Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans.

Abstract

Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genomewide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p ~109 c M from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from p t e r. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include G B E 1 and A C O X 2, which encode enzymes involved in glycogen and fatty acid metabolism, r e s p e c t i v e l y. Diabetes 49:513-516, 2000 I nsulin is a polypeptide hormone that plays a vital role in glucose homeostasis by stimulating the uptake of glucose into the cell. Serum insulin concentrations are correlated with tissue sensitivity to insulin, and elevated insulin levels are associated with insulin resistance, dyslipidemia, obesity, hypertension, and an increased risk of t y p e 2 diabetes and cardiovascular disease. Within populations, the degree of insulin sensitivity varies widely among individuals, and in fact, the range observed in normal individuals can equal that seen in diabetic individuals (1). Moreo v e r, while insulin resistance is a consistent predictor of t y p e 2 diabetes, mild or even severe insulin resistance may often occur in individuals who will never develop diabetes.Although the causes of insulin resistance (and hyperinsulinemia) are not well understood, family and twin studies have consistently shown that genes play a substantial role in determining variation in serum insulin concentrations (2-5). Genes modulating serum insulin levels could operate at several different levels. For example, at the level of the target cells, there are a host of genes that regulate peripheral insulin action, such as those that encode the molecules that mediate insulin signaling and those that catalyze the uptake and metabolism of glucose. Genes influencing insulin sensitivity could also act on tissues extrinsic to the target cell as, for example, on tissues involved in any of the pathways regulating energy homeosta...

Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

“…These data are suggestive that abnormalities in the regulation of SLMAP expression in the db/db mouse may be linked to endothelial dysfunction. A single gene that encodes SLMAP maps to the human chromosome 3p14.2-21 region (40, 41), a region that also has been reported to carry genes linked to Type 2 diabetes-related disorders (26). Whether the SLMAP gene locus is involved in these diabetic patients now needs to be further investigated.…”

Genome-Wide Linkage Analyses of Type 2 Diabetes in Mexican Americans

“…Specifically, Duggirala et al (24) in 1999 reported a multipoint LOD of 2.56 for diabetes near marker GATA128C02 (Marshfield map, 112 cM) in 440 San Antonio Family Diabetes study participants who were examined at baseline and in 2001 reported a multipoint LOD Ն 1.00 for fasting-specific insulin in 310 nondiabetic San Antonio Family Diabetes study participants at the same locus (38). Moreover, the San Antonio Family Heart Study comprised of a similar study population reports a LOD for serum insulin in 391 nondiabetic individuals of 3.07 on chromosome 3p in the region flanked by D3S1600 (86.0 cM, Marshfield map) and D3S1285 (91.0 cM, Marshfield map) (39). Similar to the SAFDGS, the San Antonio Family Heart study is an extended pedigree study of low-income Mexican Americans in San Antonio, Texas.…”

A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study

“…In most studies however, the families and participants were collected through an index patient with Type 2 diabetes, and the study cohorts were known to have a higher risk for developing Type 2 diabetes, such as Pima Indians, Mexican Americans and Australian Aborigines. in unaffected individuals three genome scans carried out from such higher risk populations resulted in several candidate regions on chromosome 3 [4,5], chromosome 4 [4], chromosome 9 [4], chromosome 10 [6], chromosome 13 [6], chromosome 17 [6] and chromosome 22 [4]. However, probably due to the complex nature of the disease, failure of replication of postulated genes and false-positive discovery of new loci remains a major concern.…”