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      Study of Five Pubertal Transition-Related Gene Polymorphisms as Risk Factors for Premature Coronary Artery Disease in a Chinese Han Population

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          Abstract

          Background

          Recently, single nucleotide polymorphisms (SNPs) (DLK-rs10144321, SIX6-rs1254337, MKRN3-rs12148769, LIN28B-rs7759938, and KCNK9-rs1469039) were found to be strongly associated with age at menarche. Recent studies also suggested that age at menarche is a heritable trait and is associated with risks for obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and all-cause mortality. Since an association between these five SNPs and premature coronary artery disease (CAD) has never been reported, we investigated whether these SNPs are associated with premature CAD and its severity in a Chinese Han population.

          Methods

          We enrolled 432 consecutive patients including 198 with premature CAD (<55 years in men and <65 years in women) and 234 controls. All subjects were genotyped for the five SNPs by the PCR-ligase detection reaction method. The associations between these SNPs and premature CAD and its severity were analyzed.

          Results

          The following genotypes were identified: GG, AG, and AA at rs10144321 and rs12148769; TT, AT, and AA at rs1254337; CC, CT, and TT at rs1469039; and TT and CT at rs7759938. Significant differences in genotype distribution frequencies at rs1254337 were found between controls and patients with premature CAD ( P<0.05). No associations were found between the five SNPs and the severity of coronary lesions (all P>0.05). Compared with controls, patients with premature CAD had a higher prevalence of T2DM and dyslipidemia, and the proportion of patients with T2DM rose significantly with an increase in the number of stenosed coronary vessels (all P<0.05). After adjustment for the clinical parameters in multivariable analysis, three factors were identified that significantly increased the risk of premature CAD: the AA genotype at rs1254337 (OR: 2.388, 95% CI: 1.190–4.792, P = 0.014), male gender (OR: 1.565, 95% CI: 1.012–2.420, P = 0.044), and T2DM (OR 2.252, 95% CI: 1.233–4.348, P = 0.015).

          Conclusions

          Among the five pubertal transition-related gene polymorphisms, we identified an association between rs1254337 and premature CAD in a Chinese Han population.

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          Most cited references14

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          Genomewide association analysis of coronary artery disease.

          Nilesh J. Samani, Jeanette Erdmann, Alistair S. Hall … (2007)
          Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. Copyright 2007 Massachusetts Medical Society.
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            Major causes of death among men and women in China.

            Jiang He, Dongfeng Gu, Xigui Wu … (2005)
            With China's rapid economic development, the disease burden may have changed in the country. We studied the major causes of death and modifiable risk factors in a nationally representative cohort of 169,871 men and women 40 years of age and older in China. Baseline data on the participants' demographic characteristics, medical history, lifestyle-related risk factors, blood pressure, and body weight were obtained in 1991 with the use of a standard protocol. The follow-up evaluation was conducted in 1999 and 2000, with a follow-up rate of 93.4 percent. We documented 20,033 deaths in 1,239,191 person-years of follow-up. The mortality from all causes was 1480.1 per 100,000 person-years among men and 1190.2 per 100,000 person-years among women. The five leading causes of death were malignant neoplasms (mortality, 374.1 per 100,000 person-years), diseases of the heart (319.1), cerebrovascular disease (310.5), accidents (54.0), and infectious diseases (50.5) among men and diseases of the heart (268.5), cerebrovascular disease (242.3), malignant neoplasms (214.1), pneumonia and influenza (45.9), and infectious diseases (35.3) among women. The multivariate-adjusted relative risk of death and the population attributable risk for preventable risk factors were as follows: hypertension, 1.48 (95 percent confidence interval, 1.44 to 1.53) and 11.7 percent, respectively; cigarette smoking, 1.23 (95 percent confidence interval, 1.18 to 1.27) and 7.9 percent; physical inactivity, 1.20 (95 percent confidence interval, 1.16 to 1.24) and 6.8 percent; and underweight (body-mass index [the weight in kilograms divided by the square of the height in meters] below 18.5), 1.47 (95 percent confidence interval, 1.42 to 1.53) and 5.2 percent. Vascular disease and cancer have become the leading causes of death among Chinese adults. Our findings suggest that control of hypertension, smoking cessation, increased physical activity, and improved nutrition should be important strategies for reducing the burden of premature death among adults in China. Copyright 2005 Massachusetts Medical Society.
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              Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

              John RB Perry, Felix Day, Cathy E Elks … (2014)
              Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality 1 . Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation 2,3 , but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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                Author and article information

                Contributors
                Shantanu Sengupta: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 25 August 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 8
                Electronic Location Identifier: e0136496
                Affiliations
                [1 ]Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, China
                [2 ]Central Laboratory, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, China
                [3 ]Department of Cardiology, The Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Nanjing 210009, China
                [4 ]Department of Endocrinology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, China
                CSIR-INSTITUTE OF GENOMICS AND INTEGRATIVE BIOLOGY, INDIA
                Author notes

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

                Conceived and designed the experiments: ZC. Performed the experiments: BC FYX. Analyzed the data: ZC. Contributed reagents/materials/analysis tools: CCT GSM LW. Wrote the paper: ZC.

                Article
                Publisher ID: PONE-D-15-14632
                DOI: 10.1371/journal.pone.0136496
                PMC ID: 4549330
                PubMed ID: 26305337
                SO-VID: 1bc63c69-a6d5-41b3-bb07-7bbe4180e572
                Copyright statement: Copyright @ 2015
                License:

                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

                History
                Date received : 16 April 2015
                Date accepted : 4 August 2015
                Page count
                Figures: 0, Tables: 5, Pages: 10
                Funding
                The study was funded by Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (Dr. Li Wei), Pudong New Area Science and Technology Development Fund (PKJ2014-Y09), and Shanghai Municipal Commission of Health and Family Planning Research Project (201440309) (Dr. Zhong Chen). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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