Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes

TY - JOUR

T1 - Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes

AU - Ketterer, Caroline

AU - Müssig, Karsten

AU - Heni, Martin

AU - Dudziak, Katarzyna

AU - Randrianarisoa, Elko

AU - Wagner, Robert

AU - Machicao, Fausto

AU - Stefan, Norbert

AU - Holst, Jens Juul

AU - Fritsche, Andreas

AU - Häring, Hans-Ulrich

AU - Staiger, Harald

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2011/9

Y1 - 2011/9

N2 - The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic β-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r2 ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤.0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P =.0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P =.0097), but not in men (P =.3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P =.0124), whereas in male subjects, no significant differences were found (P =.3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.

AB - The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic β-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r2 ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤.0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P =.0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P =.0097), but not in men (P =.3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P =.0124), whereas in male subjects, no significant differences were found (P =.3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Genetic Variation

KW - Glucose Tolerance Test

KW - Humans

KW - Insulin

KW - Male

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Prediabetic State

KW - Risk

KW - TRPM Cation Channels

U2 - 10.1016/j.metabol.2011.02.002

DO - 10.1016/j.metabol.2011.02.002

M3 - Journal article

C2 - 21489577

SN - 0026-0495

VL - 60

SP - 1325

EP - 1333

JO - Metabolism

JF - Metabolism

IS - 9

ER -