TY - JOUR
T1 - A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans
AU - Duggirala, Ravindranath
AU - Blangero, John
AU - Almasy, Laura
AU - Arya, Rector
AU - Dyer, Thomas D.
AU - Williams, Kenneth L.
AU - Leach, Robin J.
AU - O’Connell, Peter
AU - Stern, Michael P.
N1 - Funding Information:
This research was supported by grants from the National Institutes of Health (R01 DK42273, R01 DK47482, R01 DK53889, and MH59490). We are grateful to Professor C. N. Hales of the University of Cambridge, who kindly measured the specific insulin levels used for this study. R.A. was supported by the ADA Mentor-Based Postdoctoral Fellowship Program. We thank Drs. Anthony G. Comuzzie and Jeff T. Williams for helpful suggestions. We also thank Dr. Mary Pat Moyer and Ms. Florence Wall for establishing some of the lymphoblastoid cell lines. We wish to acknowledge Edgardo Benavides, Stefenie Fleming, Rajeswari Cheruvu, Michelle Zavala, and Bonnie Reus for excellent technical support. We warmly thank the families from SAFADS for their support and participation.
PY - 2001
Y1 - 2001
N2 - Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P < .0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P < .0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LODeq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LODeq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.
AB - Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P < .0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P < .0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LODeq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LODeq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.
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U2 - 10.1086/320100
DO - 10.1086/320100
M3 - Article
C2 - 11283790
AN - SCOPUS:0035016103
SN - 0002-9297
VL - 68
SP - 1149
EP - 1164
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
M1 - 61224
ER -