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 resequencedBGLAPgene 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 ofBGLAPvariants were examined in 127 nondiabetic members of Caucasian T2D families and in 498 unrelated nondiabetic African American and Caucasian individuals.BGLAPexpression 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(uncorrectedp= 0.05) and glucose-mediated glucose disposal (SG; uncorrectedp= 0.03) in African Americans. No SNP altered measures of insulin secretion or obesity, nor wasBGLAPexpression associated with rs1800247. Our study was sufficiently powered to excludeBGLAPvariants 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.
Highlights
Type 2 Diabetes (T2D) is one of the complex metabolic diseases for which convincing evidence, including twin and family studies, supports the role of genetic susceptibility loci1
The putative promoter single nucleotide polymorphisms (SNPs) rs1800247 was observed in both cohorts, whereas the nonsynonymous SNP rs34702397 (R94Q) was observed only in African Americans and synonymous SNP rs35330985 only in Caucasians
We tested rs1800247 in both populations, and coding SNPs rs34702397 (R94Q) and A92A in African American individuals
Summary
Type 2 Diabetes (T2D) is one of the complex metabolic diseases for which convincing evidence, including twin and family studies, supports the role of genetic susceptibility loci. In last two years over 12 published genome wide association (GWA) scans for T2D identified at least 19 novel common variants that increase the susceptibility to T2D [14,22,23,25]. Recent studies in mice identified osteocalcin (OCN) as a bone-derived hormone that regulated glucose metabolism by modulating insulin secretion and insulin sensitivity [8,13]. OCN stimulated insulin gene expression in pancreatic β-cells and adiponectin expression from adipocytes. Circulating levels of both total and the non-carboxylated active form of OCN were correlated with insulin sensitivity and insulin secretion in hu-
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