Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia

Authors: Geurts, Jan M.W.; Janssen, RobG.J.H.; van, MarleenM.J.; van, Carla J.H.; Cantor, RitaM.; Bu, Xiang-dong; Aouizerat, Bradley E.; Allayee, Hooman; Rotter, Jerome I.; de, Tjerk W.A.

Source: Human Molecular Genetics, Volume 9, Number 14, 1 September 2000 , pp. 2067-2074(8)

Publisher: Oxford University Press

Buy & download fulltext article:

Price: $42.29 plus tax (Refund Policy)

Abstract:

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of ±1% in the general population and 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P= 0.032), and, borderline, with apolipoprotein B levels (P= 0.064). Furthermore, in a case–control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P= 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P= 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1Bwas found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.

Document Type: Research article

Publication date: 2000-09-01

More about this publication?

Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.

Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia

Buy & download fulltext article:

Tools

Key

Text size:

Useful pages