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Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis

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Kheirkhah, Azin 
Gadin, Jesper R 
Kleber, Marcus E 
Delgado, Graciela E 


jats:titleAbstract</jats:title>jats:sec jats:titleBackground</jats:title> jats:pProprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics.</jats:p> </jats:sec>jats:sec jats:titleMethods</jats:title> jats:pWe performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the jats:italicPCSK9</jats:italic> gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups.</jats:p> </jats:sec>jats:sec jats:titleResults</jats:title> jats:pWe identified 11 loci associated with PCSK9 in at least one stratified subgroup (jats:italicp</jats:italic> < 1.0 × 10jats:sup–6</jats:sup>), including the jats:italicPCSK9</jats:italic> gene locus and five other lipid loci: jats:italicAPOB</jats:italic>, jats:italicTM6SF2</jats:italic>, jats:italicFADS1</jats:italic>/jats:italicFADS2</jats:italic>, jats:italicJMJD1C</jats:italic>, and jats:italicHP</jats:italic>/jats:italicHPR</jats:italic>. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the jats:italicPCSK9</jats:italic> gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in jats:italicPCSK9</jats:italic> missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within jats:italicKHDRBS2</jats:italic>) and one for males at 12q24.22 (near jats:italicKSR2</jats:italic>/jats:italicNOS1</jats:italic>), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals.</jats:p> </jats:sec>jats:sec jats:titleConclusions</jats:title> jats:pWe performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.</jats:p> </jats:sec>


Acknowledgements: We thank Robert John Konrad and his team at Ely Lilly and Company for the PCSK9 measurements in serum samples from the TwinGene cohort. We thank Sylvia Henger for data QC of LIFE-Adult and LIFE-Heart, Kay Olischer and Annegret Unger for technical assistance regarding LIFE-Heart, and Kerstin Wirkner for running the LIFE-Adult study center. We thank all study participants of the LIFE-Adult study whose personal dedication and commitment have made this project possible. LIFE-Adult genotyping (round3) was done at the Cologne Center for Genomics (CCG, University of Cologne, Peter Nürnberg and Mohammad R. Toliat). For LIFE-Adult genotype imputation, compute infrastructure provided by ScaDS (Dresden/Leipzig Competence Center for Scalable Data Services and Solutions) at the Leipzig University Computing Centre was used. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. We thank all participants of the GCKD and KORA studies for enabling our research through their participation. The vigorous effort of the study personnel of the regional centers of the GCKD study and the KORA study is highly appreciated.

Funder: Universität Leipzig (1039)


Sex, GWAS, Interaction, PCSK9, Statin

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Biology of Sex Differences

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Springer Science and Business Media LLC
Medical Research Council (MC_UU_0002/7)
Deutsche Forschungsgemeinschaft (209933838 - SFB-1052/4B11)
Bundesministerium für Bildung und Forschung (#01ZX1906B, SYMPATH, FKZ 01ER 0804, 01ER 0818, 01ER 0819, 01ER 0820, 01ER 0821)
Fondation Leducq (13CVD03)
Vetenskapsrådet (12660)
Hjärt-Lungfonden (201202729)
European Regional Development Fund (713–241202, 713–241202, 14505/2470, 14575/2470)
Seventh Framework Programme (AtheroRemo (201668), RiskyCAD (305739))
Horizon 2020 (848146, 101017424, IMI2 Consortium BEAt‐DKD (115974))
Österreichischer Wissenschaftsfond (W-1253 DK HOROS)
Wellcome Trust (225790/Z/22/Z)