Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Elisabeth M van Leeuwen; Jennifer E Huffman; Joshua C Bis; Aaron Isaacs; Monique Mulder; Aniko Sabo; Albert V Smith; Serkalem Demissie; Ani Manichaikul; Jennifer A Brody; Mary F Feitosa; Qing Duan; Katharina E Schraut; Pau Navarro; Jana V van Vliet-Ostaptchouk; Gu Zhu; Hamdi Mbarek; Stella Trompet; Niek Verweij; Leo-Pekka Lyytikäinen; Joris Deelen; Ilja M Nolte; Sander W van der Laan; Gail Davies; Andrea Jm Vermeij-Verdoold; Andy Alj van Oosterhout; Jeannette M Vergeer-Drop; Dan E Arking; Holly Trochet; Carolina Medina-Gomez; Fernando Rivadeneira; Andre G Uitterlinden; Abbas Dehghan; Oscar H Franco; Eric J Sijbrands; Albert Hofman; Charles C White; Josyf C Mychaleckyj; Gina M Peloso; Morris A Swertz; Gonneke Willemsen; Eco J de Geus; Yuri Milaneschi; Brenda Wjh Penninx; Ian Ford; Brendan M Buckley; Anton Jm de Craen; John M Starr; Ian J Deary; Gerard Pasterkamp; Generation Scotland; C. van Duijn

doi:10.1038/npjamd.2015.11

Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Elisabeth M van Leeuwen, Jennifer E Huffman, Joshua C Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A Brody, Mary F Feitosa, Qing Duan, Katharina E Schraut, Pau Navarro, Jana V van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka LyytikäinenJoris Deelen, Ilja M Nolte, Sander W van der Laan, Gail Davies, Andrea Jm Vermeij-Verdoold, Andy Alj van Oosterhout, Jeannette M Vergeer-Drop, Dan E Arking, Holly Trochet, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G Uitterlinden, Abbas Dehghan, Oscar H Franco, Eric J Sijbrands, Albert Hofman, Charles C White, Josyf C Mychaleckyj, Gina M Peloso, Morris A Swertz, Gonneke Willemsen, Eco J de Geus, Yuri Milaneschi, Brenda Wjh Penninx, Ian Ford, Brendan M Buckley, Anton Jm de Craen, John M Starr, Ian J Deary, Gerard Pasterkamp, Generation Scotland, C. van Duijn^*

^*Corresponding author for this work

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

Abstract

BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.

METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.

RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.

CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Original language	English
Pages (from-to)	15011
Journal	NPJ aging and mechanisms of disease
Volume	1
DOIs	https://doi.org/10.1038/npjamd.2015.11
Publication status	Published - 2015
Externally published	Yes

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Cite this

van Leeuwen, E. M., Huffman, J. E., Bis, J. C., Isaacs, A., Mulder, M., Sabo, A., Smith, A. V., Demissie, S., Manichaikul, A., Brody, J. A., Feitosa, M. F., Duan, Q., Schraut, K. E., Navarro, P., van Vliet-Ostaptchouk, J. V., Zhu, G., Mbarek, H., Trompet, S., Verweij, N., ... van Duijn, C. (2015). Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C. NPJ aging and mechanisms of disease, 1, 15011. https://doi.org/10.1038/npjamd.2015.11

@article{3eab060634694a949157807897a5034f,

title = "Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C",

abstract = "BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.",

author = "{van Leeuwen}, {Elisabeth M} and Huffman, {Jennifer E} and Bis, {Joshua C} and Aaron Isaacs and Monique Mulder and Aniko Sabo and Smith, {Albert V} and Serkalem Demissie and Ani Manichaikul and Brody, {Jennifer A} and Feitosa, {Mary F} and Qing Duan and Schraut, {Katharina E} and Pau Navarro and {van Vliet-Ostaptchouk}, {Jana V} and Gu Zhu and Hamdi Mbarek and Stella Trompet and Niek Verweij and Leo-Pekka Lyytik{\"a}inen and Joris Deelen and Nolte, {Ilja M} and {van der Laan}, {Sander W} and Gail Davies and Vermeij-Verdoold, {Andrea Jm} and {van Oosterhout}, {Andy Alj} and Vergeer-Drop, {Jeannette M} and Arking, {Dan E} and Holly Trochet and Carolina Medina-Gomez and Fernando Rivadeneira and Uitterlinden, {Andre G} and Abbas Dehghan and Franco, {Oscar H} and Sijbrands, {Eric J} and Albert Hofman and White, {Charles C} and Mychaleckyj, {Josyf C} and Peloso, {Gina M} and Swertz, {Morris A} and Gonneke Willemsen and {de Geus}, {Eco J} and Yuri Milaneschi and Penninx, {Brenda Wjh} and Ian Ford and Buckley, {Brendan M} and {de Craen}, {Anton Jm} and Starr, {John M} and Deary, {Ian J} and Gerard Pasterkamp and {Generation Scotland} and {van Duijn}, C.",

year = "2015",

doi = "10.1038/npjamd.2015.11",

language = "English",

volume = "1",

pages = "15011",

journal = "NPJ aging and mechanisms of disease",

issn = "2056-3973",

publisher = "Springer Nature",

}

van Leeuwen, EM, Huffman, JE, Bis, JC, Isaacs, A, Mulder, M, Sabo, A, Smith, AV, Demissie, S, Manichaikul, A, Brody, JA, Feitosa, MF, Duan, Q, Schraut, KE, Navarro, P, van Vliet-Ostaptchouk, JV, Zhu, G, Mbarek, H, Trompet, S, Verweij, N, Lyytikäinen, L-P, Deelen, J, Nolte, IM, van der Laan, SW, Davies, G, Vermeij-Verdoold, AJ, van Oosterhout, AA, Vergeer-Drop, JM, Arking, DE, Trochet, H, Medina-Gomez, C, Rivadeneira, F, Uitterlinden, AG, Dehghan, A, Franco, OH, Sijbrands, EJ, Hofman, A, White, CC, Mychaleckyj, JC, Peloso, GM, Swertz, MA, Willemsen, G, de Geus, EJ, Milaneschi, Y, Penninx, BW, Ford, I, Buckley, BM, de Craen, AJ, Starr, JM, Deary, IJ, Pasterkamp, G, Generation Scotland & van Duijn, C 2015, 'Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C', NPJ aging and mechanisms of disease, vol. 1, pp. 15011. https://doi.org/10.1038/npjamd.2015.11

TY - JOUR

T1 - Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

AU - van Leeuwen, Elisabeth M

AU - Huffman, Jennifer E

AU - Bis, Joshua C

AU - Isaacs, Aaron

AU - Mulder, Monique

AU - Sabo, Aniko

AU - Smith, Albert V

AU - Demissie, Serkalem

AU - Manichaikul, Ani

AU - Brody, Jennifer A

AU - Feitosa, Mary F

AU - Duan, Qing

AU - Schraut, Katharina E

AU - Navarro, Pau

AU - van Vliet-Ostaptchouk, Jana V

AU - Zhu, Gu

AU - Mbarek, Hamdi

AU - Trompet, Stella

AU - Verweij, Niek

AU - Lyytikäinen, Leo-Pekka

AU - Deelen, Joris

AU - Nolte, Ilja M

AU - van der Laan, Sander W

AU - Davies, Gail

AU - Vermeij-Verdoold, Andrea Jm

AU - van Oosterhout, Andy Alj

AU - Vergeer-Drop, Jeannette M

AU - Arking, Dan E

AU - Trochet, Holly

AU - Medina-Gomez, Carolina

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G

AU - Dehghan, Abbas

AU - Franco, Oscar H

AU - Sijbrands, Eric J

AU - Hofman, Albert

AU - White, Charles C

AU - Mychaleckyj, Josyf C

AU - Peloso, Gina M

AU - Swertz, Morris A

AU - Willemsen, Gonneke

AU - de Geus, Eco J

AU - Milaneschi, Yuri

AU - Penninx, Brenda Wjh

AU - Ford, Ian

AU - Buckley, Brendan M

AU - de Craen, Anton Jm

AU - Starr, John M

AU - Deary, Ian J

AU - Pasterkamp, Gerard

AU - Generation Scotland

AU - van Duijn, C.

PY - 2015

Y1 - 2015

N2 - BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

AB - BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

U2 - 10.1038/npjamd.2015.11

DO - 10.1038/npjamd.2015.11

M3 - Article

C2 - 28721259

SN - 2056-3973

VL - 1

SP - 15011

JO - NPJ aging and mechanisms of disease

JF - NPJ aging and mechanisms of disease

ER -