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Analysis of osteocalcin as a candidate gene for type 2 diabetes (T2D) and intermediate traits in Caucasians and African Americans.

ABSTRACT: Recent studies in mice and human identified osteocalcin (OCN) as a bone-derived hormone that modulates insulin secretion and insulin sensitivity. OCN is synthesized by the bone gamma-carboxyglutamate protein (BGLAP) gene located in the well replicated region of type 2 diabetes (T2D) linkage on chromosome 1q22. We resequenced BGLAP gene in 192 individuals with T2D and performed case-control studies in 766 Caucasian (461 T2D and 305 controls) and 563 African American individuals (371 T2D and 192 controls). Metabolic effects of BGLAP variants were examined in 127 nondiabetic members of Caucasian T2D families and in 498 unrelated nondiabetic African American and Caucasian individuals. BGLAP expression was tested in transformed lymphocytes from 60 Caucasian individuals. We identified 17 single nucleotide polymorphisms (SNPs) in African Americans, but observed only the two known SNPs in Caucasians. No SNP was associated with T2D. Promoter SNP rs1800247 was not associated with metabolic traits including insulin sensitivity (S(I)) or fasting glucose in either population, but nonsynonymous SNP rs34702397 (R94Q) was nominally associated with S(I) (uncorrected p=0.05) and glucose-mediated glucose disposal (S(G); uncorrected p=0.03) in African Americans. No SNP altered measures of insulin secretion or obesity, nor was BGLAP expression associated with rs1800247. Our study was sufficiently powered to exclude BGLAP variants as a major risk factor (OR > 1.5) for T2D in Caucasians, but coding variants in exon 4 may alter glucose homeostasis and diabetes risk in African Americans.

SUBMITTER: Das SK

PROVIDER: S-EPMC3304587 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CIDR: Type 2 Diabetes in African Americans

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Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans

Project description:Background: African Americans (AA) have more pronounced insulin resistance and higher insulin secretion than European Americans (Caucasians or CA) when matched for age, gender, and body mass index (BMI). We hypothesize that physiological differences (including insulin sensitivity [SI]) between CAs and AAs can be explained by co-regulated gene networks in tissues involved in glucose homeostasis. Methods: We performed integrative gene network analyses of transcriptomic data in subcutaneous adipose tissue of 99 CA and 37 AA subjects metabolically characterized as non-diabetic, with a range of SI and BMI values. Results: Transcripts negatively correlated with SI in only the CA or AA subjects were enriched for inflammatory response genes and integrin-signaling genes, respectively. A sub-network (module) with TYROBP as a hub enriched for genes involved in inflammatory response (corrected p= 1.7E-26) was negatively correlated with SI (r= -0.426, p= 4.95E-04) in CA subjects. SI was positively correlated with transcript modules enriched for mitochondrial metabolism in both groups. Several SI-associated co-expressed modules were enriched for genes differentially expressed between groups. Two modules involved in immune response to viral infections and function of adherens junction, are significantly correlated with SI only in CAs. Five modules involved in drug/intracellular transport and oxidoreductase activity, among other activities, are correlated with SI only in AAs. Furthermore, we identified driver genes of these race-specific SI-associated modules. Conclusions: SI-associated transcriptional networks that were deranged predominantly in one ethnic group may explain the distinctive physiological features of glucose homeostasis among AA subjects.

2016-01-22 | GSE65221 | GEO

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