Variants in ACAD10 are associated with type 2 diabetes, insulin resistance and lipid oxidation in Pima Indians.
OBJECTIVE
A prior genome-wide association study in Pima Indians identified a variant within the ACAD10 gene that is associated with early-onset type 2 diabetes. Acylcoenzyme A dehydrogenase 10 (ACAD10) catalyses mitochondrial fatty acid beta-oxidation, which plays a pivotal role in developing insulin resistance and type 2 diabetes. Therefore, ACAD10 was analysed as a positional and biological candidate for type 2 diabetes.


METHODS
Twenty-three SNPs were genotyped in 1,500 Pima Indians to determine the linkage disequilibrium pattern across ACAD10. Association with type 2 diabetes was determined by genotyping four tag single nucleotide polymorphisms (SNPs) in a population-based sample of 3,501 full-heritage Pima Indians; two associated SNPs were further genotyped in a second population-based sample of 3,723 American Indians. Associations with quantitative traits were assessed in 415 non-diabetic full heritage Pima individuals who had been metabolically phenotyped.


RESULTS
SNPs rs601663 and rs659964 were associated with type 2 diabetes in the full-heritage Pima Indian sample (p=0.04 and 0.0006, respectively), and rs659964 was further associated with type 2 diabetes in the second American Indian sample (p=0.04). Combination of these two samples provided the strongest evidence for association (p=0.009 and 0.00007, for rs601663 and rs659964, respectively). Quantitative trait analyses identified nominal associations with both lower lipid oxidation rate and larger subcutaneous abdominal adipocyte size, which is consistent with the known physiology of ACAD10, and also identified associations with increased insulin resistance.


CONCLUSIONS
We propose that ACAD10 variation may increase type 2 diabetes susceptibility by impairing insulin sensitivity via abnormal lipid oxidation.
Bian
L
L
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 N. 5th Street, Suite 210, Phoenix, AZ 85004, USA.
Hanson
R L
RL
Muller
Y L
YL
Ma
L
L
Kobes
S
S
Knowler
W C
WC
Bogardus
C
C
Baier
L J
LJ
D042964:Acyl-CoA Dehydrogenase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
C499845:ACAD10 protein, human; D042964:Acyl-CoA Dehydrogenase
Diabetes. 2005 Jan;54(1):284-9
15616040
Nat Genet. 2008 May;40(5):638-45
18372903
Science. 2002 Jun 21;296(5576):2225-9
12029063
J Clin Invest. 2000 Jul;106(2):171-6
10903330
Diabetologia. 2000 Dec;43(12):1498-506
11151758
N Engl J Med. 1993 Dec 30;329(27):1988-92
8247074
Am J Epidemiol. 1978 Dec;108(6):497-505
736028
Am J Physiol. 1986 Sep;251(3 Pt 1):E306-10
3529983
Am J Hum Genet. 2007 Jun;80(6):1014-23
17557415
Diabetes. 2007 Dec;56(12):3045-52
17846125