bluuebunny/crossref_metadata_2025_split huggingface dataset:
1460-P: Prevalence of Chronic Kidney Disease Associated with Type 1 Diabetes in the U.S.
Authors: ROSSING PETER , GROOP PER-HENRIK , SINGH RAKESH , LAWATSCHECK ROBERT , TUTTLE KATHERINE R. 
Published: June 2023

Background: Chronic kidney disease (CKD) is associated with an increased risk of kidney failure, cardiovascular events, and mortality in patients with type 1 diabetes (T1D). However, the prevalence of CKD associated with T1D in the US is unclear. The aim of this study was to estimate the prevalence of CKD in people with T1D in the US using data collected in the National Health Examinations Survey (NHANES).
Methods: People with T1D were identified from NHANES using an established algorithm (Mosslemi et al. Cardiovasc Endocrinol Metab. 2020). Adults aged ≥18 years with CKD in this group were identified by single measurements of estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 or urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g. The NHANES data were used to create corresponding weighted variables to represent the US
Results: During 2015 to 2018, diabetes was identified in 1647 of 19,225 adults surveyed in NHANES. Among those with diabetes, CKD was present in 20 out of 47 people with T1D with evaluable eGFR and UACR, corresponding to an unweighted estimate of 43%. CKD status was uncertain in 7 patients with T1D as their eGFR and/or UACR measurements were not available (unweighted estimate). In the CKD and T1D group, 59% were male and 60% were non-Hispanic White (weighted characteristics). Mean eGFR (SD) was 57 (4) mL/min/1.73 m2 and median UACR (IQR) was 89 (8-875) mg/g (weighted characteristics). Since the weighted overall number of adult people with T1D in the US was estimated at 1,202,739 (95% CI: 681,820-1,723,657), the corresponding number with T1D and CKD with evaluable eGFR and UACR was 258,196 (95% CI: 71,189-445,203), corresponding to a weighted estimate of 21%.
Conclusions: CKD was common in people with T1D and evaluable eGFR and UACR based on recent US data. Since the absolute number in NHANES was small, these prevalence estimates should be interpreted cautiously and validated in other cohorts.

Disclosure
P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. P.Groop: Advisory Panel; Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Bayer Inc., Merck Sharp & Dohme Corp., Medscape, Nestlé Health Science. R.Singh: None. R.Lawatscheck: Employee; Bayer Inc. K.R.Tuttle: Consultant; Lilly, AstraZeneca, Gilead Sciences, Inc., Research Support; Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Novo Nordisk, Goldfinch Bio, Inc., Traveere Pharmaceuticals.

Funding
Bayer AG
1461-P: HbA1c-Independent Association between DNA Methylation (DNAm) and 28-Year Risk of Microvascular Complications in Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , MYCHALECKYJ JOSYF , ONENGUT-GUMUSCU SUNA , ORCHARD TREVOR J. , COSTACOU TINA 
Published: June 2023

DNAm has been associated with microvascular disease but the few epigenome-wide association studies (EWAS) of complications in T1D were largely cross-sectional with limited data on glycemic exposure. We thus performed separate EWAS of 28-yr overt nephropathy (ON) and proliferative retinopathy (PR) risk to determine whether DNAm associations are independent of concurrent HbA1c or differ by long-term HbA1c trajectory in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (&lt;17 yrs) T1D (baseline mean age 29, T1D duration 21 yrs). After quality control, baseline whole blood DNAm (Illumina EPIC array) at 683,597 CpGs was analyzed in Cox models for time-to-ON (albumin excretion rate &gt;200µg/min in ≥2 of 3 timed urines, n=306 free of ON at baseline) and PR (ETDRS grade≥60 or laser photocoagulation, n=265 free of PR), adjusting for T1D duration, sex, smoking pack-years, est. blood cell composition, and technical covariates. Additional EWAS further adjusted for baseline HbA1c. CpGs with false discovery rate (FDR) &lt;0.20 were examined by previously derived latent HbA1c trajectory (Low: stable 7-8%, Improved: 10% decreasing to 7%, Intermediate-High: stable 9%-11%). Over 28 yrs, 65 (21.2%) developed ON; 139 (52.5%) PR. For ON, DNAm at cg19693031 (TXNIP) was associated (β per 5% DNAm=−0.43±0.09, p=2.84E-07, FDR=0.19) but attenuated in a baseline HbA1c-adjusted EWAS (β=−0.32±0.08, p=7.76E-05, FDR=0.98). For PR, 3 CpGs (cg27512687 [KIF16B]; cg04202206 [ISCA1]; cg14678509 [intergenic]) had FDR&lt;0.20; only cg27512687 remained so after HbA1c adjustment (β=−2.6±0.49, p=8.46E-08, FDR=0.06). There was no interaction with baseline HbA1c (p=0.49); the magnitude of the cg27512687-PR association was similar regardless of HbA1c trajectory. Thus, further study of cg27512687 in KIF16B, a locus encoding a kinesin involved in receptor recycling/degradation, is warranted as it may make an HbA1c-independent contribution to PR risk T1D.

Disclosure
R.G.Miller: None. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None.

Funding
American Diabetes Association (1-19-JDF-109 to R.G.M.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK034818)
1464-P: Identification of Candidate Biomarkers for Type 1 Diabetes Mellitus by Bioinformatics Analysis of Pooled Microarray Gene Expression Datasets in Gene Expression Omnibus
Authors: FENG KEVIN 
Published: June 2023

Background: Type 1 diabetes (T1DM) is a serious threat to childhood life and has a complicated pathogenesis. Currently, molecular mechanisms of T1DM remain largely unclear. The aim of this study was to identify the candidate genes in T1DM by integrated bioinformatics analysis.
Methods: Transcriptomic datasets (GSE156035) in the GEO database were analyzed for differentially expressed genes (DEGs) using the R statistical language. The differentially expressed genes (DEGs) were identified, and the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A protein - protein interaction (PPI) network was applied to screen out the candidate genes.
Results: The results revealed that 273 DEGs of the three datasets were ascertained in our study, including 135 upregulated genes and 138 downregulated genes. The GO and KEGG enrichment analysis results showed that the functions of DEGs mainly involved in regulation of transcription from RNA polymerase II promoter, specific granule lumen, transcriptional activator activity, Osteoclast differentiation pathway, etc. Through the PPI analysis network, the core genes with the highest degree of 6 nodes were selected: FOS, RHOA, CXCL8, FOSB, EGR1, and DUSP1.
Conclusion: The genes, identified in this study, may play a vital regulatory role in the occurrence and development of T1DM. Also, they are closely related to obesity and diabetes mellitus. Our results provide novel biomarkers that could be used as representative reference indicators or potential therapeutic targets for T1DM clinical applications.

Disclosure
K.Feng: None.

Funding
SBHS (2022-16)
1468-P: Integrating Whole-Genome Sequence Analysis and eQTL Data from the TOPMed Program Improves Understanding of Type 2 Diabetes Risk Loci in Diverse Populations
Authors: WANG NINGYUAN , DICORPO DANIEL A. , ZHANG YIXIN , WESSEL JENNIFER , MANNING ALISA 
Published: June 2023

Type 2 diabetes (T2D) has been well characterized by genetic studies with over 550 risk loci identified in mostly European populations. To better understand the genetic basis of T2D in diverse ancestries, we performed a whole genome sequence association analysis with T2D and related traits of fasting insulin (FI), glucose (FG) and hemoglobin A1c (HbA1c). We then used the colocalization method COLOC to evaluate if the risk locus and expression quantitative trait loci (eQTL) region shared a variant. Four relevant eQTL specific to tissues or cell types were obtained from the NHLBI Trans Omics for Precision Medicine (TOPMed) program, including 6,602 samples for whole blood, 1,265 for peripheral blood mononuclear cells (PBMC), 368 for T cells, and 352 for monocytes. A signal was considered colocalized if the posterior probability of colocalization (PP.coloc) was &gt;0.5.
Our analysis included 21,913 prevalent T2D cases, 61,036 controls, and up to 50,201 non-T2D individuals with FG, FI or HbA1c from African, Atlantic Islander, East Asian, European, Hispanic, and Samoan groups. Single variant analysis identified 35 variants in known regions that were significantly associated with T2D or related traits (P &lt; 4.00 × 10−9). Among these regions, we detected six genes (SLC2A2, NKX6-3, KCNQ1, HBB, FN3K, and G6PD) having colocalizing signals in at least one relevant tissue or cell type. For example, variant rs1050828 near G6PD on chromosome X was strongly associated with HbA1c (P &lt;1.0×10−200). Colocalization analysis revealed that rs1050828 also affected the gene expression in various tissues or cell types, including BCAP31 in whole blood, TKTL1 in PBMC, MPP1 in T cell, and RENBP in monocytes. This novel finding, obtained using TOPMed eQTL data from multiple cohorts, suggests a link between risk-associated variation and effector genes, providing insight into potential causal genes and regulatory variants at T2D risk loci in diverse populations.

Disclosure
N.Wang: None. D.A.Dicorpo: None. Y.Zhang: None. J.Wessel: None. A.Manning: None. Topmed diabetes working group: n/a.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (UM1DK078616, R01HL151855)
1469-P: Gene-Level Gene–Mediterranean Diet Interaction Detection Influencing Inflammatory and Glycemic Biomarkers in 137,000 UK Biobank Participants
Authors: WESTERMAN KENNETH E. , MEIGS JAMES B. , MANNING ALISA 
Published: June 2023

Adherence to a Mediterranean diet pattern strongly reduces type 2 diabetes risk on average, but there is substantial heterogeneity in the long-term glycemic and inflammatory response to dietary changes, likely due in part to genetic factors. Using a genome-wide interaction association analysis in the UK Biobank (UKB) cohort, we sought to prioritize and characterize genes contributing to this heterogeneity in the Mediterranean diet-risk factor relationship. We studied an unrelated, multi-ancestry UKB subset who completed at least one 24-hour diet questionnaire, had available glycemic (hemoglobin A1c; HbA1c) and inflammatory (high-sensitivity C-reactive protein; hsCRP) biomarkers measured in blood, and were free of major disease at baseline (N = 136,880). A nine-item, point-based Mediterranean diet score (MDS) based on food group and nutrient intakes was calculated. We conducted a series of genome-wide interaction studies (GWIS) to test for significant variant-diet interactions: one for the MDS itself and one for each sub-component. Variant-level results were aggregated by gene using the MAGMA tool. Gene-level MDS interaction results revealed two genes with false discovery rate &lt; 0.1 for HbA1c: LRRC24 (p = 3.2×10−6) and CCDC40 (p = 3.3×10−6). Gene-level sub-component-specific analysis showed that these two interactions were primarily driven by alcohol and fish intake, respectively, and further prioritized an interaction between intake of nuts and LIN9 gene variants impacting HbA1c (p = 8.8×10−8). Follow-up analysis at the top variant in LIN9, rs9729447, showed a substantial attenuation of the negative nut intake-HbA1c association in major allele carriers and revealed a stronger interaction effect size in individuals who completed at least two dietary questionnaires. Our GWIS analysis suggests that there are locus-specific interactors with Mediterranean diet patterns influencing glycemic and inflammatory health.

Disclosure
K.E.Westerman: None. J.B.Meigs: Consultant; Quest Diagnostics. A.Manning: None.

Funding
National Institutes of Health (K01DK133637)
1470-P: Novel Associations of Glycometabolic Traits in Ethnically Diverse Africans
Authors: HANSEN MATTHEW , HARRIS DANIEL , HARRIS ALEXANDRE M. , NYAMBO THOMAS B. , BELAY GURJA , MPOLOKA SUNUNGUKO , BURANT CHARLES , TISHKOFF SARAH A. 
Published: June 2023

Prior studies have identified genetic factors that impact an individual’s risk of developing type 2 diabetes (T2D). However, African ancestry is underrepresented in genetic studies despite the higher prevalence of T2D in African Americans compared to European or Asian Americans. To better understand risk factors for this health disparity, we used a unique dataset of T2D biomarkers (C-peptide and standing glucose) and ~5 million single nucleotide polymorphism genotypes from an ethnically diverse sampling of sub-Saharan Africans (N~1,250) to identify genetic variants associated with these traits. Because the individuals in our dataset practice traditional subsistence patterns and live in rural settings, there is less environmental heterogeneity than observed in urban settings. Between both traits, we uncovered hundreds of novel marginal associations (p&lt;10−5) and three genome-wide significant associations (p&lt;5×10−8), one with C-peptide (rs147703855, in DAAM1) and two with glucose (rs74085215, near KLC1; rs951516, intergenic). The minor alleles for these three associations are rare outside of Africa (&lt;0.1%) but attain frequencies ~5-10% in at least one African ancestry group. Although none of these associations have been previously reported, the genes near the marginal C-peptide associations (&lt;200kbp) are enriched for variants with previously reported T2D associations (GWAS catalogue), as well as chylomicron, VLDL, and triglyceride associations. The genes near our marginal glucose associations were not found to be enriched for previously reported T2D associations (p&gt;0.05), though they were significantly enriched for body size, chylomicron, and triglyceride associations (p&lt;0.006). We are following up this preliminary study with an expanded GWAS using a new proteomics dataset in ~500 subjects, and a metabolomics dataset in ~700 subjects. These data will be used to construct polygenic risk scores for biomarkers of T2D that are more effective in people of recent African descent.

Disclosure
M.Hansen: None. D.Harris: None. A.M.Harris: None. T.B.Nyambo: None. G.Belay: None. S.Mpoloka: None. C.Burant: Research Support; Rhythm Pharmaceuticals, Inc. S.A.Tishkoff: None.

Funding
American Diabetes Association (1-19-VSN-02 to S.A.T.); National Institutes of Health (R35GM134922)
1471-P: Metabolomic Profiling of Type 2 Diabetes Pathway-Partitioned Polygenic Risk Scores Offers Insights into Disease Etiology
Authors: SEVILLA MAGDALENA , LAMIQUIZ-MONEO ITZIAR , SMITH KIRK , CANYELLES MARINA , FLOREZ JOSE C. , MANNING ALISA , CIVEIRA FERNANDO , MERINO JORDI , UDLER MIRIAM 
Published: June 2023

Previous studies have identified type 2 diabetes (T2D) subtypes using clinical phenotypes and/or genetic information. This study aimed to identify molecular signatures associated with genetically based T2D subtypes. We analyzed data from ~100,000 unrelated European UK Biobank participants without T2D and not taking lipid-lowering medications. T2D subtypes were characterized using five polygenic scores denoting three forms of insulin resistance (lipodystrophy, obesity, and impaired lipid/hepatic metabolism) and two subtypes of insulin secretion (beta-cell dysfunction and impaired proinsulin synthesis). Nuclear magnetic resonance profiles of 249 plasma metabolites on the Nightingale platform were tested for association with T2D subtypes using linear regression adjusted for age, sex, batch, and ancestry-derived principal components; P&lt;0.0002 was considered significant. Independent validation was conducted in two independent cohorts, including 720 from the ANTORCHA cohort. In general, the T2D subtypes driven by insulin resistance were characterized by alterations in lipid and lipoproteins, while the impaired insulin secretion subtypes showed aberrant plasma amino acid levels. The lipodystrophy cluster showed the most distinct molecular signature, with higher concentrations of extremely large, very large, and large VLDL particles which were enriched by triglycerides and phospholipids, and lower concentrations of HDL. The beta-cell dysfunction cluster was characterized by higher concentrations of amino acids (alanine, valine, leucine, and tyrosine). These associations were broadly consistent after adjusting for BMI, and the pattern of alterations in lipid metabolites was partially replicated in the ANTORCHA cohort. We identified specific metabolic signatures related to T2D genetic clusters before T2D onset, offering further characterization of the putative underlying pathways.

Disclosure
M.Sevilla: None. I.Lamiquiz-moneo: None. K.Smith: None. M.Canyelles: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. A.Manning: None. F.Civeira: None. J.Merino: None. M.Udler: None.

Funding
American Diabetes Association (9-22-PDFPM-04 to M.S.)
1479-P: Targeted Exome Sequencing for Long-Term Efficacy and Weight Loss of Dulaglutide in Type 2 Diabetes
Authors: AN KIM YE , HYUN SEO JE 
Published: June 2023

Introduction: There are individual differences in glucose lowering effect and weight reduction of dulaglutide, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is expected that genetic variations in the mechanism of action of drugs are involved in treatment response to drugs. This study aims to investigate genetic variants associated with long-term efficacy and weight reduction of dulaglutide using targeted next-generation sequencing.
Methods: We recruited 77 patients those who were treated with dulaglutide at least one year after switching from DPP-4 inhibitors (±basal insulin) due to uncontrolled type 2 diabetes (HbA1c ≥8.0%) at Korean VHS medical center between September 2018 and October 2019, and followed up until March 2021. The responder was defined by ≥1.0% HbA1c reduction at 24 weeks and achievement of HbA1c ≤7.5% at 52 weeks. We designed targeted exome panel based on the mechanism of drug action, and candidate genetic variants included known GLP-1 response related genes (n=10), gastric emptying related genes (n=18), pancreatic insulin secretion related genes (n=25). At the same time, we also performed whole exome sequencing.
Results: During follow-up period of median 2.5±1.3 years, HbA1c was 9.7±1.3% at baseline and reduced to 8.2±1.5% at 6 months, and maintained thereafter up to 4 years. Glycemic response was associated with GNB3, SPARC, and COL4A1 genes. Weight loss (n=13) was more frequently observed in patients with minor G alleles of COL4A1 gene (OR 2.516, 95% CI 1.013, 6.249, p=0.047). Glycemic effectiveness of dulaglutide therapy is associated with genetic variants (OR 2.106, 95% CI 1.358, 3.265, p=0.001) as well as baseline HbA1c (OR 1.682, 95% CI 1.067, 2.650, p=0.025).
Conclusion: The glucose lowering effect of dulaglutide, which exempts some patients from insulin therapy, has been associated with GNB3, SPARC, and COL4A1 variants. Polymorphisms in COL4A1 gene was associated with weight loss, although further studies are needed for validation.

Disclosure
Y.Kim: None. J.Seo: None.

Funding
VHS Medical Center (VHSMC20026)
1480-P: Mitochondrial Haplogroup H Is Protective against Type 2 Diabetes in Arabs from Gulf Region
Authors: DASHTI MOHAMMED H. , ALI NASER , ALSALEH HUSSAIN , NIZAM RASHEEBA , ALMULLA FAHD , THANGAVEL ALPHONSE T. 
Published: June 2023

Background: Mitochondrial dysfunction is implicated in the pathogenesis of type 2 diabetes (T2D) via impaired glucose-stimulated insulin secretion in pancreatic beta cells and decreased oxidative phosphorylation in insulin target tissues. Several global studies have been performed to delineate the genetic associations of mitochondrial DNA (mtDNA) haplogroups and variants with T2D incidence. Maternal haplogroups F, D, M9 and N9a and a rare variant (mtDNA 3243 A&gt;G) and a common variant (mtDNA 16189 T&gt;C) were associated with increased risk of T2D in different populations. It is worth noting that some of these proposed associations were not consistent across populations. Since the Gulf Cooperation Council (GCC) countries are marked by high prevalence of T2D, we aim to study association of mitochondrial haplogroups and variants in Arabs from GCC region.
Methods: We examined mitochondrial haplogroups and variants in 1,112 Kuwaiti and Qatari native individuals using whole exome sequencing data. The cohort was divided into T2D cases (685) and non-T2D controls (427).
Results: The association tests indicated that individuals with haplogroup H have a protective effect against T2D with a suggestive significance [odds ratio (OR) = 0.65; P = 0.022]. The haplogroup H association remained significant even after adjusting for age, sex, and body mass index (BMI) (OR= 0.607; P= 0.021). We also identified mtDNA variants with suggestive significance of association (adjusting for covariates) with T2D.
Conclusion: The study demonstrates that maternal H haplogroup, which we previously identified as protective towards obesity in Kuwaiti Arabs, is a protective haplogroup for T2D in Arabs from GCC. Further, the mtDNA variants delineated as associated with T2D are from genes involved in cell energy production.

Disclosure
M.H.Dashti: None. N.Ali: None. H.Alsaleh: None. R.Nizam: None. F.Almulla: None. A.T.Thangavel: None.
1484-P: CD57+CD8+T Cells Exhibit Distinct Features in T1D Patients with Partial Remission Phase
Authors: LI XIA , ZHONG TING , TANG RONG , LI XINYU , KANG LEI 
Published: June 2023

Partial remission (PR) in type 1 diabetes (T1D) is accompanied by downregulation of the immune response. The CD8+ CD57+ T cells, termed effector memory cells, is expanded in several immune-mediated diseases, but their changes in the PR phase are unclear. Combined with flow cytometry and bioinformatics analysis, we found that CD8+ CD57+ T cells had strong cytotoxic functions and transcriptional heterogeneity, and that the proportion of CD8+ CD57+ T cells increased in new-onset patients, decreased in patients during PR and then repleted again after the end of PR. These findings suggests that CD8+ CD57+ T cells might have potential roles in immune modulation during the PR stage and might serve as a therapeutic target.

Disclosure
X.Li: None. T.Zhong: None. R.Tang: None. X.Li: None. L.Kang: None.