Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study

Pipal, Kanchan V.; Mamtani, Manju; Patel, Ashwini A.; Jaiswal, Sujeet G.; Jaisinghani, Manisha T.; Kulkarni, Hemant

doi:10.3390/genes13081298

Cited by 7 publications

(3 citation statements)

References 54 publications

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“…This study utilized nationwide data, including a large number of participants (about 60,000). Several studies have previously suggested that some genes were genetically associated with metabolic disease [ 32 , 33 ]. On the other hand, we found gene-related SNPs that are more vulnerable to MI, especially in the group with NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants Linked to Myocardial Infarction in Individuals with Non-Alcoholic Fatty Liver Disease and Their Potential Interaction with Dietary Patterns

Lee,

Choi,

Hong

et al. 2024

Nutrients

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In recent studies, non-alcoholic fatty liver disease (NAFLD) has been associated with a high risk of ischemic heart disease. This study aimed to investigate a genetic variant within a specific gene associated with myocardial infarction (MI) among patients with NAFLD. We included 57,205 participants from a Korean genome and epidemiology study. The baseline population consisted of 45,400 individuals, with 11,805 identified as patients with NAFLD. Genome-wide association studies were conducted for three groups: the entire sample, the healthy population, and patients with NAFLD. We defined the p-value < 1 × 10−5 as the nominal significance and the p-value < 5 × 10−2 as statistically significant for the gene-by-nutrient interaction. Among the significant single-nucleotide polymorphisms (SNPs), the lead SNP of each locus was further analyzed. In this cross-sectional study, a total of 1529 participants (2.8%) had experienced MI. Multivariable logistic regression was performed to evaluate the association of 102 SNPs across nine loci. Nine SNPs (rs11891202, rs2278549, rs13146480, rs17293047, rs184257317, rs183081683, rs1887427, rs146939423, and rs76662689) demonstrated an association with MI in the group with NAFLD Notably, the MI-associated SNP, rs134146480, located within the SORCS2 gene, known for its role in secreting insulin in islet cells, showed the most significant association with MI (p-value = 2.55 × 10−7). Our study identifies candidate genetic polymorphisms associated with NAFLD-related MI. These findings may serve as valuable indicators for estimating MI risk and for conducting future investigations into the underlying mechanisms of NAFLD-related MI.

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Section: Discussionmentioning

confidence: 99%

Genetic Variants Linked to Myocardial Infarction in Individuals with Non-Alcoholic Fatty Liver Disease and Their Potential Interaction with Dietary Patterns

Lee,

Choi,

Hong

et al. 2024

Nutrients

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“…ZNF385 is one of the top expressed genes that defines β-cells in snRNAseq, as we have previously reported (17). Importantly, Gene-Wide Association Studies have strongly associated ZNF385D gene variants with T2D onset (70,71) and forced expression of ZNF385D together with retinoic acid receptor β ( RARB ) and Growth Arrest Specific 7 ( GAS7 ) genes in non-diabetic human islets leads to the appearance of a T2D-β-like phenotype in these islets (72). Interestingly, ZNF385D expression occurs mostly in the snRNA-seq dataset (pre-mRNA).…”

Section: Discussionmentioning

confidence: 99%

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Kang,

Lee,

Varela

et al. 2023

Preprint

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Prior studies have shown that pancreatic α-cells can transdifferentiate into β-cells, and that β-cells de-differentiate and are prone to acquire an α-cell phenotype in type 2 diabetes (T2D). However, the specific human α-cell and β-cell subtypes that are involved in α-to-β-cell and β-to-α-cell transitions are unknown. Here, we have integrated single cell RNA sequencing (scRNA-seq) and single nucleus RNA-seq (snRNA-seq) of isolated human islets and human islet grafts and provide additional insight into α-β cell fate switching. Using this approach, we make seven novel observations. 1) There are five differentGCG-expressing human α-cell subclusters [α1, α2, α-β-transition 1 (AB-Tr1), α-β-transition 2 (AB-Tr2), and α-β (AB) cluster] with different transcriptome profiles in human islets from non-diabetic donors. 2) The AB subcluster displays multihormonal gene expression, inferred mostly from snRNA-seq data suggesting identification by pre-mRNA expression. 3) The α1, α2, AB-Tr1, and AB-Tr2 subclusters are enriched in genes specific for α-cell function while AB cells are enriched in genes related to pancreatic progenitor and β-cell pathways; 4) Trajectory inference analysis of extracted α- and β-cell clusters and RNA velocity/PAGA analysis suggests a bifurcate transition potential for AB towards both α- and β-cells. 5) Gene commonality analysis identifiesZNF385D, TRPM3, CASR, MEG3andHDAC9as signature for trajectories moving towards β-cells andSMOC1, PLCE1, PAPPA2, ZNF331, ALDH1A1, SLC30A8, BTG2, TM4SF4, NR4A1andPSCK2as signature for trajectories moving towards α-cells. 6) Remarkably, in contrast to the eventsin vitro, the AB subcluster is not identifiedin vivoin human islet grafts and trajectory inference analysis suggests only unidirectional transition from α-to-β-cellsin vivo. 7) Analysis of scRNA-seq datasets from adult human T2D donor islets reveals a clear unidirectional transition from β-to-α-cells compatible with dedifferentiation or conversion into α-cells. Collectively, these studies show that snRNA-seq and scRNA-seq can be leveraged to identify transitions in the transcriptional status among human islet endocrine cell subpopulationsin vitro,in vivo, in non-diabetes and in T2D. They reveal the potential gene signatures for common trajectories involved in interconversion between α- and β-cells and highlight the utility and power of studying single nuclear transcriptomes of human isletsin vivo. Most importantly, they illustrate the importance of studying human islets in their naturalin vivosetting.

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“…The TTN gene in the skeletal muscle and has been associated to cardiac serum proteins and fractal structure of the heart, as well as T2DM and nephron-related variables, such glomerular filtration rate (65)(66)(67). While gene PI16, DPY6, FRMD4A and CROCC have not been reported to be associated with nephropathy, they have been identified in T2DM (53,68) and obesity-related traits (69,70). PPP1R3A gene is associated with T2DM and plays a crucial role in glycogen synthesis in the tubules of the kidney, leading to diabetic nephropathy.…”

Section: Nephropathy Complicationsmentioning

confidence: 99%

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

et al. 2023

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BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina’s Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina’s Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

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Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study

Cited by 7 publications

References 54 publications

Genetic Variants Linked to Myocardial Infarction in Individuals with Non-Alcoholic Fatty Liver Disease and Their Potential Interaction with Dietary Patterns

Genetic Variants Linked to Myocardial Infarction in Individuals with Non-Alcoholic Fatty Liver Disease and Their Potential Interaction with Dietary Patterns

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

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