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      Genetic Variants in PCSK1 Gene Are Associated with the Risk of Coronary Artery Disease in Type 2 Diabetes in a Chinese Han Population: A Case Control Study

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          Abstract

          Background

          Insulin and glucagon-like peptide 1 (GLP-1), converted by proprotein convertase 1 (PC1/3) from proinsulin and proglucagon, are associated with type 2 diabetes (T2DM) and coronary artery disease (CAD). The aim of this study is to investigate the association of PCSK1 gene, which encodes PC1/3, with the risk of CAD in Chinese patients with T2DM.

          Methods

          We selected and genotyped 5 haplotype-tagging single nucleotide polymorphisms (SNPs) at PCSK1 gene (across 39873bp locus) in a case-control study of Chinese Han population involving 425 diabetic patients (62.1% male, mean age 63.2 years) with CAD as positive cases and 258 diabetic patients (44.2% male, mean age 62.0 years) without CAD as controls.

          Results

          The allele frequencies at rs3811951 were significantly different between cases and controls (30.7% vs. 37.2%), with the allele G associated with decreased risk for CAD (OR = 0.75, 95% CI = 0.59–0.94, p = 0.013). In recessive inheritance mode, the carriers of GG had a lower risk (OR = 0.50, 95%CI = 0.31–0.82, p = 0.005), even after adjusted for gender, age, BMI and smoking (OR = 0.43, 95%CI = 0.24–0.77, p = 0.004). The carriers of the minor allele A at rs156019 had a higher risk (OR = 1.66, 95%CI = 1.10–2.50, p = 0.016 after adjustment) in dominant inheritance mode. The SNP rs6234 was also significantly associated with CAD risk in women, with the carriers of the minor allele G at rs6234 associated with a reduced CAD risk in recessive inheritance mode (OR = 0.42, 95% CI = 0.18–0.95, p = 0.036 after adjustment).

          Conclusions

          Our results found that common genetic variants in PCSK1 were associated with CAD in Chinese patients with T2DM.

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          Most cited references16

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          Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.

          Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
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            Diabetes and cardiovascular risk factors: the Framingham study.

            The impact of cardiovascular disease was compared in non-diabetics and diabetics in the Framingham cohort. In the first 20 years of the study about 6% of the women and 8% of the men were diagnosed as diabetics. The incidence of cardiovascular disease among diabetic men was twice that among non-diabetic men. Among diabetic women the incidence of cardiovascular disease was three times that among non-diabetic women. Judging from a comparison of standardized coefficients for the regression of incidence of cardiovascular disease on specified risk factors, there is no indication that the relationship of risk factors to the subsequent development of cardiovascular disease is different for diabetics and non-diabetics. This study suggests that the role of diabetes as a cardiovascular risk factor does not derive from an altered ability to contend with known risk factors.
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              Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3.

              Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported. We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient. In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome. This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                28 January 2014
                : 9
                : 1
                Affiliations
                [1]Department of Endocrinology, Peking University First Hospital, Beijing, China
                Children's National Medical Center, Washington, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: XM. Performed the experiments: XW. Analyzed the data: XW. Contributed reagents/materials/analysis tools: RL GB JZ RD NG NF XG. Wrote the paper: XW XM. Collected information: RL GB JZ RD NG NF.

                Article
                PONE-D-13-37902
                10.1371/journal.pone.0087168
                3904973
                e6b2cfed-b824-4a69-a75f-cbf27e2862ce

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 6
                Funding
                The study was granted by National 973 project (2006CB503903, 2006CB503908) in China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Population Genetics
                Genetic Polymorphism
                Medicine
                Anatomy and Physiology
                Cardiovascular System
                Endocrine System
                Cardiovascular
                Atherosclerosis
                Coronary Artery Disease
                Valvular Disease
                Clinical Genetics
                Gene Therapy
                Endocrinology
                Diabetic Endocrinology
                Diabetes Mellitus Type 2

                Uncategorized

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