title: Variation in the gene for muscle-specific AMP deaminase is associated with insulin clearance, a highly heritable trait.
abstract: The rising prevalence of the insulin resistance syndrome in our society necessitates a better understanding of the genetic determinants of all aspects of insulin action and metabolism. We evaluated the heritability of insulin sensitivity and the metabolic clearance rate of insulin (MCRI) as quantified by the euglycemic-hyperinsulinemic clamp in 403 Mexican Americans. We tested the candidate gene AMP deaminase 1 (AMPD1) for association with insulin-related traits because it codes for an enzyme that has the potential to influence multiple aspects of insulin pharmacodynamics. By converting AMP to inosine monophosphate, AMPD1 plays a major role in regulating cellular AMP levels; AMP activates AMP kinase, an enzyme that modulates cellular energy and insulin action. We determined that nine AMPD1 single nucleotide polymorphisms (SNPs) defined two haplotype blocks. Insulin clearance was found to have a higher heritability (h(2) = 0.58) than fasting insulin (h(2) = 0.38) or insulin sensitivity (h(2) = 0.44). The MCRI was associated with AMPD1 SNPs and haplotypes. Insulin clearance is a highly heritable trait, and specific haplotypes within the AMPD1 gene, which encodes a skeletal muscle-specific protein, are associated with variation in insulin clearance. We postulated that the processes of insulin action and insulin clearance in skeletal muscle are highly regulated and that AMPD1 function may play an important role in these phenomena.
authors.affiliation: Medical Genetics Institute, Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. mark.goodarzi@cshs.org <mark.goodarzi@cshs.org>
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Quiñones
authors.forename: Jinrui
authors.initials: J
authors.lastname: Cui
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Tieu
authors.initials: T
authors.lastname: Hang
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.forename: Edward
authors.initials: E
authors.lastname: Holmes
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: Jerrold
authors.initials: J
authors.lastname: Olefsky
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
mesh_terms: D000659:AMP Deaminase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D007328:Insulin; D000659:AMP Deaminase