Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs fUS$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-␣ (TNF-␣; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The ؊308A allele of the TNF-␣ gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P ‫؍‬ 0.034). Subjects with both the A allele of the TNF-␣ gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P ‫؍‬ 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the ؊308A allele of the promoter polymorphism (G-308A) of the TNF-␣ gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.

1Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n ‫؍‬ 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13. 68 ; P ‫؍‬ 0.016). The rates of both oxidative (P ‫؍‬ 0.013) and nonoxidative (P ‫؍‬ 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies. Diabetes 52:558 -561, 2003 I nterleukin-6 (IL-6) is a multifunctional cytokine expressed in many tissues, including adipose tissue, skeletal muscle and hypothalamus, which are involved in the regulation of body energy balance. In IL-6 null mice, the lack of circulating IL-6 was associated with obesity and low energy expenditure (1). Moreover, IL-6 -deficient mice exhibited high leptin levels and leptin insensitivity, and did not lose weight or decrease food intake after leptin treatment. The promoter of the IL-6 gene is dynamically regulated at many sites, including the multiple response element (Ϫ173 to 145), which responds to interleukin-1, tumor necrosis factor-␣, and other factors (2). The recently described C-174G promoter polymorphism of the IL-6 gene has been found to influence transcriptional regulation (2,3) and plasma IL-6 levels in patients with systemic-onset juvenile chronic arthritis and in patients with primary Sjö gren's syndrome (3,4). Moreover, the C-164G polymorphism has been found to be associated with insulin resistance measured by a frequently sampled intravenous glucose tolerance test in one previous study (5).In humans, the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure has not been previously studied. Therefore, we investigated the effect of this polymorphism on energy expenditure and insulin sensitivity during fasting and during the euglycemic-hyperinsulinemic clamp in 124 healthy normoglycemic subjects.The frequency of the CC genotype was 30%, the CG genotype 44%, and the GG genotype 26% in our study subjects. Age, BMI and waist-to-hip ratio, systolic and diastolic blood pressure, fasting plasma glucose and insulin levels, and IL-6 concentration (n ϭ 72) did not differ among the genotypes (Table 1).Fasting energy expenditure was 8% lower in subjects with the CC genotype than in subjects with the CG or GG genotypes (13.68 Ϯ 1.98, 14.73 Ϯ 1.57...

Predictive testing, with genetic counseling. Management included surgical resection of the existing pheochromocytoma. The patient continues to be monitored with MRI scans of the neck, thorax, abdomen and pelvis every 1-2 years and an annual 24h urine collection for the measurement of metanephrines and catecholamines.

A mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene with a cytosine to guanine substitution results in an exchange of proline (Pro) with alanine (Ala) in exon B (codon 12) of this gene. This polymorphism has been associated with high insulin sensitivity and low body weight, but no data have been published to date about its effect on early atherosclerosis. We investigated the relationship of the Pro(12)Ala polymorphism to early atherosclerosis, measured by the intima-media thickness (IMT). A total of 622 subjects were included, aged 40-70 yr, who were participants of the RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study and were at risk of developing type 2 diabetes. Altogether, 449 of the subjects had the common genotype (Pro(12)Pro), 162 had the Pro(12)Ala genotype, and 11 the Ala(12)Ala genotype. IMT was significantly decreased in subjects with the Ala(12)Ala genotype compared with subjects with the other two genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the Ala(12)Ala genotype compared with subjects with the Pro(12)Pro or Pro(12)Ala genotypes. In multivariate analysis, the Ala(12)Ala genotype was a significant independent determinant of IMT. Furthermore, we demonstrated specific expression of the PPARgamma2 gene in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells. In conclusion, our data suggest that the Ala(12)Ala genotype of the PPARgamma2 gene may protect from early atherosclerosis in subjects at risk for diabetes.