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. 2015 Jul-Sep;7(3):89-99.

Genomic Study of Cardiovascular Continuum Comorbidity

O A Makeeva  1 , A A Sleptsov  2 , E V Kulish  2 , O L Barbarash  3 , A M Mazur  4 , E B Prokhorchuk  4 , N N Chekanov  4 , V A Stepanov  2 , V P Puzyrev  5
Affiliations

Genomic Study of Cardiovascular Continuum Comorbidity

O A Makeeva et al. Acta Naturae. 2015 Jul-Sep.

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.

Keywords: association studies; cardiovascular continuum; comorbidity; genetic polymorphism; multifactorial diseases; syntropy.

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Figures

Fig. 1
Fig. 1
Venn diagram of genetic markers associated with the studied phenotypes: common and specific variants
Fig. 2
Fig. 2
Venn diagram of the relationships between all phenotype–associated genes and polymorphic variants with allowance for their association with a functional class. Intergenic relationships were developed based on the data of the SearchTool for the Retrieval of Interacting Genes/Proteins (STRING) online service
See this image and copyright information in PMC

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