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OBJECTIVE--We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS--DNA from 124 type 2 diabetic case subjects and [...]

Transcription factor 7-like 2 (TCF7L2) regulates genes involved in cell proliferation and differentiation. The TCF7L2 gene is located on chromosome 10q25 in a region of replicated linkage to type 2 diabetes. Recently, a micro-satellite marker in intron 3 (DG10S478) and five correlated single nucleotide polymorphisms (SNPs) were identified in Icelandic individuals that showed strong association with type 2 diabetes, which was replicated in Danish and European-American cohorts. We genotyped four of the SNPs (rs7901695, rs7903146, rs11196205, and rs12255372) in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT; n = 139), and normal glucose tolerance (NGT; n = 342). We compared genotype frequencies in subjects with type 2 diabetes with those with NGT and found marginal association for rs7901695 (P = 0.05; odds ratio [OR] 1.51); comparison between NGT control subjects and the combined type 2 diabetes/IGT case group showed strong association with rs7901695 and rs7903146 (P = 0.008-0.01; OR 1.53-1.57) and marginal association with rs11196205 and rs12255372 (P = 0.07 and P = 0.04, respectively). In an expanded set of 698 Amish subjects without diabetes, we found no association with insulin and glucose levels during a 3-h oral glucose tolerance test. We also genotyped these SNPs in nondiabetic, non-Amish subjects (n = 48), in whom intravenous glucose tolerance tests were performed, and found an association between rs7901695 and rs7903146 and insulin sensitivity (P = 0.003 and P = 0.005, respectively) and disposition index (P = 0.04 and P = 0.007, respectively). These data provide replicating evidence that variants in TCF7L2 increase the risk for type 2 diabetes and novel evidence that the variants likely influence both insulin secretion and insulin sensitivity., The transcription factor 7-like 2 (TCFTL2) gene is a member of the T-cell factor (TCF)/lymphoid-enhancing factor family of high mobility group box-containing transcription factors involved in the Wnt signaling pathway. [...]

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah Subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a moor contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits. Diabetes 55:2541-2548, 2006, Positional cloning within regions previously highlighted by genome-wide linkage analysis represents one of the dominant strategies for identification of sequence variants influencing individual risk of type 2 diabetes. A region [...]

Adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) are newly identified receptors for adiponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties. We screened for polymorphisms by performing sequence analysis on all eight exons, splice junctions, and ~2 kb of the 5' flanking regions of each receptor. We detected 5 single nucleotide polymorphisms (SNPs) in ADIPOR1 and 16 SNPs in ADIPOR2. We genotyped these SNPs in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) to test for association with type 2 diabetes. Three intronic SNPs in ADIPOR1 were significantly associated with type 2 diabetes (P = 0.014-0.007; odds ratio [OR] 1.61-1.65) and in high linkage disequilibrium ([r.sup.2] = 0.97-1.0). In ADIPOR2, we found that five SNPs delineated one large haplotype block ([r.sup.2] = 0.9-1.0) spanning >98 kb of the gene and promoter region, which was strongly associated with the combined type 2 diabetes/IGT trait (P [less than or equal to] 0.001; OR 1.64-1.71). To our knowledge, these data provide the first evidence for association between variation in the adiponectin receptors and type 2 diabetes., Adiponectin is an adipocytokine that is involved in lipid and glucose metabolism, energy homeostasis, and inflammatory pathways (1-5). Circulating concentrations of adiponectin are reduced in subjects with type 2 diabetes [...]

We performed a genome-wide linkage scan of plasma adiponectin levels in 569 nondiabetic participants in the Amish Family Diabetes Study. The highest logarithm of odds (LOD) score (2.13; P = 0.0009) occurred on chromosome 3q27 between markers D3S1602 and D3S1580, which flank APM1/ACDC, the adiponectin gene. The APM1 +2019 A/- insertion/deletion polymorphism in the 3' untranslated region (single nucleotide polymorphism [SNP] +2019; deletion allele frequency 0.30 in Amish) showed strong association with adiponectin levels in a dosage-dependent manner in a direction consistent with that reported in previous studies, with deletion heterozygosity increasing adiponectin levels by 1.3 [+ or -] 0.5 [micro]g/ml and deletion homozygosity increasing levels by 3.0 [+ or -] 0.8 [micro]g/ml (P < 0.0001). Two other SNPs, rs2241766 and rs1501299, showed moderate association. In a subset of 523 subjects genotyped for both SNP +2019 and rs2241766, including the APM1 SNP +2019 genotype as a covariate reduced the linkage signal at 3q27 by 1.26 LOD units (from 2.22 to 0.96) and including both SNPs reduced the signal by 1.51 LOD units (to 0.71). These findings, combined with a two-point LOD score of 2.35 for SNP +2019, provide evidence that variation in APM1 is responsible for linkage of adiponectin levels to 3q27 in the Old Order Amish., Adiponectin is a fat-secreted hormone involved in insulin sensitivity, free fatty acid oxidation, and inhibition of inflammation (1,2). Circulating adiponectin levels are decreased in obesity (3), diabetes (4), hypertension (5), [...]

Background: Lower resting energy expenditure (REE) in African American women may contribute to their obesity. The identification of uncoupling protein (UCP) genes has fueled a search for genes involved in energy metabolism in humans. Objective: We examined variation in REE in relation to variation in UCP1, UCP2, and UCP3 in 141 women aged 18-21 y. Design: Standard methods were used for REE measurements and genetic analysis. Body composition was determined with the use of dual-energy X-ray absorptiometry. Multivariate analysis was used to examine the effect of genotypes on REE and on fat mass in relation to other potentially confounding variables. Results: REE was 295 kJ/d lower in African American women than in white women. No significant variation in REE was seen for UCP1, UCP2, and UCP3 (p-55; exon 3a; and exon 3b) variants after adjustment for other variables including smoking status. For the UCP3 exon 5 variant, REE was significantly (P = 0.019) lower in African American women with the CC genotype than in those with the TT genotype. In African American women, there was a significant trend (P = 0.012) toward lower REE and a weak but nonsignificant trend (P = 0.1) toward greater fat mass across the 3 genotypes (TT, CT, and CC). Conclusions: The significant and dose-dependent relation between lower REE and the C allele suggests that it may be a thrifty allele. The presence of this parsimonious energy metabolism in African American women, possibly linked to UCP3, may be implicated in their susceptibility to obesity. The absence of a UCP3 effect in white women is intriguing and needs to be explored to further understand possible interactions between UCP3 and other genes. Am J Clin Nutr 2002;75:714-9. KEY WORDS Uncoupling protein genes, UCP1, UCP2, UCP3, African American women, white women, thrifty gene, energy metabolism, obesity, genetics

Fetal growth and birth weight are associated with the development of adult-onset metabolic diseases. Both environmental insults (i.e., maternal nutrition, smoking, and drug use) and genetic factors have been implicated [...]