This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

/pdf/the-human-obesity-gene-map-the-2005-update-3zvtci1u6f.pdf

The human obesity gene map: the 2005 update.

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single-gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity-related phenotypes from 50 genome-wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http://obesitygene.pbrc.edu.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2005.50

The human obesity gene map: the 2004 update.

Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death

The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARalpha, PPARdelta, and PPARgamma) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARalpha and PPARdelta appear primarily to stimulate oxidative lipid metabolism, while PPARgamma is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARgamma in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARgamma in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.

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PPARγ and human metabolic disease

Purpose No biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. Patients and Methods DNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. Results The VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio 0.58; 95% CI, 0.36 to 0.93; P .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio 0.62; 95% CI, 0.46 to 0.83; P .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P .005 and P .022, respectively).

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Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100

Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5'-untranslated region (UTR) and 3'UTR of the VEGF gene, genotype distribution of the C(-634)G polymorphism differed significantly (P = 0.011) between patients with (n = 150) and without (n = 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P = 0.0037). The odds ratio (OR) for the CC genotype of C(-634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P = 0.0046). The -634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P = 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P = 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(-634)G polymorphism was strongly associated with an increased risk of retinopathy (P = 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(-634)G polymorphism than in those with the other genotypes. These data suggest that the C(-634)G polymorphism in the 5'UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

https://diabetes.diabetesjournals.org/content/diabetes/51/5/1635.full.pdf

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes.

Adiponectin is an adipocyte-derived factor that plays pivotal roles in lipid and glucose metabolism in muscle and liver. The following two adiponectin receptor types were recently identified: Adipo...

Regulation of adiponectin receptor gene expression in diabetic mice.

OBJECTIVE —We examined the endothelial nitric oxide (eNOS) gene polymorphisms to assess its possible association with diabetic retinopathy and macular edema. RESEARCH DESIGN AND METHODS —A total of 226 patients with type 2 diabetes and 186 healthy subjects were studied. Type 2 diabetic patients consisted of 110 patients without retinopathy, 46 patients with nonproliferative diabetic retinopathy, and 71 patients with proliferative diabetic retinopathy. Diabetic macular edema was present in 48 patients. Three polymorphisms of the eNOS gene were determined: T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7. RESULTS —Close linkage disequilibrium was observed between the T-786C polymorphism and the 27-bp repeat, as has been previously reported, but Glu298Asp was not in linkage disequilibrium with the other two polymorphisms. The eNOS gene polymorphisms were not significantly associated with the presence of retinopathy or with retinopathy severity or type 2 diabetes itself. However, by both association study and multiple logistic regression analysis, the T-786C and 27-bp repeat polymorphisms were significantly associated with a risk of developing macular edema with the −786C allele and the “a” allele increasing the risk. CONCLUSIONS —The present study suggests that the eNOS gene is a novel genetic risk factor for diabetic macular edema. The eNOS gene polymorphisms may contribute to the development of macular edema by impairing basal eNOS expression and resulting in the breakdown of the blood-retina barrier.

https://care.diabetesjournals.org/content/diacare/27/9/2184.full.pdf

Masaki Watanabe

Papers

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes.

Regulation of adiponectin receptor gene expression in diabetic mice.

Endothelial nitric oxide synthase gene is associated with diabetic macular edema in type 2 diabetes.

ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states