Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study.
BACKGROUND
Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS) participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4).


METHODS
SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs) influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses.


RESULTS
Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P < 0.02). In analysis accounting for QTL-specific interaction (P < 0.001), we detected a QTL for weight on chromosome 1 at 242 cM (LOD = 3.7). This chromosome region harbors the adiponectin receptor 1 gene, which has been previously associated with obesity.


CONCLUSIONS
These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.
Franceschini
Nora
N
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. noraf@unc.edu
Almasy
Laura
L
MacCluer
Jean W
JW
Göring
Harald H H
HH
Cole
Shelley A
SA
Diego
Vincent P
VP
Laston
Sandra
S
Howard
Barbara V
BV
Lee
Elisa T
ET
Best
Lyle G
LG
Fabsitz
Richard R
RR
North
Kari E
KE
D000328:Adult; D000368:Aged; D001130:Arizona; D015992:Body Mass Index; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009658:North Dakota; D009765:Obesity / Q000150:complications / Q000235:genetics*; D009825:Oklahoma; D040641:Quantitative Trait Loci; D054419:Receptors, Adiponectin / Q000235:genetics; D013023:South Dakota
C475418:ADIPOR1 protein, human; D054419:Receptors, Adiponectin