Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.
Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10(-7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes.
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Michael
M
Traurig
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Robert L
RL
Hanson
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Alejandra
A
Marinelarena
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Sayuko
S
Kobes
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Paolo
P
Piaggi
Texas Biomedical Research Institute, San Antonio, TX.
Shelley
S
Cole
South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
Joanne E
JE
Curran
South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
John
J
Blangero
South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
Harald
H
Göring
South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
Satish
S
Kumar
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Robert G
RG
Nelson
MedStar Health Research Institute, Hyattsville, MD Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC.
Barbara V
BV
Howard
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
William C
WC
Knowler
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
Leslie J
LJ
Baier
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ cbogardu@mail.nih.gov.
Clifton
C
Bogardus
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001130:Arizona; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004722:Endoribonucleases / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009658:North Dakota; D009765:Obesity / Q000150:complications / Q000235:genetics*; D009825:Oklahoma; D013023:South Dakota; D015431:Weight Loss / Q000235:genetics; D055815:Young Adult
D027501:Monocarboxylic Acid Transporters; C586426:SLC16A11 protein, human; D004722:Endoribonucleases; C065559:ribonuclease K