The Influence of Rare Genetic Variation in SLC30A8 on Diabetes Incidence and beta-Cell Function

Context/Objective: The variant rs13266634 in SLC30A8, encoding a beta-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair beta-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 and insulinogenic index during year 1 of follow-up. We did 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 beta-cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases.

Jablonski, Kathleen A. (author)
Ackerman, Rachel J. (author)
Taylor, Andrew (author)
Fanelli, Rebecca R. (author)
McAteer, Jarred B. (author)
Guiducci, Candace (author)
Delahanty, Linda M. (author)
Dabelea, Dana (author)
Kahn, Steven E. (author)
Franks, PaulLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups(Swepub:lu)med-plf (author)
Hanson, Robert L. (author)
Maruthur, Nisa M. (author)
Shuldiner, Alan R. (author)
Mayer-Davis, Elizabeth J. (author)
Knowler, William C. (author)
Florez, Jose C. (author)
Genetisk och molekylär epidemiologiForskargrupper vid Lunds universitet (creator_code:org_t)

In:Journal of Clinical Endocrinology and Metabolism: The Endocrine Society99:5, s. 926-9301945-71970021-972X

By the author/editor: Billings, Liana ...; Jablonski, Kathl ...; Ackerman, Rachel ...; Taylor, Andrew; Fanelli, Rebecca ...; McAteer, Jarred ...; show more...; Guiducci, Candac ...; Delahanty, Linda ...; Dabelea, Dana; Kahn, Steven E.; Franks, Paul; Hanson, Robert L ...; Maruthur, Nisa M ...; Shuldiner, Alan ...; Mayer-Davis, Eli ...; Knowler, William ...; Florez, Jose C.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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