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Leptin acts as a satiety signal regulating food intake and energy expenditure. The relation between variants in the leptin (LEP; 19 G>A) gene and its receptor (LEPR; Q223R and K109R) with obesity and type 2 diabetes has been studied extensively, but results are inconclusive and the relation remains unclear. In a population-based association study, we examined the effect of these variants on pre-diabetic phenotypes measured in young healthy twins. In this study, 396 monozygotic and 230 dizygotic twins (286 men and 340 women, mean age 25 years) were recruited from the East Flanders Prospective Twin Survey. Several diabetes-related traits were measured, including birth weight, adult body composition, fasting concentrations of cholesterol (LDL and HDL), triglycerides, free fatty acids, leptin, insulin and glucose. Genotyping was performed using Pyrosequencing. Linear mixed models, including a random effect term for twin pair membership, were used to evaluate associations between the variants and the measured traits. When appropriate, traits were adjusted for covariates including sex, (gestational) age, height and fat. Subjects carrying the 19 G allele of LEP had higher HDL-cholesterol levels compared to 19 A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol/1;p=0.008). The K109R variant in the LEPR was associated with birth weight (KK, KR and RR (95% CI): 2507 (2462-2553), 2577 (2519-2536) and 2762 (2643-2882) gram; p=0.0002). Also the Q223R variant in the LEPR showed association with birth weight (QQ, QR and RR (95% CI): 2493 (2431-2554), 2542 (2492-2591) and 2670 (2583-2756) gram; p=0.002). These results indicate that genetic variation in the LEP gene affects HDL-cholesterol levels. Furthermore, this study suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adult life. [ABSTRACT FROM AUTHOR]

Objective: Fluoropyrimidine treatment can be optimized based on dihydropyrimidine dehydrogenase (DPD) activity. DPD dysfunction leads to increased exposure to active metabolites, which can result in severe or even fatal toxicity., Methods: We provide an overview of 8 years of DPD diagnostic testing (n = 1194)., Results: Within the study period, our diagnostic test evolved from a single-enzyme measurement using first a radiochemical and then a nonradiochemical assay by ultra HPLC-MS in peripheral blood mononuclear cells with uracil, to a combined enzymatic and genetic test (ie, polymerase chain reaction) followed by Sanger sequence analysis of 4 variants of the DPYD gene (ie, DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G; allele frequencies 0.58%, 0.03%, 0.29%, and 1.35%, respectively). Patients who have 1 of the 4 variants tested (n = 814) have lower enzyme activity than the overall patient group. The majority of patients with the DPYD*2A variant (83%) consistently showed decreased enzyme activity. Only 24 (25.3%) of 95 patients (tested for 4 variants) with low enzyme activity carried a variant. Complete DPYD sequencing in a subgroup with low enzyme activity and without DPYD*2A variant (n = 47) revealed 10 genetic variants, of which 4 have not been described previously. We did not observe a strong link between DPYD genotype and enzyme activity., Conclusions: Previous studies have shown that DPD status should be determined before treatment with fluoropyrimidine agents to prevent unnecessary side effects with possible fatal consequences. Our study in combination with literature shows that there is a discrepancy between the DPD enzyme activity and the presence of clinically relevant single nucleotide polymorphisms. At this moment, a combination of a genetic and enzyme test is preferable for diagnostic testing. ( Curr Ther Res Clin Exp . 2018; 79:XXX-XXX).