Elsevier

Gene

Volume 533, Issue 1, 1 January 2014, Pages 32-37
Gene

Association of the rs6235 variant in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene with obesity and related traits in a Taiwanese population

https://doi.org/10.1016/j.gene.2013.10.016Get rights and content

Highlights

  • We tested the association between PCSK1 rs6235 and obesity or overweight in Taiwan.

  • PCSK1 rs6235 had no association with obesity or overweight in the complete samples.

  • PCSK1 rs6235 had a significant association with overweight in male subjects.

  • PCSK1 rs6235 may predict waist circumference and diastolic blood pressure.

Abstract

One particularly interesting single nucleotide polymorphism (SNP), rs6235 (encoding an S690T substitution), in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene has been widely associated with obesity in several European cohorts. The present study was intended to investigate the association between the PCSK1 rs6235 SNP and the prevalence of overweight or obesity, or obesity-related metabolic traits in a Taiwanese population. A total of 964 Taiwanese subjects with general health examinations were analyzed. Our data revealed no association of PCSK1 rs6235 with the risk of obesity or overweight in the complete subjects. However, the PCSK1 rs6235 SNP exhibited a significant association with overweight among the male subjects (P = 0.03), but not among the female subjects. Furthermore, the carriers of GG variant had a significantly higher waist circumference than those with the CC variant (82.5 ± 11.5 vs. 81.2 ± 10.2 cm; P = 0.01) and those with the CG variant (82.5 ± 11.5 vs. 81.4 ± 10.4 cm; P = 0.021). In addition, the carriers of GG variant had a higher diastolic blood pressure than those with the CC variant (81.9 ± 14.2 vs. 80.3 ± 12.9 mm Hg; P = 0.023). Our study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects.

Introduction

The proprotein convertase subtilisin/kexin type 1 (PCSK1) gene encodes the prohormone convertase 1/3 enzyme, expressed in neuroendocrine cells, that converts inactive prohormones into functional key hormones which regulate central and/or peripheral energy metabolism (Benzinou et al., 2008). The key functions of the prohormone convertase 1/3 enzyme also include the processing of proinsulin and glucose-dependent insulinotropic polypeptide (GIP) (Ugleholdt et al., 2006). The nonsynonymous rs6235 single nucleotide polymorphism (SNP) in the PCSK1 gene encodes the S690T substitution located in the C-terminal region of the protein, which has been shown to be important for correct targeting and specificity of the prohormone convertase 1/3 enzyme (Zhou and Mains, 1994). The PCSK1 rs6235 SNP alters the amino acid sequence of the protein and substitutes serine by threonine (S690T) without any effect on the enzymatic activity (Benzinou et al., 2008). Further, the PCSK1 rs6235 SNP was shown to be associated with reduced levels of fasting plasma glucose and increased serum GIP levels (Gjesing et al., 2011). Heni et al. (2010) also suggested that the C allele of the PCSK1 rs6235 SNP was associated with significantly higher glucose-stimulated proinsulin levels, indicating reduced proinsulin conversion. In addition, Gjesing et al. (2011) proposed that PCSK1 rs6235 may be involved in increased uptake of nutrients leading to increased waist circumference as well as the increased level of circulating insulin causing reduced glycemia.

Obesity is considered as an important public health problem in Taiwan because its prevalence keeps increasing rapidly and it elevates the risk of several chronic diseases, such as T2D, stroke, and hypertension (Pan et al., 2008, Phillips, 2013). In genome-wide linkage studies, a genomic locus on chromosome 5q, which harbors the PCSK1 gene among other genes, has been identified to be associated with obesity (Bell et al., 2004, Chagnon et al., 2001, Chen et al., 2005, Hager et al., 1998). Mutations in the PCSK1 gene have been found to cause congenital deficiency of the prohormone convertase 1/3 enzyme in humans, which leads to monogenic obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis (Creemers et al., 1998, Creemers et al., 2012, Farooqi et al., 2007, Jackson et al., 1997, Jackson et al., 2003, O'Rahilly et al., 1995). These associations have clearly demonstrated that the common SNP rs6235, located at exon 14 of the PCSK1 gene, is linked with obesity and type 2 diabetes (T2D) (Benzinou et al., 2008, Rouskas et al., 2012, Strawbridge et al., 2011). However, evidence for relevance of PCSK1 rs6235 to obesity is currently discordant. The PCSK1 rs6235 SNP has been reported to predispose to childhood and adulthood obesity in individuals of European ancestry (Benzinou et al., 2008) and to be associated with obesity in Caucasian women in the United Kingdom (Kilpeläinen et al., 2009), in middle-aged Danish subjects (Sandholt et al., 2010), and in African-American subjects (Choquet et al., 2013). On the contrary, this association with obesity has not been replicated in several recent studies in Swedish (Renström et al., 2009), German (Heni et al., 2010), Chinese (Chang et al., 2010, Qi et al., 2010), Danish (Gjesing et al., 2011), and Mexican (Villalobos-Comparán et al., 2012), East Asian (Wen et al., 2012), and European-American (Choquet et al., 2013) populations.

Due to the inconsistent results, further replication studies are essential to confirm the relationship between PCSK1 rs6235 and obesity. In this Taiwanese population-based study, we aimed to assess whether the PCSK1 rs6235 polymorphism is associated with obesity and obesity-related metabolic traits. We performed a case–control association study using obese individuals with a body mass index (BMI)  27 kg/m2 and nonobese controls with a BMI < 24 kg/m2.

Section snippets

Study population

The study subjects were partially original to the previous study by Hsiao et al. (2013). The study cohort consisted of volunteers who underwent general health examinations at the Taipei Medical University Hospital in Taipei, Taiwan in 2008 (Hsiao et al., 2013). The study population included 981 participants which were in common with the previous study by Hsiao et al. (2013). All subjects were adults and unrelated. Nine participants had incomplete clinical measurements and eight participants

Results

Table 1 describes the demographic and clinical characteristics of the study population. The PCSK1 rs6235 SNP was evaluated for its contribution to obesity in the complete sample population, including 499 lean subjects (BMI < 24), 290 overweight subjects (24  BMI < 27), and 175 obese subjects (BMI  27). As shown in Table 1, the distribution of age was well matched (P = 0.616) in unrelated obese and lean subjects, but it was not matched (P = 0.022) between overweight and lean subjects. In addition, there

Discussion

Our study is the first to date to have examined whether the main effects of the PCSK1 rs6235 (S690T) SNP are significantly associated with the risk of obesity and obesity-related metabolic traits among Taiwanese individuals from general health examinations. In this study, our results showed that PCSK1 rs6235 was associated with overweight in men and obesity-related metabolic traits including both waist circumference and diastolic blood pressure levels in the Taiwanese subjects with general

Conclusions

In conclusion, our study has tested the association of PCSK1 rs6235 SNP with obesity and obesity-related metabolic traits in Taiwanese subjects with general health examinations. Our findings support the possibilities that the PCSK1 rs6235 SNP may be a determinant of overweight in men and obesity-related metabolic traits such as waist circumference and diastolic blood pressure levels in a Taiwanese population. Independent replications in large sample sizes are needed to confirm the role of the

Conflict of interest statement

The authors declare that there are no conflicts of interests.

Acknowledgments

The authors extend their sincere thanks to Vita Genomics, Inc. and SBIR grants from the Department of Economic Affairs in Taiwan for funding this research.

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