Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels.
Insulin-degrading enzyme (IDE) plays a principal role in the proteolysis of several peptides in addition to insulin and is encoded by IDE, which resides in a region of chromosome 10q that is linked to type 2 diabetes. Two recent studies presented genetic association data on IDE and type 2 diabetes (one positive and the other negative), but neither explored the fundamental question of whether polymorphism in IDE has a measurable influence on insulin levels in human populations. To address this possibility, 14 single nucleotide polymorphisms (SNPs) from a linkage disequilibrium block encompassing IDE have been genotyped in a sample of 321 impaired glucose tolerant and 403 nondiabetic control subjects. Analyses based on haplotypic genotypes (diplotypes), constructed with SNPs that differentiate common extant haplotypes extending across IDE, provided compelling evidence of association with fasting insulin levels (P = 0.0009), 2-h insulin levels (P = 0.0027), homeostasis model assessment of insulin resistance (P = 0.0001), and BMI (P = 0.0067), with effects exclusively evident in men. The strongest evidence for an effect of a single marker was obtained for rs2251101 (located near the 3' untranslated region of IDE) on 2-h insulin levels (P = 0.000023). Diplotype analyses, however, suggest the presence of multiple interacting trait-modifying sequences in the region. Results indicate that polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits, but questions of sex specificity and allelic heterogeneity will need to be taken into consideration as the molecular basis of the observed phenotypic effects unfolds.
Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Hospital, Stockholm, Sweden.
Harvest F
HF
Gu
Suad
S
Efendic
Sofia
S
Nordman
Claes-Göran
CG
Ostenson
Kerstin
K
Brismar
Anthony J
AJ
Brookes
Jonathan A
JA
Prince
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics; D007339:Insulysin / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
D020413:3' Untranslated Regions; D017931:DNA Primers; D005819:Genetic Markers; D007328:Insulin; D007339:Insulysin