Early Human Development 90 (2014) 607–611
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Circulating PCSK9 levels correlate with the serum LDL cholesterol level in newborn infants Shunsuke Araki a,b,⁎, Shutaro Suga a,b, Fuyu Miyake a,b, Shun Ichikawa a,b, Tadamune Kinjo a,b, Yukiyo Yamamoto a, Koichi Kusuhara a a b
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan Center of Maternal, Fetal and Neonatal Medicine, University of Occupational and Environmental Health Hospital, Kitakyushu, Japan
a r t i c l e
i n f o
Article history: Received 10 May 2014 Received in revised form 25 July 2014 Accepted 28 July 2014 Available online xxxx Keywords: PCSK9 newborn infants LDL-C metabolic syndrome small-for-gestational age
a b s t r a c t Background and aims: Protein convertase subtilisin/Kexin type-9 (PCSK9) is a substantial player in lipoprotein metabolism. This study was designed to elucidate the role of PCSK9 in the regulation of lipoprotein during the fetal period. Study design and subjects: This study was a cross-sectional study. Eighty-one neonates (45 males, 36 females) who were admitted to the neonatal intensive care unit were enrolled in the study. The median age in gestational weeks and weight at birth were 37.1 weeks and 2493 g, respectively. There were no gender differences, but the proportion of infants who were small-for-gestational age (SGA) was significantly higher among females than males. The prefed serum PCSK9 level was assayed with ELISA kits. Results: The median PCSK9 concentration in male newborns was significantly lower than that in females (148.2 ng/ml vs. 171.4 ng/ml, respectively, p b 0.001). Circulating serum PCSK9 levels were positively correlated with total cholesterol (r = 0.281, p b 0.05) and low-density lipoprotein cholesterol (LDL-C; r = 0.272, p b 0.05). However, there were no correlations between PCSK9 levels and birth weight, gestational age or SGA. Multivariate forward stepwise linear regression analysis revealed that gestational age and circulating PCSK9 levels were independent predictors of the serum LDL-C levels in newborn infants. Conclusion: Our first quantitative analysis of neonatal serum PCSK9 levels at birth showed that circulating PCSK9 levels show gender-based differences and are significantly correlated with LDL-C. These results suggest that PCSK9 could play an important role in regulating LDL-C levels during the fetal period. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lipoprotein plays a crucial role in fetal neuronal maturation and postnatal development. Protein convertase subtilisin/Kexin type-9 (PCSK9) is a 692-amino acid serine protease of 72 kDa that is encoded by the PCSK9 gene, which is located at chromosomal region 1p32.3 [1–3]. PCSK9 is mainly expressed in the liver, intestine and kidney [1,2]. PCSK9 promotes the degradation of the low-density lipoprotein receptor (LDLR) in hepatocytes and increases the plasma LDL cholesterol (LDL-C) level. PCSK9 gain-of-function mutations lead to the
Abbreviations: PCSK9, protein convertase subtilisin/Kexin type-9; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; AGA, appropriate-for-gestational age; SGA, small-for-gestational age; FH, familiar hypercholesterolemia; NICU, neonatal intensive care unit. ⁎ Corresponding author at: Department of Pediatrics, School of Medicine University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 8078555 Japan. Tel.: +81 93 691 7254; fax: +81 93 691 9338. E-mail address: [email protected] (S. Araki).
http://dx.doi.org/10.1016/j.earlhumdev.2014.07.013 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
familiar hypercholesterolemia (FH) phenotype [4], whereas loss of function mutations are associated with low LDL-C levels [5]. In some adult studies, the levels of plasma PCSK9 were positively correlated with the plasma LDL-C and total cholesterol (TC) levels [6,7]. Moreover, PCSK9 levels are significantly correlated to fasting glucose and body mass index (BMI) [8]. Bass et al. [9] reported that the plasma levels of PCSK9 are affected by age, sex and multiple metabolic markers in childhood. Otherwise, little is known about the circulating PCSK9 levels in umbilical cord blood or newborn infants. Only one report has addressed the circulating PCSK9 levels in umbilical cord blood and found that the serum concentration of PCSK9 was significantly lower in umbilical cord blood than in maternal blood, and the level was positively correlated with TC, LDL-C, and high-density lipoprotein cholesterol (HDL-C) [10]. This study was designed to elucidate which perinatal factors [e.g., gestational age, birth weight, small-for-gestational age (SGA)] contribute to circulating PCSK9 levels and to reveal whether PCSK9 is a significant player in lipoprotein metabolism during the fetal period.
608
S. Araki et al. / Early Human Development 90 (2014) 607–611
Table 1 Subject characteristics and lipid profiles. Gender
Gestational age (weeks) Birth weight (g) Head circumference (cm)
Lipid profiles TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl)
Birth size
Total (n = 81)
Male (n = 45)
Female (n = 36)
AGA (n = 58)
SGA (n = 23)
38.1 [27.0–41.1] 2951 [717–4066] 32.0 [23.1–38.5]
37.3 [33.7–41.4] 2322 [1174–3704] 31.5 [28.0–35.4]
37.3 [31.3–41.4] 2749 [1782–4066] 31.9 [26.2–38.5]
36.7 [27.0–40.6] 1936** [717–2490] 30.9** [23.1–33.6]
37.2 [27.0–41.4] 2311 [717–4066] 32.5 [23.1–38.5]
67.1 [46.2–124.0] 28.4 [7.2–100.4] 35.0 [14.1–56.0] 23.5 [10.3–85.0]
81.3* [46.8–200] 43.5 [15.0–118.6] 39.0* [21.0–78.0] 22 [7.0–47.0]
72.1 [46.2–125.0] 31.5 [7.2–100.4] 37.2 [14.1–61.0] 21.5 [9.8–85.0]
74.4 [46.2–200] 32.6 [13.6–118.6] 30.1 [18.0–78.0] 26.4** [7.0–47.0]
72.3 [46.2–200] 31.7 [7.2–118.6] 36.5 [14.1–78.0] 21 [14.00–85.0]
Data are expressed as median [range]. Statistical differences were evaluated by Mann–Whitney U test for two groups. * vs. male, p b 0.05, ** vs. AGA. p b 0.01. TC, total cholesterol; LDL-C, low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; TG, triglyceride. AGA, appropriate-for-gestational age; SGA, small-for-gestational age.
2. Methods 2.1. Subjects Eighty-one neonates (45 male, 36 female), who were admitted to the neonatal intensive care unit (NICU) of the University of Occupational
(A)
and Environmental Health (UOEH) Hospital, were enrolled in the study. Neonatal data were collected, including gestational age, birth weight and head circumference. SGA was defined as both a birth weight and a birth length below the 10th percentile for gestational age. Gestational age was calculated from the mother's menstrual history and confirmed by ultrasonography. We excluded neonates with congenital
(B) r=-0.513 p
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Circulating PCSK9 levels correlate with the serum LDL cholesterol level in newborn infants Shunsuke Araki a,b,⁎, Shutaro Suga a,b, Fuyu Miyake a,b, Shun Ichikawa a,b, Tadamune Kinjo a,b, Yukiyo Yamamoto a, Koichi Kusuhara a a b
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan Center of Maternal, Fetal and Neonatal Medicine, University of Occupational and Environmental Health Hospital, Kitakyushu, Japan
a r t i c l e
i n f o
Article history: Received 10 May 2014 Received in revised form 25 July 2014 Accepted 28 July 2014 Available online xxxx Keywords: PCSK9 newborn infants LDL-C metabolic syndrome small-for-gestational age
a b s t r a c t Background and aims: Protein convertase subtilisin/Kexin type-9 (PCSK9) is a substantial player in lipoprotein metabolism. This study was designed to elucidate the role of PCSK9 in the regulation of lipoprotein during the fetal period. Study design and subjects: This study was a cross-sectional study. Eighty-one neonates (45 males, 36 females) who were admitted to the neonatal intensive care unit were enrolled in the study. The median age in gestational weeks and weight at birth were 37.1 weeks and 2493 g, respectively. There were no gender differences, but the proportion of infants who were small-for-gestational age (SGA) was significantly higher among females than males. The prefed serum PCSK9 level was assayed with ELISA kits. Results: The median PCSK9 concentration in male newborns was significantly lower than that in females (148.2 ng/ml vs. 171.4 ng/ml, respectively, p b 0.001). Circulating serum PCSK9 levels were positively correlated with total cholesterol (r = 0.281, p b 0.05) and low-density lipoprotein cholesterol (LDL-C; r = 0.272, p b 0.05). However, there were no correlations between PCSK9 levels and birth weight, gestational age or SGA. Multivariate forward stepwise linear regression analysis revealed that gestational age and circulating PCSK9 levels were independent predictors of the serum LDL-C levels in newborn infants. Conclusion: Our first quantitative analysis of neonatal serum PCSK9 levels at birth showed that circulating PCSK9 levels show gender-based differences and are significantly correlated with LDL-C. These results suggest that PCSK9 could play an important role in regulating LDL-C levels during the fetal period. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lipoprotein plays a crucial role in fetal neuronal maturation and postnatal development. Protein convertase subtilisin/Kexin type-9 (PCSK9) is a 692-amino acid serine protease of 72 kDa that is encoded by the PCSK9 gene, which is located at chromosomal region 1p32.3 [1–3]. PCSK9 is mainly expressed in the liver, intestine and kidney [1,2]. PCSK9 promotes the degradation of the low-density lipoprotein receptor (LDLR) in hepatocytes and increases the plasma LDL cholesterol (LDL-C) level. PCSK9 gain-of-function mutations lead to the
Abbreviations: PCSK9, protein convertase subtilisin/Kexin type-9; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; AGA, appropriate-for-gestational age; SGA, small-for-gestational age; FH, familiar hypercholesterolemia; NICU, neonatal intensive care unit. ⁎ Corresponding author at: Department of Pediatrics, School of Medicine University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 8078555 Japan. Tel.: +81 93 691 7254; fax: +81 93 691 9338. E-mail address: [email protected] (S. Araki).
http://dx.doi.org/10.1016/j.earlhumdev.2014.07.013 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
familiar hypercholesterolemia (FH) phenotype [4], whereas loss of function mutations are associated with low LDL-C levels [5]. In some adult studies, the levels of plasma PCSK9 were positively correlated with the plasma LDL-C and total cholesterol (TC) levels [6,7]. Moreover, PCSK9 levels are significantly correlated to fasting glucose and body mass index (BMI) [8]. Bass et al. [9] reported that the plasma levels of PCSK9 are affected by age, sex and multiple metabolic markers in childhood. Otherwise, little is known about the circulating PCSK9 levels in umbilical cord blood or newborn infants. Only one report has addressed the circulating PCSK9 levels in umbilical cord blood and found that the serum concentration of PCSK9 was significantly lower in umbilical cord blood than in maternal blood, and the level was positively correlated with TC, LDL-C, and high-density lipoprotein cholesterol (HDL-C) [10]. This study was designed to elucidate which perinatal factors [e.g., gestational age, birth weight, small-for-gestational age (SGA)] contribute to circulating PCSK9 levels and to reveal whether PCSK9 is a significant player in lipoprotein metabolism during the fetal period.
608
S. Araki et al. / Early Human Development 90 (2014) 607–611
Table 1 Subject characteristics and lipid profiles. Gender
Gestational age (weeks) Birth weight (g) Head circumference (cm)
Lipid profiles TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl)
Birth size
Total (n = 81)
Male (n = 45)
Female (n = 36)
AGA (n = 58)
SGA (n = 23)
38.1 [27.0–41.1] 2951 [717–4066] 32.0 [23.1–38.5]
37.3 [33.7–41.4] 2322 [1174–3704] 31.5 [28.0–35.4]
37.3 [31.3–41.4] 2749 [1782–4066] 31.9 [26.2–38.5]
36.7 [27.0–40.6] 1936** [717–2490] 30.9** [23.1–33.6]
37.2 [27.0–41.4] 2311 [717–4066] 32.5 [23.1–38.5]
67.1 [46.2–124.0] 28.4 [7.2–100.4] 35.0 [14.1–56.0] 23.5 [10.3–85.0]
81.3* [46.8–200] 43.5 [15.0–118.6] 39.0* [21.0–78.0] 22 [7.0–47.0]
72.1 [46.2–125.0] 31.5 [7.2–100.4] 37.2 [14.1–61.0] 21.5 [9.8–85.0]
74.4 [46.2–200] 32.6 [13.6–118.6] 30.1 [18.0–78.0] 26.4** [7.0–47.0]
72.3 [46.2–200] 31.7 [7.2–118.6] 36.5 [14.1–78.0] 21 [14.00–85.0]
Data are expressed as median [range]. Statistical differences were evaluated by Mann–Whitney U test for two groups. * vs. male, p b 0.05, ** vs. AGA. p b 0.01. TC, total cholesterol; LDL-C, low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; TG, triglyceride. AGA, appropriate-for-gestational age; SGA, small-for-gestational age.
2. Methods 2.1. Subjects Eighty-one neonates (45 male, 36 female), who were admitted to the neonatal intensive care unit (NICU) of the University of Occupational
(A)
and Environmental Health (UOEH) Hospital, were enrolled in the study. Neonatal data were collected, including gestational age, birth weight and head circumference. SGA was defined as both a birth weight and a birth length below the 10th percentile for gestational age. Gestational age was calculated from the mother's menstrual history and confirmed by ultrasonography. We excluded neonates with congenital
(B) r=-0.513 p
