title: Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes.
abstract: Genetic studies suggest a diabetes susceptibility locus on human chromosome 20, near the melanocortin receptor-3 (MC3-R) gene. We examined the MC3-R as a candidate gene for type 2 diabetes in 12 members of a large Maori kindred with multiple affected members. The coding region of the MC3-R gene was sequenced for both diabetic and non-diabetic individuals. Two separate single base pair substitutions were found in the MC3-R coding sequence and these resulted in amino acid changes, Lysine6Threonine and Isoleucine81Valine. Neither of these MC3-R variants tracked with the presence of diabetes. Furthermore, the variant and wild type MC3-R showed similar functional coupling to adenylyl cyclase. A polymorphic marker (D20S32e) close to the human MC3-R (hMC3-R) coding sequence was investigated in a 60-member pedigree for association with diabetes and other metabolic parameters. There was an association between D20S32e genotype and fasting insulin (P=0.0085) and the insulin resistance index, HOMA-R (P=0.0042). An association was also found between genotype and HDL levels during oral glucose tolerance testing (P=0.0037). These associations were independent of BMI, age, gender and diabetes. Our data do not support a role for variations in the coding region of the hMC3-R in the development of type 2 diabetes in this Maori kindred, but suggest that a locus on chromosome 20 q, close to D20S32e, may contribute to both insulin secretion and action in the Maori kindred.
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Jencia
authors.initials: J
authors.lastname: Wong
authors.forename: Don R
authors.initials: DR
authors.lastname: Love
authors.forename: Cam
authors.initials: C
authors.lastname: Kyle
authors.forename: Andre
authors.initials: A
authors.lastname: Daniels
authors.forename: Marie
authors.initials: M
authors.lastname: White
authors.forename: Alistair W
authors.initials: AW
authors.lastname: Stewart
authors.forename: Audrey H
authors.initials: AH
authors.lastname: Schnell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.forename: Ian M
authors.initials: IM
authors.lastname: Holdaway
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Mountjoy
mesh_terms: D017668:Age of Onset; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D015992:Body Mass Index; D002460:Cell Line; D002890:Chromosomes, Human, Pair 20; D003001:Cloning, Molecular; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D008875:Middle Aged; D009520:New Zealand; D009765:Obesity; D010375:Pedigree; D016133:Polymerase Chain Reaction; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000235:genetics*; D014162:Transfection; D044465:White People
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin