Age and Sex-Related Chromogranin A Gene Polymorphisms and its Association with Metabolic Syndrome Components

Abdoljalal Marjani; Nahid  Poursharifi; Atefe  Sajedi; Mahin  Tatari

doi:10.15605/jafes.039.01.09

Authors

Abdoljalal Marjani Golestan University of Medical Sciences
Nahid Poursharifi Golestan University of Medical Sciences
Atefe Sajedi Golestan University of Medical Sciences https://orcid.org/0000-0003-1112-0545
Mahin Tatari Golestan University of Medical Sciences

DOI:

https://doi.org/10.15605/jafes.039.01.09

Keywords:

age, sex, Chromogranin A, genotype, metabolic syndrome

Abstract

Introduction. The purpose of this study was to determine the possible differences in genetic polymorphisms and serum levels of chromogranin A (CgA), according to age and sex, in subjects with and without metabolic syndrome (MetS).

Methodology. The genotyping and serum level of CgA and biochemical parameters were measured by the T-ARMS-PCR and PCR-RFLP and ELISA and spectrophotometer methods, respectively.

Results. A comparison of males with and without MetS showed significantly lower high-density lipoprotein-cholesterol (HDL-C) levels than those of females.

At ages 30-70 years, both sexes showed significant differences in triglycerides (TG), fasting blood sugar (FBS), CgA levels and waist circumference (WC) when compared to the two groups. Both sexes with MetS indicated significant differences in systolic blood pressure (SBP) at ages 40-70 years, while at ages 40-59 years, there was a significant difference in HDL-C level in males.

There was a significant correlation between serum levels of FBS, TG, SBP and WC (in both sexes), and CgA in subjects with MetS. Significant correlation was found between HDL-C level and diastolic blood pressure (DBP), and CgA level in males and females, respectively. CgA genotype frequency (T-415C and C+87T polymorphisms) showed no significant differences between males and females with and without MetS, while there was only a significant difference in frequency of the genotypes T-415C when compared to males with and without MetS.

Conclusion. The CgA appears to be strongly associated with MetS components in both sexes. Variation in CgA gene expression may affect the T–415C polymorphism in males. This may mean that the structure of CgA genetics differs in different ethnic groups. Differences in the serum level and expression of CgA gene may show valuable study results that it may be expected a relationship between these variables and the MetS.

Downloads

Download data is not yet available.

Author Biographies

Abdoljalal Marjani, Golestan University of Medical Sciences

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University of Medical Sciences, Golestan Province, Gorgan, Iran

Nahid Poursharifi, Golestan University of Medical Sciences

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University of Medical Sciences, Golestan Province, Gorgan, Iran

Atefe Sajedi, Golestan University of Medical Sciences

Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University of Medical Sciences, Golestan Province, Gorgan, Iran

Mahin Tatari, Golestan University of Medical Sciences

Biostatistics Counseling and Reproductive Health Research Center, Golestan University of Medical Sciences, Golestan Province, Gorgan, Iran

References

Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-52. https://pubmed.ncbi.nlm.nih.gov/16157765. https://doi.org/10.1161/CIRCULATIONAHA.105.169404.

Marjani A, Hezarkhani S, Shahini N. Prevalence of metabolic syndrome among Fars ethnic women in North East of Iran. World J Med Sci. 2012;7(1):17-22. https://core.ac.uk/download/pdf/52204786.pdf.

Shahini N, Shahini I, Marjani A. Prevalence of metabolic syndrome in Turkmen ethnic groups in Gorgan. J Clin Diagn Res. 2013;7(9):1849-51. https://pubmed.ncbi.nlm.nih.gov/24179879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809618. https://doi.org/10.7860/JCDR/2013/6035.3331.

Marjani A, Shahini N. Age related metabolic syndrome among Fars ethnic women in Gorgan, Iran. J Pharm Biomed Sci. 2013;30 (30):929-35.

Marjani A, Moghasemi S. The metabolic syndrome among postmenopausal women in Gorgan. Biomed Res. 2012;2012:953627. https://pubmed.ncbi.nlm.nih.gov/22518135. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296160. https://doi.org/10.1155/2012/953627.

Sarbijani HM, Khoshnia M, Marjani A. The association between Metabolic Syndrome and serum levels of lipid peroxidation and interleukin-6 in Gorgan. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S86-9. https://pubmed.ncbi.nlm.nih.gov/26482051. https://doi.org/10.1016/j.dsx.2015.09.024.

Lakka HM, Laaksonen DE, Lakka TA, et al. JAMA. 2002;288(21):2709-16. https://pubmed.ncbi.nlm.nih.gov/12460094. https://doi.org/10.1001/jama.288.21.2709.

Kolovou GD, Anagnostopoulou KK, Salpea KD, Mikhailidis DP. The prevalence of metabolic syndrome in various populations. Am J Med Sci. 2007;333(6):362-71. https://pubmed.ncbi.nlm.nih.gov/17570989. https://doi.org/10.1097/MAJ.0b013e318065c3a1.

Balkau B, Vernay M, Mhamdi L, et al. The incidence and persistence of the NCEP (National Cholesterol Education Program) metabolic syndrome. The French D.E.S.I.R. study. Diabetes Metab. 2003;29(5):526-32. https://pubmed.ncbi.nlm.nih.gov/14631330. https://doi.org/10.1016/s1262-3636(07)70067-8.

Ramachandran A, Snehalatha C, Satyavani K, et al. Metabolic syndrome in urban Asian Indian adults-a population study using modified ATP III criteria. Diabetes Res Clin Pract. 2003; 60(3):199-204. https://pubmed.ncbi.nlm.nih.gov/12757982. https://doi.org/10.1016/s0168-8227(03)00060-3.

Cameron AJ, Shaw JE and Zimmet PZ. The metabolic syndrome: Prevalence in worldwide populations. Endocrinol Metab Clin North Am. 2004;33(2):351-75. https://pubmed.ncbi.nlm.nih.gov/15158523. https://doi.org/10.1016/j.ecl.2004.03.005.

The Research Group ATS-RF2 of the Italian National Research Council. Distribution of some risk factors for atherosclerosis in nine Italian population samples. Am J Epidemiol. 1981; 113(3):338-46. https://pubmed.ncbi.nlm.nih.gov/7468586. https://doi.org/10.1093/oxfordjournals.aje.a113102.

Meigs JB. Invited commentary: Insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol. 2000;152:908-11. https://pubmed.ncbi.nlm.nih.gov/11092432. https://doi.org/10.1093/aje/152.10.908.

Hanley AJ, Karter AJ, Williams K, et al. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation, 2005;112(24):3713–21. https://pubmed.ncbi.nlm.nih.gov/16344402. https://doi.org/10.1161/CIRCULATIONAHA.105.559633.

Banks P, Helle K. The release of protein from the stimulated adrenal medulla. Biochem J. 1965;97(3):40C–1. https://pubmed.ncbi.nlm.nih.gov/5881651. PMCID: PMC1264782. https://doi.org/10.1042/bj0970040c.

Blaschko H, Comline RS, Schneider FH, et al. Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic stimulation. Nature. 1967;215(5096):58-9. https://pubmed.ncbi.nlm.nih.gov/6053402. https://doi.org/10.1038/215058a0.

Schneider FH, A.D. Smith AD, Winkler H. Secretion from the adrenal medulla: biochemical evidence for exocytosis. Br J Pharmacol Chemother. 1967;31(1):94–104. https://pubmed.ncbi.nlm.nih.gov/6058830. PMCID: PMC1557278. https://doi.org/10.1111/j.1476-5381.1967.tb01980.x.

Taupenot L, Harper KL, O’Connor DT. The chromogranin–secretogranin family. N Engl J Med. 2003;348(12):1134–49. https://pubmed.ncbi.nlm.nih.gov/12646671. https://doi.org/10.1056/NEJMra021405.

Takiyyuddin MA, Parmer RJ, Kailasam MT, et al. Chromogranin A in human hypertension: influence of heredity. Hypertension, 1995;26(1):213–20. https://pubmed.ncbi.nlm.nih.gov/7607727. https://doi.org/10.1161/01.hyp.26.1.213.

Estensen ME, Hognestad A, Syversen U, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J. 2006;152(5):927.e1–6. https://pubmed.ncbi.nlm.nih.gov/17070161. https://doi.org/10.1016/j.ahj.2006.05.008.

Jansson AM, Røsjø H, Omland T, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes. Eur Heart J. 2009;30(1):25–32. https://pubmed.ncbi.nlm.nih.gov/19028779. PMCID: PMC2639087. https://doi.org/10.1093/eurheartj/ehn513.

Groop L, Orho-Melander M. The dysmetabolic syndrome. J Intern Med. 2001;250(2):105-20. https://pubmed.ncbi.nlm.nih.gov/11489060. https://doi.org/10.1046/j.1365-2796.2001.00864.x.

Tatemoto K, Efendic S, Mutt V, Makk G, Feistner GJ, Barchas JD. Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Nature. 1986; 324(6096):476–8. https://pubmed.ncbi.nlm.nih.gov/3537810. https://doi.org/10.1038/324476a0.

Gonzalez-Yanes C, Sanchez-Margalet V. Pancreastatin modulates insulin signaling in rat adipocytes: mechanisms of cross-talk. Diabetes. 2000; 49(8):1288–94. https://pubmed.ncbi.nlm.nih.gov/10923627. https://doi.org/10.2337/diabetes.49.8.1288.

Wen G, Mahata SK, Cadman P, et al. Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet. 2004;7492):197–207. https://pubmed.ncbi.nlm.nih.gov/14740315. PMCID: PMC1181918. https://doi.org/10.1086/381399.

Močnik M, Varda NM. Cardiovascular risk factors in children with obesity, preventive diagnostics and possible interventions. Metabolites. 2021;11(8):551-69. https://pubmed.ncbi.nlm.nih.gov/34436493. PMCID: PMC8398426. https://doi.org/10.3390/metabo11080551.

Simunovic M, Supe Domic D, Karin Z, et al. Serum catestatin concentrations are decreased in obese children and adolescents. Pediatr Diabetes. 2019;20(5):549-55. https://pubmed.ncbi.nlm.nih.gov/30714297. https://doi.org/10.1111/pedi.12825.

Mahapatra NR, Ghosh S, Mahata M, et al. Naturally occurring single nucleotide polymorphisms in human Chromogranin A (CHGA) gene: Association with hypertension and associated diseases. In: Chromogranins: from Cell Biology to Physiology and Biomedicine: Springer, 2017. https://doi.org/10.1007/978-3-319-58338-9_12.

Kogawa EM, Grisi DC, Falcão DP, et al. Salivary function impairment in type 2 Diabetes patients associated with concentration and genetic polymorphisms of chromogranin A. Clin Oral Investig. 2016; 20(8):2083-95. https://pubmed.ncbi.nlm.nih.gov/26750135. https://doi.org/10.1007/s00784-015-1705-z.

Zhang K, Mir SA, Hightower CM, et al. Molecular mechanism for hypertensive renal disease: Differential regulation of chromogranin a expression at 3′-untranslated region polymorphism C+ 87T by MicroRNA-107. J Am Soc Nephrol. 2015; 26(8):1816-25. https://pubmed.ncbi.nlm.nih.gov/25392232. PMCID: PMC4520173. https://doi.org/10.1681/ASN.2014060537.

Liu JL, Chen XY, Gu NN, et al. Correlation study on chromogranin A genetic polymorphism and prognosis of critically ill patients. J Crit Care. 2017;39:137-42. https://pubmed.ncbi.nlm.nih.gov/28254729. https://doi.org/10.1016/j.jcrc.2017.02.015.

O'Connor DT, Kailasam MT, Kennedy BP, Ziegler MG, Yanaihara N, Parmer RJ. Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens. 2002;20(7):1335-45. https://pubmed.ncbi.nlm.nih.gov/12131530. https://doi.org/10.1097/00004872-200207000-00020.

Mahapatra NR, O'Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest. 2005;115(7):1942-52. https://pubmed.ncbi.nlm.nih.gov/16007257. PMCID: PMC1159140. https://doi.org/10.1172/JCI24354.

Chen Y, Rao F, Rodriguez-Flores JL, et al. Common genetic variants in the chromogranin A promoter alter autonomic activity and blood pressure. Kidney Int. 2008;74(1):115–25. https://pubmed.ncbi.nlm.nih.gov/18432188. PMCID: PMC2576285. https://doi.org/10.1038/ki.2008.113.

Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics. 1995;5(6):358-63. https://pubmed.ncbi.nlm.nih.gov/8747407. https://doi.org/10.1097/00008571-199512000-00004.

Kolovou GD, Anagnostopoulou KK, Salpea KD, Mikhailidis DP. The prevalence of metabolic syndrome in various populations. Am J Med Sci. 2007;333(6):362-71. https://pubmed.ncbi.nlm.nih.gov/17570989. https://doi.org/10.1097/MAJ.0b013e318065c3a1.

Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann NY Acad Sci. 2019;1455(1):34–58. https://pubmed.ncbi.nlm.nih.gov/31588572. PMCID: PMC6899468. https://doi.org/10.1111/nyas.14249.

Herold Z, Doleschall M, Kovesdi A, Patocs A, Somogyi A. Chromogranin A and its role in the pathogenesis of diabetes mellitus. Endokrynol Pol. 2018;69(5):598-610. https://pubmed.ncbi.nlm.nih.gov/30074235. https://doi.org/10.5603/EP.a2018.0052.

D’amico MA, Ghinassi B, Izzicupo P, Manzoli L, Di Baldassarre A. Biological function and clinical relevance of chromogranin A and derived peptides. Endocr Connect. 2014;3(2): R45-54. https://pubmed.ncbi.nlm.nih.gov/24671122. PMCID: PMC5395093. https://doi.org/10.1530/EC-14-0027.

Bandyopadhyay GK, Mahata SK. Chromogranin A regulation of obesity and peripheral insulin sensitivity. Front Endocrinol (Lausanne). 2017;8:20. https://pubmed.ncbi.nlm.nih.gov/28228748. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296320. https://doi.org/10.3389/fendo.2017.00020.

Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: A report from the American Heart Association. Circulation 2015;131(4):e29-322. https://pubmed.ncbi.nlm.nih.gov/25520374. https://doi.org/10.1161/CIR.0000000000000152.

Mearinia, L, Zucchia A, Scarponia E, et al. Correlation between age and Chromogranin A determination in prostate diseases. Cancer Biomark. 2011-2012;10(3-4):117-23. https://pubmed.ncbi.nlm.nih.gov/22674297. https://doi.org/10.3233/CBM-2012-0237.

Ahmed A, Turner G, King B, et al. Midgut Neuroendocrine Tumours With Liver Metastases: Results of the UKINETS Study. Endocr Relat Cancer. 2009; 16(3):885–94. https://pubmed.ncbi.nlm.nih.gov/19458024. https://doi.org/10.1677/ERC-09-0042.

Manaf MRA, Nawi AM, Tauhid NM, et al. Prevalence of metabolic syndrome and its associated risk factors among staffs in a Malaysian public university. Sci Rep. 2021;11(1):8132. https://pubmed.ncbi.nlm.nih.gov/33854087. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047014. https://doi.org/10.1038/s41598-021-87248-1.

Sahu BS, Sonawane PJ, Mahapatra, NR. Chromogranin A: A novel susceptibility gene for essential hypertension. Cell Mol Life Sci. 2010;67(6):861–74. https://pubmed.ncbi.nlm.nih.gov/19943077. https://doi.org/10.1007/s00018-009-0208-y.

Tota B, Angelone T, Cerra MC. The surging role of chromogranin A in cardiovascular homeostasis. Front Chem. 2014;2:64. https://pubmed.ncbi.nlm.nih.gov/25177680. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132265. https://doi.org/10.3389/fchem.2014.00064.

Rao F, Chiron S, Wei Z, et al. Genetic variation within a metabolic motif in the chromogranin A promoter: pleiotropic influence on cardiometabolic risk traits in twins. Am. J. Hypertens. 2012;25(1):29–40. https://pubmed.ncbi.nlm.nih.gov/21918574. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664223. https://doi.org/10.1038/ajh.2011.163.

Chandalia M, Grundy SM, Adams-Huet B, Abate N. Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort. J Diabetes Complications. 2007;21(3):143-8. https://pubmed.ncbi.nlm.nih.gov/17493546. https://doi.org/10.1016/j.jdiacomp.2006.11.003.

Fesinmeyer MD, North KE, Ritchie MD, et al. Genetic risk factors for BMI and obesity in an ethnically diverse population: Results from the population architecture using genomics and epidemiology (PAGE) study. Obesity (Silver Spring). 2013;21(4):835–46. https://pubmed.ncbi.nlm.nih.gov/23712987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482415. https://doi.org/10.1002/oby.20268.

Ioannidis JP, Ntzani EE, Trikalinos TA. 'Racial’ differences in genetic effects for complex diseases. Nat Genet. 2004;36(12):1312–8. https://pubmed.ncbi.nlm.nih.gov/15543147. https://doi.org/10.1038/ng1474.

Lan Q, Shen M, Garcia-Rossi D, et al. Genotype frequency and F ST analysis of polymorphisms in immunoregulatory genes in Chinese and Caucasian populations. Immunogenetics. 2007;59(11):839–52. https://pubmed.ncbi.nlm.nih.gov/17938902. https://doi.org/10.1007/s00251-007-0253-3.

Spielman RS, Bastone LA, Burdick JT, Morley M, Ewens WJ, Cheung,VG. Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet. 2007;39(2):226–31. https://pubmed.ncbi.nlm.nih.gov/17206142. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005333. https://doi.org/10.1038/ng1955.

Chen Y, Rao F, Rodriguez-Flores JL, et al. Naturally occurring human genetic variation in the 3’-untranslated region of the secretory protein chromogranin A is associated with autonomic blood pressure regulation and hypertension in a sex-dependent fashion. J Am Coll Cardiol. 2008;52(18):1468-81. https://pubmed.ncbi.nlm.nih.gov/19017515. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659417. https://doi.org/10.1016/j.jacc.2008.07.047.

Subramanian L, Khan AA, Allu PKR, et al. A haplotype variant of the human chromogranin A gene (CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders. J Biol Chem.. 2017; 292(34): 13970 –85. https://pubmed.ncbi.nlm.nih.gov/28667172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572921. https://doi.org/10.1074/jbc.M117.778134.

Friese RS, Gayen JR, Mahapatra NR, Schmid-Schönbein GW, O’Connor DT, Mahata SK. Global metabolic consequences of the chromogranin A-null model of hypertension: Transcriptomic detection, pathway identification, and experimental verification. Physiol Genomics. 2010; 40: 195–207. https://pubmed.ncbi.nlm.nih.gov/19952279. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825767. https://doi.org/10.1152/physiolgenomics.00164.2009.

McBride P. Triglycerides and risk for coronary artery disease. Curr Atheroscler Rep. 2008; 10: 386–90. https://pubmed.ncbi.nlm.nih.gov/18706279. https://doi.org/10.1007/s11883-008-0060-9.