Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes
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Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes. / Ketterer, Caroline; Müssig, Karsten; Heni, Martin; Dudziak, Katarzyna; Randrianarisoa, Elko; Wagner, Robert; Machicao, Fausto; Stefan, Norbert; Holst, Jens Juul; Fritsche, Andreas; Häring, Hans-Ulrich; Staiger, Harald.
I: Metabolism, Bind 60, Nr. 9, 2011, s. 1325-1333.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2011
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 ß-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 ß-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
VL - 60
SP - 1325
EP - 1333
JO - Metabolism
JF - Metabolism
SN - 0026-0495
IS - 9
ER -
ID: 38531521