Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

C.J.H. van der Kallen; R.M. Cantor; M.M.J. van Greevenbroek; J.M.W. Geurts; F.G. Bouwman; B.E. Aouizerat; H. Allayee; W.A. Buurman; A.J. Lusis; J.L. Rotter; T.W.A. de Bruin

doi:10.1038/sj.ijo.0801412

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

C.J.H. van der Kallen, R.M. Cantor, M.M.J. van Greevenbroek, J.M.W. Geurts, F.G. Bouwman, B.E. Aouizerat, H. Allayee, W.A. Buurman, A.J. Lusis, J.L. Rotter, T.W.A. de Bruin

NUTRIM School of Nutrition and Translational Research in Metabolism

Research output: Contribution to journal › Article › Academic › peer-review

48 Citations (Scopus)

Abstract

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3), CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome, Navel loci on chromosome 8 and 10 qter need further study.

Original language	English
Pages (from-to)	1381-1391
Number of pages	10
Journal	International Journal of Obesity
Volume	24
Issue number	11
DOIs	https://doi.org/10.1038/sj.ijo.0801412
Publication status	Published - 1 Jan 2000

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van der Kallen, C. J. H., Cantor, R. M., van Greevenbroek, M. M. J., Geurts, J. M. W., Bouwman, F. G., Aouizerat, B. E., Allayee, H., Buurman, W. A., Lusis, A. J., Rotter, J. L., & de Bruin, T. W. A. (2000). Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A. International Journal of Obesity, 24(11), 1381-1391. https://doi.org/10.1038/sj.ijo.0801412

van der Kallen, C.J.H. ; Cantor, R.M. ; van Greevenbroek, M.M.J. ; Geurts, J.M.W. ; Bouwman, F.G. ; Aouizerat, B.E. ; Allayee, H. ; Buurman, W.A. ; Lusis, A.J. ; Rotter, J.L. ; de Bruin, T.W.A. / Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A. In: International Journal of Obesity. 2000 ; Vol. 24, No. 11. pp. 1381-1391.

@article{cdec81409b8a4ff596b6f98c19e7be38,

title = "Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A",

abstract = "OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3), CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome, Navel loci on chromosome 8 and 10 qter need further study.",

author = "{van der Kallen}, C.J.H. and R.M. Cantor and {van Greevenbroek}, M.M.J. and J.M.W. Geurts and F.G. Bouwman and B.E. Aouizerat and H. Allayee and W.A. Buurman and A.J. Lusis and J.L. Rotter and {de Bruin}, T.W.A.",

year = "2000",

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doi = "10.1038/sj.ijo.0801412",

language = "English",

volume = "24",

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journal = "International Journal of Obesity",

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van der Kallen, CJH, Cantor, RM, van Greevenbroek, MMJ, Geurts, JMW, Bouwman, FG, Aouizerat, BE, Allayee, H, Buurman, WA, Lusis, AJ, Rotter, JL & de Bruin, TWA 2000, 'Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A', International Journal of Obesity, vol. 24, no. 11, pp. 1381-1391. https://doi.org/10.1038/sj.ijo.0801412

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A. / van der Kallen, C.J.H.; Cantor, R.M.; van Greevenbroek, M.M.J.; Geurts, J.M.W.; Bouwman, F.G.; Aouizerat, B.E.; Allayee, H.; Buurman, W.A.; Lusis, A.J.; Rotter, J.L.; de Bruin, T.W.A.

In: International Journal of Obesity, Vol. 24, No. 11, 01.01.2000, p. 1381-1391.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

AU - van der Kallen, C.J.H.

AU - Cantor, R.M.

AU - van Greevenbroek, M.M.J.

AU - Geurts, J.M.W.

AU - Bouwman, F.G.

AU - Aouizerat, B.E.

AU - Allayee, H.

AU - Buurman, W.A.

AU - Lusis, A.J.

AU - Rotter, J.L.

AU - de Bruin, T.W.A.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3), CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome, Navel loci on chromosome 8 and 10 qter need further study.

AB - OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3), CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome, Navel loci on chromosome 8 and 10 qter need further study.

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DO - 10.1038/sj.ijo.0801412

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JO - International Journal of Obesity

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van der Kallen CJH, Cantor RM, van Greevenbroek MMJ, Geurts JMW, Bouwman FG, Aouizerat BE et al. Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A. International Journal of Obesity. 2000 Jan 1;24(11):1381-1391. https://doi.org/10.1038/sj.ijo.0801412