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1. Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP)

   https://doi.org/10.2337/dc23-1927  

   Yang, Peter K. ; Jackson, Sandra L. ; Charest, Brian R. ; Cheng, Yiling J. ; Sun, Yan V. ; Raghavan, Sridharan ; Litkowski, Elizabeth M. ; Legvold, Brian T. ; Rhee, Mary K. ; Oram, Richard A. ; et al ( April 2024 , Diabetes Care)

   To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates.

   Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011–2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%).

   T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥ 90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and they resembled T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001.

   Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

    

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2. Mixed Patterns of Intergenerational DNA Methylation Inheritance in Acropora

   https://doi.org/10.1093/molbev/msae008  

   Peterson, Christopher R. ; Scott, Carly B. ; Ghaffari, Rashin ; Dixon, Groves ; Matz, Mikhail V. ; Mulligan, ed., Connie ( January 2024 , Molecular Biology and Evolution)

   For sessile organisms at high risk from climate change, phenotypic plasticity can be critical to rapid acclimation. Epigenetic markers like DNA methylation are hypothesized as mediators of plasticity; methylation is associated with the regulation of gene expression, can change in response to ecological cues, and is a proposed basis for the inheritance of acquired traits. Within reef-building corals, gene-body methylation (gbM) can change in response to ecological stressors. If coral DNA methylation is transmissible across generations, this could potentially facilitate rapid acclimation to environmental change. We investigated methylation heritability in Acropora, a stony reef-building coral. Two Acropora millepora and two Acropora selago adults were crossed, producing eight offspring crosses (four hybrid, two of each species). We used whole-genome bisulfite sequencing to identify methylated loci and allele-specific alignments to quantify per-locus inheritance. If methylation is heritable, differential methylation (DM) between the parents should equal DM between paired offspring alleles at a given locus. We found a mixture of heritable and nonheritable loci, with heritable portions ranging from 44% to 90% among crosses. gBM was more heritable than intergenic methylation, and most loci had a consistent degree of heritability between crosses (i.e. the deviation between parental and offspring DM were of similar magnitude and direction). Our results provide evidence that coral methylation can be inherited but that heritability is heterogenous throughout the genome. Future investigations into this heterogeneity and its phenotypic implications will be important to understanding the potential capability of intergenerational environmental acclimation in reef building corals.

    

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3. Twenty years of pediatric diabetes surveillance: what do we know and why it matters

   https://doi.org/10.1111/nyas.14573  

   Dabelea, Dana ; Sauder, Katherine A. ; Jensen, Elizabeth T. ; Mottl, Amy K. ; Huang, Alyssa ; Pihoker, Catherine ; Hamman, Richard F. ; Lawrence, Jean ; Dolan, Lawrence M. ; Agostino, Jr., Ralph D’ ; et al ( February 2021 , Annals of the New York Academy of Sciences)

   SEARCH for Diabetes in Youth (SEARCH) was initiated in 2000 as a multicenter study to address major gaps in the understanding of childhood diabetes in the United States. An active registry of youth diagnosed with diabetes at age <20 years since 2002 assessed prevalence, annual incidence, and trends by age, race/ethnicity, sex, and diabetes type. An observational cohort nested within the population‐based registry was established to assess the natural history and risk factors for acute and chronic diabetes‐related complications, as well as the quality of care and quality of life of children and adolescents with diabetes from diagnosis into young adulthood. SEARCH findings have contributed to a better understanding of the complex and heterogeneous nature of youth‐onset diabetes. Continued surveillance of the burden and risk of type 1 and type 2 diabetes is important to track and monitor incidence and prevalence within the population. SEARCH reported evidence of early diabetes complications highlighting that continuing the long‐term follow‐up of youth with diabetes is necessary to further our understanding of its natural history and to develop the most appropriate approaches to primary, secondary, and tertiary prevention of diabetes and its complications. This review summarizes two decades of research and suggests avenues for further work.

    

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4. CLEC11A methylation is correlated to AML subtypes and cytogenetic risk factors but not patient demographics

   https://doi.org/10.1371/journal.pone.0300477  

   Swanson, Allyson J. ; Rogowski, Victor J. ; Bishop, Jacob A. ; Walker, Dylan M. ; Roxas, Gina M. ; Raimondi, Stacey L. ( March 2024 , PLOS ONE)

   Baysal, Mehmet (Ed.)

   Acute myeloid leukemia (AML) is an aggressive and lethal cancer of the blood, which leads to the death of over 11,000 patients in the United States each year. Research on identifying, characterizing, and treating AML is crucial in the fight against this deadly disease. Recent studies have examined the role of CLEC11A in cancer, including AML. However, there have been conflicting reports related to tumor progression and survival. Because survival is based on a variety of factors, including classification of the tumor, genetic risk factors, and demographics, it is imperative that we determine what role CLEC11A may have in cancer survival. Therefore, utilizing data from the Genomic Data Commons, we analyzed CLEC11A methylation in 108 AML patients compared to FAB classification, cytogenetic risk factors, age, race, and gender. Our results show statistically significant correlations between methylation of CLEC11A and FAB classification as well as poor genetic risk factors. However, no difference was observed in CLEC11A methylation when compared to demographic data. Our results, matched with a known biological function of CLEC11A in early hematopoiesis, indicate that CLEC11A may be an important marker for AML diagnosis and prognosis and provide relevant data in the ongoing search for novel therapeutics to improve AML survival. 

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5. Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels

   https://doi.org/10.13110  

   Clukay, Chris J ; Hughes, David A ; Kertes, Darlene A ; Mulligan, Connie J ( April 2019 , Human biology)

   null (Ed.)

   Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p < 1.95 × 10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10-7 and 8.3 × 10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM. 

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