Molecular Genetics of Type 2 Diabetes in New Zealand Polynesians

Abstract

The risk of developing type 2 diabetes is four fold higher in New Zealand(NZ) Polynesians compared to Caucasians. Hence diabetes is more prevalent in Maori (16.5% of the general population) and Pacific Island people (10.1%) compared to NZ Caucasians (9.3%). It is generally accepted that type 2 diabetes has major genetic determinants and heterozygous mutations in a number of genes have previously been identified in some subsets of type 2 diabetes and certain ethnic groups. The high prevalence of diabetes in NZ Polynesians, when compared with NZ Caucasians, after controlling for age, income and body mass index (BMI), suggest that genes may be important in this population. Therefore, the prevalence of allelic variations in the genes encoding amylin and insulin promoter factor-1 (IPF-1), and exon 2 of the hepatocyte nuclear factor-1α (HNF-1α) gene in NZ Polynesians with type 2 diabetes was determined. These genes are known to produce type 2 diabetes in other populations. The genes investigated were screened for mutations by PCR amplification and direct sequencing of promoter regions, exons and adjacent intronic sequences from genomic DNA. DNA was obtained from 146 NZ Polynesians (131 Maori and 15 Pacific Island) with type 2 diabetes and 387 NZ Polynesian non-diabetic control subjects (258 Maori and 129 Pacific Island). Sequences were compared to previously published sequences in the National Centre for Biotechnology Information database. Allelic variations in IPF-1 and exon 2 of the HNF-1α gene were not associated with type 2 diabetes in NZ Polynesians. However, in the amylin gene, two new and one previously described allele was identified in the Maori population including: two alleles in the promoter region (-132G>A and -215T>G), and a missense mutation in exon 3 (QlOR). The -215T>G allele was observed in 5.4% and l% of type 2 diabetic and non-diabetic Maori respectively, and predisposed the carrier to diabetes with a relative risk of 7.23. The -215T>G allele was inherited with a previously described amylin promoter polymorphism(-230A>C) in 3% of Maori with type 2 diabetes, which suggests linkage equilibrium exists between these two alleles. Both Q10R and -132G>A were observed in 0.76% of type 2 diabetic patients and were absent in non-diabetic subjects. Together these allelic variations may account for approximately 7% of type 2 diabetes in Maori. These results suggest that the amylin gene maybe an important candidate marker gene for type 2 diabetes in Maori.