New genetic insights: PCSK7 linked with triglycerides

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12 February 2016

This genome-wide association study provided the first evidence that common single-nucleotide polymorphisms (SNPs) within the proprotein convertase subtilisin/kexin type 7 (PCSK7) gene are associated with plasma triglyceride levels.

Kurano M, Tsukamoto K, Kamitsuji S et al. Genome-wide association study of serum lipids confirms previously reported associations as well as new associations of common SNPs within PCSK7 gene with triglyceride. J Hum Genet 2016;doi: 10.1038/jhg.2015.170. [Epub ahead of print].

STUDY SUMMARY

Objective:

To investigate the association of single-nucleotide polymorphisms (SNPs) in the Japan Pharmacogenomics Data Science Consortium database with serum lipids (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides)

Study design:

Genome-wide association study (GWAS)

Study population:

The GWAS included about 2.5 million SNPs from 3,041 Japanese healthy volunteers in the Japan Pharmacogenomics Data Science Consortium database. Data were collected in two phases: firstly, between 2000 to 2003 (n= 1,032), and secondly, across 10 geographic regions in Japan (n= 2,009). LDL-C and HDL-C data were only obtained from phase 2.

Primary variable:

· To confirm previously reported associations of SNPs with LDL-C, HDL-C, triglycerides and phospholipids.

· To identify novel genetic loci associated with plasma levels of LDL-C, HDL-C and/or triglycerides.

Methods:

SNPs used in the GWAS were selected according to the following criteria:

SNP call rates (≥95%), Hardy–Weinberg equilibrium test (p≥0.01) and minor allele frequency (≥1%). Linear regression was used in the adjustment of lipid measures for independent variables, before log-transformation and standardization. The significance of the association between a lipid trait and genotype was evaluated using the Wald test, with genome-wide significance inferred at p<5×10− 8.

If the P-value for association between the novel SNP and lipid trait was less than the pre-specified threshold (p<1 × 10?5) replication analysis was performed using data sets obtained from the Korea Association Resource (n=6,805), a part of the Korean Genome and Epidemiology Study cohort.

Main results:

· The study confirmed previously reported associations of 14 SNPs with LDL-C, 23 SNPs with HDL-C, 16 SNPs with triglycerides and 5 SNPs with phospholipids.

· Based on the pre-specified p-value threshold, 16 possible novel SNPs associated with LDL-C, HDL-C or triglycerides were identified.

· Only associations between six SNPs in PCSK7 and triglycerides were successfully replicated by Korean data. Two of these SNPs (rs508487 and rs236911), had p-values less than the threshold for genome-wide significance (p<1 × 10?5).

Authors’ conclusion:

These data suggest that PCSK7 may be associated with lipids, especially triglycerides, and may serve as a candidate for a new drug target to treat dyslipidaemia.

COMMENT

The subtilisin-like proprotein convertase family comprises a number of proprotein convertases that that convert precursor proteins into their biologically active products. The best known of these is PCSK9 (proprotein convertase subtilisin/kexin type 9) which plays a pivotal role in cholesterol homeostasis by regulating LDL receptor availability in response to circulating LDL-C levels. Studies linking gain of function mutations in PCSK9 with familial hypercholesterolaemia initiated the search for the mechanism underlying the activity of PCSK9, and in turn, novel pharmacotherapeutic approaches to managing hypercholesterolaemia.(1)

This study adds the first evidence suggesting that another representative of this family, PCSK7, may be associated with plasma triglycerides, and thus may represent a potential novel therapeutic target. Although the study does not provide any mechanistic insights, it is relevant that the sites of expression of PCSK7 include the liver and the intestine, in addition to the colon and lymphoid-associated tissues.(2,3) PCSK7 has been implicated in the regulation of iron metabolism although the mechanism as yet to be fully elucidated.(4)The findings of this GWAS, supported by replication in another cohort, suggest an additional novel role for PCSK7 which warrants further study.

References

1. Abifadel M, Elbitar S, El Khoury P et al. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep 2014;16:439.

2. Seidah NG, Hamelin J, Mamarbachi M et al. cDNA structure, tissue distribution, and chromosomal localization of rat PC7, a novel mammalian proprotein convertase closest to yeast kexin-like proteinases. Proc Natl Acad Sci USA 1996;93:3388–93.

3. Seidah NG, Sadr MS, Chrétien M, Mbikay M. The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J Biol Chem 2013;288:21473-81.

4. Guillemot J, Canuel M, Essalmani R et al. Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin. Hepatology 2013;57:2514-24.

Key words

proprotein convertase subtilisin/kexin type 7; PCSK7; triglycerides; genome-wide association study