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 (SI) or fasting glucose in either population, but nonsynonymous SNP rs34702397 (R94Q) was nominally associated with SI (uncorrected p = 0.05) and glucose-mediated glucose disposal (SG; 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.

The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

“…Higher levels of osteocalcin were also associated with a lower odds ratio of developing metabolic syndrome in black and in white nonHispanic individuals [29,38]. A case-control study actually identified coding variants in the fourth exon of human OCN that appeared to correlate with type 2 diabetes in AfricanAmerican patients [39]. However, this finding should be interpreted cautiously as recent genome-wide association studies of large populations, including one specifically performed on an African-American cohort, did not report an association between variants in the human OCN gene and fasting blood glucose or other traits of diabetes [40,41].…”

Allelic expression imbalance screening of genes in chromosome 1q21–24 region to identify functional variants for Type 2 diabetes susceptibility

“…We also used RNA isolated from subcutaneous adipose and skeletal muscle tissue of 168 metabolically characterized subjects (31). Genomic DNA samples from 611 metabolically characterized nondiabetic CA and AA subjects (5) and 718 subjects from 67 CA T2D pedigrees (4,10) were used for sequencing and genotyping studies. Sample characteristics were published elsewhere (4,5,10,31).…”

“…Genomic DNA samples from 611 metabolically characterized nondiabetic CA and AA subjects (5) and 718 subjects from 67 CA T2D pedigrees (4,10) were used for sequencing and genotyping studies. Sample characteristics were published elsewhere (4,5,10,31). All study participants provided written, informed consent under protocols approved by the University of Arkansas for Medical Sciences.…”

“…We further selected trait-associated cSNPs and significant rSNPs to genotype in 611 CA and AA subjects to identify the role of these SNPs in glucose homeostasis (5). Subjects in this cohort was evaluated by insulin modified frequently sampled intravenous glucose tolerance test (FSIVGT) and minimal model analysis to measure insulin sensitivity index (S I) and beta-cell function (acute insulin response to glucose, AIRG) (1).…”

Osteocalcin and the Regulation of Glucose Metabolism

“…Das et al reported an association of variants in BGLAP (Bone γ-carboxy Glutamate Protein gene which synthesizes osteocalcin in humans) with diabetes in African-Americans [45] but that was not replicated in larger well-powered Genome-Wide Association Studies (GWAS) [46]. Most of these studies are observational and cross-sectional in nature and can therefore only show association not causality.…”