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

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hype rlipidemia in man, with a frequency of +/-1% in the general population and similar to 10% in myocardial infarction survivors. A genomic scan in 18 Dut ch FCHL families resulted in the identification of several loci with eviden ce for linkage. One of these regions, 1p36,2, contains TNFRSF1B which encod es one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-r epeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discrimin ant function (P = 0,032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrate d since the overall CA-repeat genotype distribution was significantly diffe rent among 40 unrelated FCHL patients and 48 unrelated healthy spouse contr ols (P = 0.029), This difference was due to a significant increase in allel e 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 nucl eotide polymorphism with two alleles, coding for methionine (196M) and argi nine (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 concentration s and the CA271-196M haplotype, In conclusion, TNFRSF1B was found to be ass ociated with susceptibility to FCHL, Our data suggest that an as yet unknow n disease-associated mutation, linked to alleles 196M and CA271, plays a ro le in the pathophysiology of FCHL.