Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations

Kheirkhah, Azin; Schachtl-Riess, Johanna Franziska; Lamina, Claudia; Di Maio, Silvia; Koller, Adriana; Schönherr, Sebastian; Coassin, Stefan; Forer, Lukas; Sekula, Peggy; Gieger, Christian; Peters, Annette; Köttgen, Anna; Eckardt, Kai-Uwe; Kronenberg, Florian

doi:10.1016/j.atherosclerosis.2023.117384

Cited by 2 publications

(5 citation statements)

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“…We also replicated two loci with suggestive significance previously detected by Kheirkhah et al [ 19 ], namely 16q22.2 ( HP / HPR ) and 10q21.3 ( JMJD1C , reported with suggestive significance only). While the hit at 16q22.2 did not show interactions with sex or statin, JMJD1C showed a significant statin-interaction (q IA = 0.027), and colocalization suggested a statin-free specific signal here (PP(H 1 ) = 0.768).…”

Section: Resultssupporting

confidence: 90%

“…We replicated three loci reported by Pott et al [ 12 ] and Kheirkhah et al [ 19 ]: 2p24.1 ( APOB ), 19p13.11 ( TM6SF2 ), and 11q12.2 ( FADS1 ) with genome-wide significance. At the APOB locus, we observed a significant statin-interaction (q IA = 5.98 × 10 –3 ), which was confirmed by colocalization analysis (PP(H 1 ) = 0.765 comparing free and treated individuals).…”

Section: Resultssupporting

confidence: 87%

“…We detected genome-wide significant hits in all four double-stratified settings, and in all single-stratified settings. While six identified loci coincide with those found in the most recent overall meta-analysis of PCSK9 levels of statin-free and statin-adjusted subjects [ 12 , 19 ], we also observed two novel genome-wide loci, one male-specific at 12q24.22, and one specific for statin-treated subjects at 6q11.1. Three additional loci with suggestive significance were found.…”

Section: Discussionsupporting

confidence: 79%

“…Finally, we were able to replicate five known loci, of which three were also significant in other subgroups than statin-free individuals considered in the most recent meta-GWAS of PCSK9 [ 19 ]. All five loci are also known for associations with other lipid traits.…”

Section: Discussionmentioning

confidence: 99%

“…A brief description of studies is given in the Additional file 1 and Additional file 2 : Table S1. Detailed information regarding PCSK9 measurements, genotyping and study level quality control can be found elsewhere [ 12 , 19 ]. LIFE-Heart, LIFE-Adult , LURIC , and TwinGene imputed their genetic data on 1000 Genomes Phase 3 [ 20 ], while KORA-F3 and GCKD were imputed on the Haplotype Reference Consortium panel (HRC r1.1 2016) [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

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

Pott,

Kheirkhah,

Gadin

et al. 2024

Biol Sex Differ

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Background Proprotein 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. Methods We 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 PCSK9 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. Results We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10–6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 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 PCSK9 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 KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), 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. Conclusions We 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.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 87%