Lack of Association between SLC30A8 Variants and Type 2 Diabetes in Mexican American Families.

Hemant Kulkarni,Michael C Mahaney,Manju Mamtani,Joanne E Curran,John Blangero,Juan Manuel Peralta,Laura Almasy,Ravindranath Duggirala,Thomas D Dyer,Sarah Williams-Blangero,Harald Goring,Vincent Diego

doi:10.1155/2016/6463214

Abstract

SLC30A8 encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association of SLC30A8 variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) around SLC30A8 for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of the SLC30A8 locus tested the association with eight T2D-related traits at four levels: (i) each SNP using measured genotype approach (MGA); (ii) interaction of SNPs with age and sex; (iii) combinations of SNPs using Bayesian Quantitative Trait Nucleotide (BQTN) analyses; and (iv) entire gene locus using the gene burden test. Only one SNP (rs7817754) was significantly associated with incident T2D but a summary statistic based on all T2D-related traits identified 11 novel SNPs. Three SNPs and one SNP were weakly but interactively associated with age and sex, respectively. BQTN analyses could not demonstrate any informative combination of SNPs over MGA. Lastly, gene burden test results showed that at best the SLC30A8 locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of the SLC30A8 SNPs with T2D in Mexican American families.

Highlights

Genome-wide association studies in humans and knockout studies in mice have increasingly pointed towards an important role of the zinc transporter 8 (ZnT8) zinc transporter in pathogenesis of type 2 diabetes (T2D) [1,2,3,4,5,6]
We investigated if the association of single nucleotide polymorphisms (SNPs) with T2D-related traits was interactively altered by age and sex
The current enthusiasm in the putative role of SLC30A8 in the pathogenesis of T2D is driven by biological plausibility as well as association results from large genetic epidemiologic studies in humans

Summary

Introduction

Genome-wide association studies in humans and knockout studies in mice have increasingly pointed towards an important role of the ZnT8 zinc transporter in pathogenesis of type 2 diabetes (T2D) [1,2,3,4,5,6]. A critical step in the release of insulin from β cells in the pancreas is proper packaging of proinsulin into the secretory granules [8]. This process is electrochemically facilitated and requires the presence of Zn2+ and Ca2+ ions which form complexes with hexamers of proinsulin in the secretory granules [9,10,11]. The Zn2+ ions required for this process are transported across electrical gradient by the zinc transporter 8 (ZnT8) protein [12] This transporter is abundant in β cells but has been observed in α cells that orchestrate the release of glucagon [13]. The biological and implied clinical underpinnings place SLC30A8 at a strategic position in the continued quest for identifying key drug targets to treat T2D

Methods

Results

Conclusion