Polymorphism in the Calsequestrin 1 ( CASQ1 ) Gene on Chromosome 1q21 Is Associated With Type 2 Diabetes in the Old Order Amish
Mao Fu 1 2 ,
Coleen M. Damcott 1 ,
Mona Sabra 1 ,
Toni I. Pollin 1 ,
Sandra H. Ott 1 ,
Jian Wang 1 ,
Michael J. Garant 1 ,
Jeffrey R. O’Connell 1 ,
Braxton D. Mitchell 1 and
Alan R. Shuldiner 1 3
1 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
2 Division of Endocrinology, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
3 Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland
Address correspondence and reprint requests to Alan R. Shuldiner, MD, Division of Endocrinology, Diabetes and Nutrition, University
of Maryland School of Medicine, 660 West Redwood St., Room 494, Baltimore, MD 21201. E-mail: ashuldin{at}medicine.umaryland.edu
Abstract
Calsequestrin (CASQ)1 is involved in intracellular storage and release of calcium, a process that has been shown to mediate
glucose transport in muscle. Its gene, CASQ1 , is encoded on chromosome 1q21, a region that has been linked to type 2 diabetes in the Amish and several other populations.
We screened all 11 exons, exon-intron junctions, and the proximal regulatory region of CASQ1 for mutations. We detected four novel single nucleotide polymorphisms (SNPs) (−1470C→T, −1456delG, −1366insG, and 593C→T).
Ten informative SNPs within CASQ1 were genotyped in Amish subjects with type 2 diabetes ( n = 145), impaired glucose tolerance ( n = 148), and normal glucose tolerance ( n = 358). Rs2275703 and rs617698 in introns 4 and 2 were significantly associated with type 2 diabetes ( P = 0.008 and 0.04, respectively); three other SNPs showed borderline evidence for association to type 2 diabetes ( P = 0.076–0.093). Furthermore, in nondiabetic subjects ( n = 754), both rs2275703 and rs617698 were significantly associated with glucose area under the curve during an oral glucose
tolerance test ( P = 0.035 and 0.013, respectively). Haplotype analysis suggested that no haplotype could explain these associations better
than rs2275703. These findings, coupled with similar findings in Utah Caucasians, suggest that sequence variation in CASQ1 may influence risk of type 2 diabetes.
AFDS, Amish Family Diabetes Study
AUC, area under the curve
CASQ, calsequestrin
HOMA, homeostasis model assessment
HOMA-IR, HOMA of insulin resistance
IGT, impaired glucose tolerance
LD, linkage disequilibrium
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
SNP, single nucleotide polymorphism
Footnotes
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
Accepted September 9, 2004.
Received May 25, 2004.
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Polymorphism in the Calsequestrin 1 (CASQ1) Gene on Chromosome 1q21 Is Associated With Type 2 Diabetes in the Old Order Amish

10.2337/diabetes.53.12.3292