Elsevier

Gene

Volume 524, Issue 2, 25 July 2013, Pages 363-367
Gene

Short communication
Significant association of urokinase plasminogen activator Pro141Leu with serum lipid profiles in a Japanese population

https://doi.org/10.1016/j.gene.2013.04.046Get rights and content

Highlights

  • Associations of PLAU Pro141Leu (rs2227564) with serum lipids among Japanese

  • The present study is the first report on the association, to our knowledge.

  • This study has a large population (about five thousands) to justify the conclusion.

Abstract

Urokinase plasminogen activator (uPA) plays important physiological and pathological roles in fibrinolysis, cancer metastasis, and atherosclerosis. One study suggested that uPA also has a major role in cholesterol biosynthesis in humans via its receptor uPAR. Thus, we investigated the associations of functional uPA polymorphism (plasminogen activator, urokinase; PLAU Pro141Leu, rs2227564) with serum lipid profiles in a Japanese cohort. The study included 5152 participants (1465 male, 3687 female; age range, 35–69 years) of the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Subjects were enrolled at the Daiko Medical Center from June 2008 to May 2010. Low-density lipoprotein cholesterol (LDL-C) and non-HDL-C (subtraction of high-density lipoprotein cholesterol from total cholesterol) in fasting blood of participants were each classified into two groups, < or ≥ 140 mg/dL, and < or ≥ 170 mg/dL, respectively. Genotype frequencies of PLAU Pro141Leu (rs2227564) were 59.1% for ProPro, 35.6% for ProLeu, and 5.3% for LeuLeu, and were in Hardy–Weinberg equilibrium (p = 0.789). The allele frequencies were 0.769 for Pro and 0.231 for Leu. The multivariate-adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for high LDL-C and non-HDL-C were 1.11 (95%CI; 1.00–1.23) and 1.16 (95%CI; 1.03–1.30) for those with Leu allele relative to ProPro. This study suggested that PLAU Pro141Leu (rs2227564) is significantly associated with serum lipid levels in a Japanese population.

Introduction

Urokinase plasminogen activator (uPA), a member of the plasminogen activator family, converts plasminogen to plasmin, which activates prometalloproteinases and degrades the extracellular matrix (ECM) (Saksela and Rifkin, 1988), and influences cancer invasion and metastasis (Crowley et al., 1993, Huang et al., 2007, Nekarda et al., 1994, Sidenius and Blasi, 2003, Tkachuk et al., 2009, Ulisse et al., 2009). uPA is a serine protease enzyme secreted by cells as a 52 kDa single glycoprotein, and has important roles physiologically in fibrinolysis (Myohanen and Vaheri, 2004), inflammation (Gyetko et al., 1996), tumor growth (Blasi, 1993), and angiogenesis (Bacharach et al., 1992).

A study reported a novel role for uPA in increasing cholesterol biosynthesis in human macrophages through the mevalonate pathway, via induction of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) by intracellular signals induced by the interaction between uPA and its receptor uPAR (Fuhrman et al., 2007). The mevalonate pathway contributes highly to cholesterol biosynthesis, and HMGCR is a rate-limiting enzyme in the pathway (Brown and Goldstein, 1986). The uPA/uPAR system has a non-proteolytic role in vivo and in vitro, which seems to be distinct from its proteolytic role (Waltz et al., 2000).

Although the roles of uPA in diverse physiological and pathological processes have been well established, the influence of uPA polymorphisms in humans, especially on serum lipid profiles, is unclear. The uPA gene is located on chromosome 10q24. In the HapMap project, several single nucleotide polymorphisms (SNPs) of the uPA gene were identified in the National Center for Biotechnology Information Database. Among them, we focused on a nonsynonymous polymorphism of the uPA gene (plasminogen activator, urokinase; PLAU Pro141Leu, rs2227564) encoding the kringle structure, which might affect the tertiary structure of the whole molecule, resulting in lower affinity of uPA to substrates (Yoshimoto et al., 1996). This SNP has been investigated in dementia research, and was reported to be associated with onset of Alzheimer disease (Finckh et al., 2003, Papassotiropoulos et al., 2005).

In the present study, we investigated the association of PLAU Pro141Leu (rs2227564) with serum lipid profiles in a Japanese population. To our knowledge, this is the first report on this association.

Section snippets

Subjects

The study included 5152 participants (1465 male, 3687 female; age range, 35–69 years) as reported in the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) (Hamajima and the J-MICC Study Group, 2007, Morita et al., 2011). Four participants withdrew, four lacked buffy coat blood cells, and 12 had no blood collected for genotyping, thus were excluded. The participants were enrolled at the Daiko Medical Center from June 2008 to May 2010. All participants

Results

Table 1 shows the characteristics of the 5152 study subjects according to PLAU genotype. In total, 28.4% were male, 71.6% were female, and mean age ± standard deviation (SD) was 52.5 ± 10.3 years, with 58.5% aged over 50 years. Current smoking was 24.1% in males and 6.9% in females, while current alcohol use was 74.9% in males and 46.0% in females. The genotype frequencies of PLAU Pro141Leu (rs2227564) were 59.1% for ProPro, 35.6% for ProLeu, and 5.3% for LeuLeu, and found to be in Hardy–Weinberg

Discussion

We have shown significant associations of PLAU Pro141Leu with serum lipid profiles of TC, non-HDL-C and LDL-C. There were no interactions with alcohol use and smoking status.

In this study, the MAF of PLAU Pro141Leu (rs2227564) was 0.231. A previous epidemiological study also reported a similar MAF for Japanese subjects (0.239 for Leu) (Goto et al., 2011). Furthermore, the HapMap project reported MAF according to race, and was 0.233 for Japanese, 0.208 for Caucasian, 0.356 for Chinese, and zero

Conclusion

This was the first study to our knowledge that suggests that PLAU Pro141Leu (rs2227564) might influence serum lipid levels in a Japanese population. Further investigations of associations with inclusion of PLAUR polymorphism, are required in other populations.

Conflict of interest

The authors have no conflicts of interest to declare.

Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 17015018 and 221S0001). The authors are grateful to Ms. Yoko Mitsuda and Ms. Keiko Shibata for their technical assistances.

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