Genome-wide scan for CAG/CTG repeat expansions in Pimas with early onset of type 2 diabetes mellitus.
The expansion of polymorphic CAG/CTG repeats in specific genes causes several neurodegenerative disorders and in many instances the length of the disease-causing repeat correlates with the onset age and/or severity of symptoms. Type 2 diabetes mellitus has features in common with diseases resulting from trinucleotide repeat expansion, including a variable age of disease onset and penetrance. We have investigated whether CAG/CTG repeat expansion contributes to the genetic etiology of type 2 diabetes in the Pima Indians, a population with the highest reported prevalence of this disease. Using the Repeat Expansion Detection (RED) method, we determined the size range in nondiabetic Pimas to be between (CAG)20 and (CAG)130 (mean repeat length = 195 bp), which is significantly larger than the mean size reported in Caucasians (150 bp). We compared the distribution of CAG/CTG repeat lengths among 40 Pimas with an early onset of type 2 diabetes (<22 years) and 38 nondiabetic subjects (>55 years). A 240-bp CAG/CTG RED product was found more frequently in early onset diabetics relative to nondiabetic controls (26% vs 11%), whereas a 210-bp band was more prominent in unaffected subjects (29% vs 13%); however, these differences were not statistically significant. In one Pima kindred, we also identified large RED products (>/=360 bp) that displayed intergenerational instability among family members. However, these expansions were not associated with diabetes or any other clinical abnormalities in the carriers. We conclude that this unstable CAG/CTG repeat may represent a novel locus, consisting of large, but apparently nonpathogenic, unstable sequences.
Wolford
J K
JK
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, 85016, USA.jwolford@exchange.nih.gov
Bogardus
C
C
Prochazka
M
M
D017668:Age of Onset; D000483:Alleles; D001130:Arizona / Q000453:epidemiology; D004247:DNA / Q000032:analysis / Q000235:genetics; D003627:Data Interpretation, Statistical; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D005820:Genetic Testing; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*