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. 2001 May;68(5):1149-64.
doi: 10.1086/320100. Epub 2001 Mar 29.

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

R Duggirala  1 , J Blangero, L Almasy, R Arya, T D Dyer, K L Williams, R J Leach, P O'Connell, M P Stern
Affiliations

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

R Duggirala et al. Am J Hum Genet. 2001 May.

Abstract

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., LOD(eq) 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., LOD(eq) 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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Figures

Figure 1
Figure 1
Summary of the multipoint linkage analyses of FSI: peak multipoint LOD score by chromosome.
Figure 2
Figure 2
Plot of LOD scores obtained for measures of insulin (FSI), HOMA %S, and HOMA %β, against map positions on chromosome 6.
Figure 3
Figure 3
Bivariate linkage profiles of various trait pairs, including FSI and other IRS-related phenotypes on chromosome 6
Figure 4
Figure 4
Bivariate linkage profiles of various trait pairs, including HOMA %S and other IRS-related phenotypes on chromosome 6
See this image and copyright information in PMC

References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for IGF2R [MIM 147280], ACAT2 [MIM 100678], and OPRM1 [MIM 600018])

References

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