Sex difference in circulating PCSK9 and its clinical implications

Jia, Fang; Fei, Si-Fan; Tong, De-Bing; Xue, Cong; Li, Jianjun

doi:10.3389/fphar.2022.953845

Cited by 19 publications

(9 citation statements)

References 98 publications

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“…Regarding LDL-C levels, the SNP is sex-biased as we described it for PCSK9, with stronger effects in men (p IA = 5.38 × 10 –5 using the GLGC data [ 8 ]). In summary, this suggests sex-regulated transcription and translation of PCSK9, which could contribute to the observed sexual dimorphism of PCSK9 levels with higher levels observed in women [ 6 ]. The third independent signal, rs11583680, displayed a significant 2-way statin-interaction with the strongest effect in statin-treated men.…”

Section: Discussionmentioning

confidence: 99%

“…Sexual dimorphisms are common in lipid metabolism, and PCSK9 also exhibits sex-differential behavior with women having higher circulating PCSK9 concentrations than men [ 6 , 7 ]. While large-scale sex-stratified genome-wide association meta-analyses (GWAMA) were already performed for the common lipid traits such as: total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and non-HDL-C [ 8 ], so far there was no GWAS on stratified PCSK9 levels to the best of our knowledge.…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Interestingly, emerging data show that women have higher circulating PCSK9 concentrations than men, suggesting that the potential roles of PCSK9 may have different impacts according to sex. 230 In a large European cohort of individuals ( n = 3673, aged 54–79 years) free of cardiovascular diseases enrolled in seven centres of five European countries: Finland, France, Italy, the Netherlands, and Sweden, PCSK9 plasma level was higher in women than in men. 231 Another study among Thai subjects confirmed that PCSK9 concentrations were significantly higher in women than in men ( P = 0.002).…”

Section: Proprotein Convertase Subtilisin Kexin Typementioning

confidence: 99%

Italian Association of Hospital Cardiologists Position Paper ‘Gender discrepancy: time to implement gender-based clinical management’

Lucà,

Pavan,

Gulizia

et al. 2024

European Heart Journal Supplements

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It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women’s diseases.

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“…Even when women with FH are prescribed PCSK9 inhibitors, women compared to men show less LDL-C reduction of PCSK9 inhibitors [ 34 , 35 ]. A reason for this sex difference may be related to the influence of estrogens on PCSK9 levels through G-protein coupled estrogen receptors on the hepatocytes, and this should be further investigated [ 36 , 37 ].…”

Section: Treatmentmentioning

confidence: 99%

Sex Differences in Familial Hypercholesterolemia

Klevmoen,

Mulder,

Roeters van Lennep

et al. 2023

Curr Atheroscler Rep

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Purpose of Review This review aims to summarize the existing research on sex differences in familial hypercholesterolemia (FH) across the lifespan. Recent Findings From childhood onward, total- and low-density lipoprotein cholesterol (LDL-C) levels in girls are higher than those in boys with FH. By the age of 30 years, women with FH have a higher LDL-C burden than men. In adulthood, women are diagnosed later than men, receive less lipid-lowering treatment, and consequently have higher LDL-C levels. An excessive atherosclerotic cardiovascular disease risk is reported in young female compared to male FH patients. The periods of pregnancy and breastfeeding contribute to treatment loss and increased cholesterol burden. Summary Earlier initiation of treatment, especially in girls with FH, and lifelong treatment during all life stages are important. Future research should aim to recruit both women and men, report sex-specific data, and investigate the impact of the female life course on cardiovascular outcomes. Future guidelines should include sex-specific aspects. Graphical abstract

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Sex difference in circulating PCSK9 and its clinical implications

Cited by 19 publications

References 98 publications

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

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

Italian Association of Hospital Cardiologists Position Paper ‘Gender discrepancy: time to implement gender-based clinical management’

Sex Differences in Familial Hypercholesterolemia

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