Genomic Study of Cardiovascular Continuum Comorbidity

Overview

Journal Acta Naturae

Specialty Biology

Date 2015 Oct 21

PMID 26483964

Citations 10

Authors

O A Makeeva

A A Sleptsov

E V Kulish

O L Barbarash

A M Mazur

E B Prokhorchuk

N N Chekanov

V A Stepanov

V P Puzyrev

Affiliations

Soon will be listed here.

Abstract

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.

Citing Articles

Molecular function of Krüppel-like factor 7 in biology.

Mao Y, Chen Y, Zhang Z Acta Biochim Biophys Sin (Shanghai). 2023; 55(5):713-725.

PMID: 37227154 PMC: 10281879. DOI: 10.3724/abbs.2023061.

KLF7 promotes preadipocyte proliferation via activation of the Akt signaling pathway by -regulating CDKN3.

Jia Z, Jin Z, Shao S, Xu H, Li W, Khan M Acta Biochim Biophys Sin (Shanghai). 2022; 54(10):1486-1496.

PMID: 36269137 PMC: 9827951. DOI: 10.3724/abbs.2022144.

Identification of an Epigenetic Signature for Coronary Heart Disease in Postmenopausal Women's PBMC DNA.

Zhong X, Song Z, Gao P, Li M, Ning Z, Song X Mediators Inflamm. 2022; 2022:2185198.

PMID: 36032780 PMC: 9417773. DOI: 10.1155/2022/2185198.

DNA methylation of CpG sites in the chicken KLF7 promoter and Exon 2 in association with mRNA expression in abdominal adipose tissue and blood metabolic indicators.

Zhang Z, Nie C, Chen Y, Dong Y, Lin T BMC Genet. 2020; 21(1):120.

PMID: 33054719 PMC: 7558735. DOI: 10.1186/s12863-020-00923-6.

Ultrastructural Pathology of Atherosclerosis, Calcific Aortic Valve Disease, and Bioprosthetic Heart Valve Degeneration: Commonalities and Differences.

Kostyunin A, Mukhamadiyarov R, Glushkova T, Bogdanov L, Shishkova D, Osyaev N Int J Mol Sci. 2020; 21(20).

PMID: 33050133 PMC: 7587971. DOI: 10.3390/ijms21207434.

References

Martinelli N, Girelli D, Lunghi B, Pinotti M, Marchetti G, Malerba G . Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood. 2010; 116(25):5688-97. DOI: 10.1182/blood-2010-03-277079. View

Bressler J, Folsom A, Couper D, Volcik K, Boerwinkle E . Genetic variants identified in a European genome-wide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study. Am J Epidemiol. 2009; 171(1):14-23. PMC: 2800304. DOI: 10.1093/aje/kwp377. View

Rochel N, Wurtz J, Mitschler A, Klaholz B, Moras D . The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000; 5(1):173-9. DOI: 10.1016/s1097-2765(00)80413-x. View

Wen H, Lin R, Jiao Y, Wang F, Wang S, Lu D . Two polymorphisms in NEDD4L gene and essential hypertension in Chinese Hans - a population-based case-control study. Clin Exp Hypertens. 2008; 30(2):87-94. DOI: 10.1080/10641960801949909. View

Puzyrev V, Makeeva O, Freidin M . Syntropy, genetic testing and personalized medicine. Per Med. 2018; 7(4):399-405. DOI: 10.2217/pme.10.35. View

Harvey M, Belleau P, Barden N . Gene interactions in depression: pathways out of darkness. Trends Genet. 2007; 23(11):547-56. DOI: 10.1016/j.tig.2007.08.011. View

Rodenas-Cuadrado P, Ho J, Vernes S . Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet. 2013; 22(2):171-8. PMC: 3895625. DOI: 10.1038/ejhg.2013.100. View

Chi Y, Frantz J, Oh B, Hansen L, Dhe-Paganon S, Shoelson S . Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell. 2002; 10(5):1129-37. DOI: 10.1016/s1097-2765(02)00704-9. View

Lanier L, Chang C, Phillips J . Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol. 1994; 153(6):2417-28. View

10.

Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg M . A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet. 2002; 31(2):141-9. DOI: 10.1038/ng892. View

11.

Miyagawa K, Tsuruga T, Kinomura A, Usui K, Katsura M, Tashiro S . A role for RAD54B in homologous recombination in human cells. EMBO J. 2002; 21(1-2):175-80. PMC: 125815. DOI: 10.1093/emboj/21.1.175. View

12.

Conroy J, Cochrane L, Anney R, Sutcliffe J, Carthy P, Dunlop A . Fine mapping and association studies in a candidate region for autism on chromosome 2q31-q32. Am J Med Genet B Neuropsychiatr Genet. 2008; 150B(4):535-44. DOI: 10.1002/ajmg.b.30854. View

13.

Vassiliadis E, Barascuk N, Didangelos A, Karsdal M . Novel cardiac-specific biomarkers and the cardiovascular continuum. Biomark Insights. 2012; 7:45-57. PMC: 3347891. DOI: 10.4137/BMI.S9536. View

14.

Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H . Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007; 131(6):1190-203. DOI: 10.1016/j.cell.2007.11.025. View

15.

Irisawa M, Inoue J, Ozawa N, Mori K, Sato R . The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage. J Biol Chem. 2009; 284(42):28995-9004. PMC: 2781446. DOI: 10.1074/jbc.M109.041376. View

16.

Galisteo M, Dikic I, Batzer A, Langdon W, Schlessinger J . Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995; 270(35):20242-5. DOI: 10.1074/jbc.270.35.20242. View

17.

Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I . Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007; 67(8):3963-9. DOI: 10.1158/0008-5472.CAN-06-2004. View

18.

Pullinger C, Hennessy L, Chatterton J, Liu W, Love J, Mendel C . Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest. 1995; 95(3):1225-34. PMC: 441461. DOI: 10.1172/JCI117772. View

19.

Cookson W . The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol. 2004; 4(12):978-88. DOI: 10.1038/nri1500. View

20.

Zhernakova A, van Diemen C, Wijmenga C . Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2008; 10(1):43-55. DOI: 10.1038/nrg2489. View