseline and during the first 2 follow-up visits in 1128 women with prior GDM. They were randomly assigned to either a 4-y lifestyle intervention involving both diet and physical activity or a control group from a randomized clinical trial, the Tianjin Gestational Diabetes Mellitus Prevention Program. We analyzed the interaction between the MC4R genotype and lifestyle intervention on changes in insulin resistance., Results: From baseline to 1.28 y, the MC4R genotype was related to changes in fasting insulin, HOMA-IR, and homeostasis model assessment of β cell function (HOMA-B) in the intervention group. Each risk allele (C) of rs6567160 was associated with a 0.08-unit greater decrease in log(insulin), log(HOMA-IR), and log(HOMA-B) (P = 0.02, 0.04, and 0.04, respectively), whereas in the control group, each C allele tended to be associated with a greater increase in HOMA-IR (P = 0.09). We found significant interactions between the MC4R genotype and lifestyle intervention on 1.28-y changes in fasting insulin and HOMA-IR (P = 0.006 and 0.008, respectively), and such interaction remained significant when we analyzed the trajectory of changes in insulin and HOMA-IR from baseline to 2.55 y (both P = 0.03)., Conclusions: The exploratory results from the first 2 follow-up visits indicate that women with prior GDM carrying a diabetes-increasing MC4R genotype (CC or TC) may obtain better improvement than the TT genotype in insulin resistance through lifestyle intervention. This trial was registered at clinicaltrials.gov as NCT01554358., (Copyright © American Society for Nutrition 2019.)

Aims: The aim was to examine associations of insulin resistance and beta cell dysfunction with macrosomia in Chinese women with gestational diabetes mellitus (GDM)., Methods: We performed a secondary analysis of 923 women with GDM enrolled in a randomized controlled trial in 2010-2012 in Tianjin, China. Insulin resistance and beta-cell function were estimated using Homeostasis model assessment. Binary logistic regression was used to obtain adjusted odds ratios (ORs) and 95% confidence intervals (CIs). A two-step adjustment scheme was used to control for effects of potential confounders., Results: A total of 138 women (16.5%) had excessive weight gain, 127 (7.3%) had macrosomia and 150 (16.3%) had a large for gestational age (LGA) infant. Compared to women in bottom tertile of insulin resistance, women in upper tertile had increased risk of excessive weight gain (OR: 4.32, 95%CI: 1.95-9.62), macrosomia and LGA (OR: 2.61, 95%CI: 1.20-5.69; 2.75, 95%CI: 1.35-5.62, respectively). The observed overall effects were mainly due to their large effect sizes among women with normal pre-pregnancy body weight. However, beta cell function was not found to be associated with either of them., Conclusions: Increased insulin resistance during pregnancy was associated with excessive weight gain, macrosomia and LGA in Chinese women with GDM., (Copyright © 2018 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)