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

Jan M W Geurts, Rob G J H Janssen, Marleen M J Van Greevenbroek, Carla J H Van Der Kallen, Rita M. Cantor, Xiang Dong Bu, Bradley E. Aouizerat, Hooman Allayee, Jerome I. Rotter, Tjerk W A De Bruin

Research output: Contribution to journalArticle

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, TNFRSF1B was 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.

Original languageEnglish (US)
Pages (from-to)2067-2074
Number of pages8
JournalHuman Molecular Genetics
Volume9
Issue number14
StatePublished - Sep 1 2000

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Familial Combined Hyperlipidemia
Modifier Genes
Alleles
Mutation
Tumor Necrosis Factor Receptors
Linkage Disequilibrium
Homozygote
Apolipoproteins B
Hyperlipidemias
Spouses
Methionine
Introns
Haplotypes
Single Nucleotide Polymorphism
Survivors
Arginine
Case-Control Studies
Exons
Linear Models

ASJC Scopus subject areas

  • Genetics

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Geurts, J. M. W., Janssen, R. G. J. H., Van Greevenbroek, M. M. J., Van Der Kallen, C. J. H., Cantor, R. M., Bu, X. D., ... De Bruin, T. W. A. (2000). Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. Human Molecular Genetics, 9(14), 2067-2074.

Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. / Geurts, Jan M W; Janssen, Rob G J H; Van Greevenbroek, Marleen M J; Van Der Kallen, Carla J H; Cantor, Rita M.; Bu, Xiang Dong; Aouizerat, Bradley E.; Allayee, Hooman; Rotter, Jerome I.; De Bruin, Tjerk W A.

In: Human Molecular Genetics, Vol. 9, No. 14, 01.09.2000, p. 2067-2074.

Research output: Contribution to journalArticle

Geurts, JMW, Janssen, RGJH, Van Greevenbroek, MMJ, Van Der Kallen, CJH, Cantor, RM, Bu, XD, Aouizerat, BE, Allayee, H, Rotter, JI & De Bruin, TWA 2000, 'Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia', Human Molecular Genetics, vol. 9, no. 14, pp. 2067-2074.
Geurts JMW, Janssen RGJH, Van Greevenbroek MMJ, Van Der Kallen CJH, Cantor RM, Bu XD et al. Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. Human Molecular Genetics. 2000 Sep 1;9(14):2067-2074.
Geurts, Jan M W ; Janssen, Rob G J H ; Van Greevenbroek, Marleen M J ; Van Der Kallen, Carla J H ; Cantor, Rita M. ; Bu, Xiang Dong ; Aouizerat, Bradley E. ; Allayee, Hooman ; Rotter, Jerome I. ; De Bruin, Tjerk W A. / Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. In: Human Molecular Genetics. 2000 ; Vol. 9, No. 14. pp. 2067-2074.
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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, TNFRSF1B was 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.",
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AU - Geurts, Jan M W

AU - Janssen, Rob G J H

AU - Van Greevenbroek, Marleen M J

AU - Van Der Kallen, Carla J H

AU - Cantor, Rita M.

AU - Bu, Xiang Dong

AU - Aouizerat, Bradley E.

AU - Allayee, Hooman

AU - Rotter, Jerome I.

AU - De Bruin, Tjerk W A

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N2 - 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, TNFRSF1B was 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.

AB - 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, TNFRSF1B was 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.

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