Analysis of the lamin A/C gene as a candidate for type II diabetes susceptibility in Pima Indians.
OBJECTIVE
Lamin A/C (LMNA) is located within a region on chromosome 1q that has been linked with Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. Rare mutations in exon 8 of LMNA underlie Dunnigan-Type familial partial lipodystrophy, a disease characterized by regional adipocyte degeneration and frequently accompanied by insulin resistance, glucose intolerance, and diabetes. A more common variant in exon 10 (3408C/T) has recently been associated with obesity in non-diabetic aboriginal Canadian subjects. Because obesity is a strongly predisposing factor for Type II diabetes, we hypothesized that the LMNA 3408C/T variant could be associated with diabetes and body mass index in Pima Indians.


METHODS
To determine whether the LMNA 3408C/T variant contributes to Type II diabetes susceptibility, we genotyped the polymorphism in 1,338 Pimas using allelic discrimination technology. The locus was screened for additional variants in 20 diabetic Pima Indians and non-diabetic Pima Indians using denaturing high performance liquid chromatography and dideoxy sequencing.


RESULTS
We found no evidence for association of 3408C/T with diabetes, body mass index, total cholesterol, HDL cholesterol, triglycerides, leptin concentrations, or indices of insulin sensitivity and secretion. Subsequent screening of the remaining LMNA exons and flanking sequences revealed only rare variants in intron 4 and the 3'UTR, showing no frequency differences between diabetic and non-diabetic Pima Indians. We reassessed the linkage with diabetes following adjustment for the LMNA 3408C/T variant; adjustment for the effects of LMNA did not substantially modify the evidence for linkage.


CONCLUSIONS
We conclude that the LMNA 3408C/T variant probably does not play a role in susceptibility to diabetes or obesity in Pima Indians.
Wolford
J K
JK
Phoenix Epidemiology and Research Branch, National Institute of Diabetes and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA.
Hanson
R L
RL
Bogardus
C
C
Prochazka
M
M
D000483:Alleles; D001483:Base Sequence / Q000235:genetics; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics
D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins