The influence of rare genetic variation in SLC30A8 on diabetes incidence and β-Cell function

Liana K. Billings, Kathleen A. Jablonski, Rachel J. Ackerman, Andrew Taylor, Rebecca R. Fanelli, Jarred B. McAteer, Candace Guiducci, Linda M. Delahanty, Dana Dabelea, Steven E. Kahn, Paul W. Franks, Robert L. Hanson, Nisa M. Maruthur, Alan R. Shuldiner, Elizabeth J. Mayer-Davis, William C. Knowler, Jose C. Florez

Research output: Contribution to journalArticlepeer-review

Abstract

Context/Objective: The variant rs13266634 in SLC30A8, encoding a-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair -cell function, and test whether zinc intake modifies this risk. Design/Outcome: We sequenced exons in SLC30A8 in 380 Diabetes Prevention Program (DPP) participants and identified 44 novel variants, which were genotyped in 3445 DPP participants and tested for association with diabetes incidence and measures of insulin secretion and processing. We examined individual common variants and used gene burden tests to test 39 rare variants in aggregate. Results: We detected a near-nominal association between a rare-variant genotype risk score and diabetes risk. Five common variants were associated with the oral disposition index. Various methods aggregating rare variants demonstrated associations with changes in oral disposition index andinsulinogenic index during year 1of follow-up.Wedid not find a clear interaction of zinc intake with genotype on diabetes incidence. Conclusions: Individual common and an aggregate of rare genetic variation in SLC30A8 are associated with measures of -cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases.

Original languageEnglish (US)
Pages (from-to)E926-E930
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number5
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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