PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.
OBJECTIVE
A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca(2+) sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes.


METHODS
Sequencing of PCLO identified four nonsynonymous variants and a 10-amino acid insertion. These variants, together with 100 additional variants identified by sequencing or chosen from databases, were genotyped for association analysis in the same 895 subjects analyzed in the prior GWA study (300 case subjects with diabetes onset at aged <25 years, 334 nondiabetic control subjects aged >45 years, and 261 discordant siblings of the case or control subjects for within-family analyses), as well as 415 nondiabetic Pima Indians who had been metabolically phenotyped for predictors of diabetes. Selected variants were further genotyped in a population-based sample of 3,501 Pima Indians.


RESULTS
Four variants were modestly associated with early-onset type 2 diabetes in both general and within-family analyses (P = 0.004-0.04, recessive model), where the diabetes risk allele was also nominally associated with a lower insulin-mediated glucose disposal rate (P = 0.009-0.14, recessive model) in nondiabetic Pima Indians. However, their association with diabetes in the population-based sample was weaker (P = 0.02-0.20, recessive model).


CONCLUSIONS
Variation within PCLO may have a modest effect on early-onset type 2 diabetes, possibly as a result of reduced insulin action, but has minimal, if any, impact on population-based risk for type 2 diabetes.
Ma
Lijun
L
Department of Health and HumanServices, Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and KidneyDiseases, National Institutes of Health, Phoenix, Arizona, USA.
Hanson
Robert L
RL
Que
Lorem N
LN
Guo
Yan
Y
Kobes
Sayuko
S
Bogardus
Clifton
C
Baier
Leslie J
LJ
D000328:Adult; D001130:Arizona; D003598:Cytoskeletal Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D003598:Cytoskeletal Proteins; D009479:Neuropeptides; C498630:PCLO protein, human