Affiliations: Section on Endocrinology and Metabolism, Department of
Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA
Note: [] Corresponding authors: Steven C. Elbein, M.D., Professor, or
Swapan Kumar Das, PhD, Assistant Professor, Section on Endocrinology and
Metabolism, Department of Internal Medicine, Wake Forest University Health
Sciences, Medical Center Boulevard, WFUBMC, NRC Building, Winston-Salem, NC
27157, USA. Tel.: +1 336 713 6057; Fax: +1 336 713 7255; E-mail:
selbein@wfubmc. edu or [email protected]
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.
