Betacellulin variants and type 2 diabetes in the Old Order Amish

Abstract

Betacellulin is a member of the epidermal growth factor (EGF) family and may play a role in islet neogenesis and regeneration. To evaluate whether polymorphisms in this gene are associated with type 2 diabetes (T2DM) and impaired glucose tolerance (IGT), we genotyped 7 previously identified betacellulin variants in Amish subjects with T2DM (n=150), IGT (n=148) and normal glucose tolerance (NGT) (n=361). There were no significant differences in the allele frequencies of the variants among the 3 groups. In an expanded set of 729 nondiabetic Amish subjects, there was no significant association between the betacellulin variants and levels of glucose or insulin either fasting or during a 3 h oral glucose tolerance test, HOMA or insulin secretion index. These results are consistent with previous studies in Caucasian populations and suggest that variants in the betacellulin gene do not play a major role in the development of T2DM in Caucasian populations.

Key words

betacellulin - type 2 diabetes - Old Order Amish - genetics

References

• 1 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1997;  20 1183-1197
• 2 Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees.  Am J Hum Genet. 1998;  62 1198-1211
• 3 Damcott CM, Hoppman N, Ott SH, Reinhart LJ, Wang J, Pollin TI, O'Connell JR, Mitchell BD, Shuldiner AR. Polymorphisms in both promoters of hepatocyte nuclear factor 4-alpha are associated with type 2 diabetes in the Amish.  Diabetes. 2004;  53 3337-3341
• 4 Damcott CM, Pollin TI, Reinhart LJ, Ott SH, Shen H, Silver K, Mitchell BD, Shuldiner AR. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.  Diabetes. 2006;  55 2654-2659
• 5 Elbein SC, Wang X, Karim MA, Chu WS, Silver KD. Analysis of coding variants in the betacellulin gene in type 2 diabetes and insulin secretion in African American subjects.  BMC Med Genet. 2006;  7 62
• 6 Fu M, Damcott CM, Sabra M, Pollin TI, Ott S H, Wang J, Garant MJ, O'Connell JR, Mitchell BD, Shuldiner AR. Polymorphism in the calsequestrin 1 (CASQ1) gene on chromosome 1q21 is associated with type 2 diabetes in the Old Order Amish.  Diabetes. 2004;  53 3292-3299
• 7 Hsueh WC, Mitchell BD, Aburomia R, Pollin T, Sakul H, Gelder EM, Michelsen BK, Wagner MJ, St Jean PL, Knowler WC, Burns DK, Bell CJ, Shuldiner AR. Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.  Diabetes Care. 2000a;  23 595-601
• 8 Hsueh WC, Mitchell BD, Schneider JL, Wagner MJ, Bell CJ, Nanthakumar E, Shuldiner AR. QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish.  Circulation. 2000b;  101 2810-2816
• 9 Hsueh WC, St Jean PL, Mitchell BD, Pollin TI, Knowler WC, Ehm MG, Bell CJ, Sakul H, Wagner MJ, Burns DK, Shuldiner AR. Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24.  Diabetes. 2003;  52 550-557
• 10 Li L, Seno M, Yamada H, Kojima I. Promotion of beta-cell regeneration by betacellulin in ninety percent-pancreatectomized rats.  Endocrinology. 2001;  142 5379-5385
• 11 Li L, Seno M, Yamada H, Kojima I. Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to beta-cells in streptozotocin-treated mice.  Am J Physiol Endocrinol Metab. 2003;  285 E577-E583
• 12 Mashima H, Ohnishi H, Wakabayashi K, Mine T, Miyagawa J, Hanafusa T, Seno M, Yamada H, Kojima I. Betacellulin and activin A coordinately convert amylase- secreting pancreatic AR42J cells into insulin-secreting cells.  J Clin Invest. 1996;  97 1647-1654
• 13 McKusick VA. Medical Genetic Studies of the Amish. Johns Hopkins University Press, Baltimore 1978
• 14 Nakagawa T, Furuta H, Sanke T, Sakagashira S, Shimomura H, Shimajiri Y, Hanabusa T, Nishi M, Sasaki H, Nanjo K. Molecular scanning of the betacellulin gene for mutations in type 2 diabetic patients.  Diabetes Res Clin Pract. 2005;  68 188-192
• 15 Nakano Y, Furuta H, Doi A, Matsuno S, Nakagawa T, Shimomura H, Sakagashira S, Horikawa Y, Nishi M, Sasaki H, Sanke T, Nanjo K. A functional variant in the human betacellulin gene promoter is associated with type 2 diabetes.  Diabetes. 2005;  54 3560-3566
• 16 Pollin TI, Hsueh WC, Steinle NI, Snitker S, Shuldiner AR, Mitchell BD. A genome-wide scan of serum lipid levels in the Old Order Amish.  Atherosclerosis. 2004;  173 89-96
• 17 Pollin TI, Tanner K, O'Connell JR, Ott SH, Damcott CM, Shuldiner AR, McLenithan JC, Mitchell BD. Linkage of plasma adiponectin levels to 3q27 explained by association with variation in the APM1 gene.  Diabetes. 2005;  54 268-274
• 18 Silver K, Tolea M, Wang J, Pollin TI, Yao F, Mitchell BD. The exon 1 Cys7Gly polymorphism within the betacellulin gene is associated with type 2 diabetes in African Americans.  Diabetes. 2005;  54 1179-1184
• 19 Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies.  Nat Genet. 2006;  38 209-213
• 20 Snitker S, Mitchell BD, Shuldiner AR. Physical activity and prevention of type 2 diabetes.  Lancet. 2003;  361 87-88

Correspondence