Molecular Analysis of KCNJ10 on 1q as a Candidate Gene for Type 2 Diabetes in Pima Indians

Objective: Type 2 diabetes (T2D) is a leading cause of end stage kidney disease (ESKD) worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease (DKD) in youth-onset than adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth-onset was associated with greater early tissue injury. Methods: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing and participants were stratified as youth-onset (<25 years) or adult-onset (≥25 years). Associations between clinical and morphometric parameters and age of onset were tested using linear models. Results: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1±9.9 vs. 51.4±10.2 years, p<0.0001), but their diabetes duration was similar (19.3±8.1 vs. 17.0±7.8 years, p=0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile, 17-470] vs. 27 [13-73] mg/g, p=0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552±128 nm vs. 490±114nm, p=0.002) and mesangial fractional volume (0.31±0.10 vs. 0.27±0.08, p=0.001) than adult-onset participants. Percentage glomerular sclerosis, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age of diabetes onset as a continuous variable. Conclusion: Younger age of T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

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Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA

Annals of Human Genetics ◽

10.1111/ahg.12252 ◽

2018 ◽

Vol 82 (5) ◽

pp. 287-299 ◽

Cited By ~ 3

Author(s):

Wen-Chi Hsueh ◽

Peter H Bennett ◽

Julian Esparza-Romero ◽

Rene Urquidez-Romero ◽

Mauro E Valencia ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Variants ◽

Pima Indians ◽

Diabetes And Obesity ◽

Allelic Differentiation

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Diabetic Retinopathy, Promoter (4G/5G) Polymorphism of PAI-1 Gene, and PAI-1 Activity in Pima Indians With Type 2 Diabetes

Diabetes Care ◽

10.2337/diacare.20.8.1304 ◽

1997 ◽

Vol 20 (8) ◽

pp. 1304-1309 ◽

Cited By ~ 41

Author(s):

D. K. Nagi ◽

L. J. McCormack ◽

V. Mohamed-Ali ◽

J. S. Yudkin ◽

W. C. Knowler ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Pima Indians ◽

Pai 1

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An Integrative Phenotype–Genotype Approach Using Phenotypic Characteristics from the UAE National Diabetes Study Identifies HSD17B12 as a Candidate Gene for Obesity and Type 2 Diabetes

Genes ◽

10.3390/genes11040461 ◽

2020 ◽

Vol 11 (4) ◽

pp. 461 ◽

Cited By ~ 1

Author(s):

Mahmood Y. Hachim ◽

Hayat Aljaibeji ◽

Rifat A. Hamoudi ◽

Ibrahim Y. Hachim ◽

Noha M. Elemam ◽

...

Keyword(s):

Type 2 Diabetes ◽

Candidate Gene ◽

United Arab Emirates ◽

Cell Function ◽

Association Studies ◽

Diabetic Patients ◽

Genome Wide Association Studies ◽

Phenotypic Characteristics ◽

Obstructive Sleep

The United Arab Emirates National Diabetes and Lifestyle Study (UAEDIAB) has identified obesity, hypertension, obstructive sleep apnea, and dyslipidemia as common phenotypic characteristics correlated with diabetes mellitus status. As these phenotypes are usually linked with genetic variants, we hypothesized that these phenotypes share single nucleotide polymorphism (SNP)-clusters that can be used to identify causal genes for diabetes. We explored the National Human Genome Research Institute-European Bioinformatics Institute Catalog of Published Genome-Wide Association Studies (NHGRI-EBI GWAS) to list SNPs with documented association with the UAEDIAB-phenotypes as well as diabetes. The shared chromosomal regions affected by SNPs were identified, intersected, and searched for Enriched Ontology Clustering. The potential SNP-clusters were validated using targeted DNA next-generation sequencing (NGS) in two Emirati diabetic patients. RNA sequencing from human pancreatic islets was used to study the expression of identified genes in diabetic and non-diabetic donors. Eight chromosomal regions containing 46 SNPs were identified in at least four out of the five UAEDIAB-phenotypes. A list of 34 genes was shown to be affected by those SNPs. Targeted NGS from two Emirati patients confirmed that the identified genes have similar SNP-clusters. ASAH1, LRP4, FES, and HSD17B12 genes showed the highest SNPs rate among the identified genes. RNA-seq analysis revealed high expression levels of HSD17B12 in human islets and to be upregulated in type 2 diabetes (T2D) donors. Our integrative phenotype-genotype approach is a novel, simple, and powerful tool to identify clinically relevant potential biomarkers in diabetes. HSD17B12 is a novel candidate gene for pancreatic β-cell function.

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