The influence of rare genetic variation in SLC30A8 on diabetes incidence and β-cell function.
OBJECTIVE
The variant rs13266634 in SLC30A8, encoding a β-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair β-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 β-cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases.
Center for Human Genetic Research (L.K.B., R.J.A., A.T., R.R.F., J.B.M., J.C.F.) and Diabetes Research Center (Diabetes Unit) (L.K.B., L.M.D., J.C.F.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Medicine (L.K.B., L.M.D., J.C.F.), Harvard Medical School, and Department of Nutrition (P.W.F.), Harvard School of Public Health, Boston, Massachusetts 02115; Department of Medicine (L.K.B.), NorthShore University HealthSystem, Evanston, Illinois 60201; University of Chicago (L.K.B.), Pritzker School of Medicine, Chicago, Illinois 60637; The Biostatistics Center (K.A.J.), George Washington University, Rockville, Maryland 20852; Program in Medical and Population Genetics (A.T., J.B.M., C.G., J.C.F.), Broad Institute, Cambridge, Massachusetts 02142; Department of Epidemiology (D.D.), Colorado School of Public Health, University of Colorado, Denver, Colorado 80045; Division of Metabolism, Endocrinology, and Nutrition (S.E.K.), VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; Department of Clinical Sciences (P.W.F.), Genetic and Molecular Epidemiology Unit, Lund University, SE-200 41 Malmö, Sweden; Diabetes Epidemiology and Clinical Research Section (R.L.H., W.C.K.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014; Department of Medicine (N.M.M.), Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (A.R.S.), Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201; and Department of Nutrition (E.J.M.-D.), University of North Carolina, Gillings School of Global Public Health, Chapel Hill, North Carolina 27599.
Liana K
LK
Billings
Kathleen A
KA
Jablonski
Rachel J
RJ
Ackerman
Andrew
A
Taylor
Rebecca R
RR
Fanelli
Jarred B
JB
McAteer
Candace
C
Guiducci
Linda M
LM
Delahanty
Dana
D
Dabelea
Steven E
SE
Kahn
Paul W
PW
Franks
Robert L
RL
Hanson
Nisa M
NM
Maruthur
Alan R
AR
Shuldiner
Elizabeth J
EJ
Mayer-Davis
William C
WC
Knowler
Jose C
JC
Florez
D000328:Adult; D000483:Alleles; D027682:Cation Transport Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000075703:Zinc Transporter 8
D027682:Cation Transport Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8