G.M. van der Vleuten

The Gln223Arg polymorphism in the leptin receptor is associated with familial combined hyperlipidemia

Objective:Familial combined hyperlipidemia (FCH) is characterized by elevated levels of total cholesterol (TC), triglycerides (TG) and apolipoprotein B (apo B) and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have also been associated with obesity, insulin resistance and atherosclerosis. Leptin exerts its effect through the leptin receptor (LEPR). The aim of this study is to determine whether the Gln223Arg polymorphism in the LEPR gene contributes to FCH and its associated phenotypes.Methods:The study population consists of 37 families, comprising 644 subjects, of whom 158 subjects were diagnosed as FCH. The FCH diagnosis was based on plasma TC and TG levels, adjusted for age and gender, and absolute apo B levels, according to our recently published nomogram. The Gln223Arg polymorphism was studied by restriction fragment length polymorphism-PCR.Results:Carriers of one or two Arg alleles had an increased risk of FCH, compared to subjects homozygous for the Gln allele (OR=1.6 [95% CI 1.0–2.4]). A difference in high-density lipoprotein cholesterol (HDL-c) levels was present between carriers and non-carriers of an Arg allele, 1.21 vs 1.28 mmol/l, respectively (P=0.04), but no differences in obesity, insulin resistance and other lipid parameters were found.Conclusion:The Gln223Arg polymorphism in the LEPR gene is associated with FCH, which is supported by a significant association between HDL-c levels and the LEPR gene.

A genome-wide linkage scan for homocysteine levels suggests three regions of interest.

Summary.  Background: An elevated plasma total homocysteine (tHcy) level is a risk factor for many clinical conditions, including vascular disease and venous thrombosis. The tHcy levels are partly determined by genetic factors. Extensive candidate gene studies have identified several genetic variants, including the MTHFR 677C>T, that influence tHcy levels, but so far only part of the genetic variation in tHcy can be explained. Objective: In order to identify chromosomal regions that influence tHcy levels, a genome‐wide linkage analysis was conducted. Patients/methods: Our study population consisted of 13 pedigrees and 469 subjects with data on fasting plasma tHcy levels. A set of 377 markers covering the genome was genotyped in 275 subjects. The variance component linkage method (SOLAR version 2.1.3) was used for the two‐point and multipoint linkage analyses. Results: The heritability of the age‐ and sex‐adjusted homocysteine levels was 44%. The multipoint linkage analysis identified one region with suggestive linkage on chromosome 16q (LOD score 1.76; nominal P = 0.0024). Weaker evidence of linkage was found for regions on chromosome 12q (LOD score 1.57; nominal P = 0.0036) and chromosome 13q (LOD score 1.52; nominal P = 0.0041). Conclusions: In our families the plasma tHcy level was highly heritable. The multipoint linkage analysis identified three regions that showed weak to suggestive linkage to tHcy levels.