vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-23-03vavilov-3627Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSГенетическая канва герменевтики феномена сочетания болезней человекаGenetic outline of the hermeneutics of the diseases connection phenomenon in humanhttps://orcid.org/0000-0002-1103-3073БрагинаЕ. Ю.BraginaE. Yu.

Томск

Tomsk

elena.bragina@medgenetics.ruhttps://orcid.org/0000-0002-2113-4556ПузырёвВ. П.PuzyrevV. P.

Томск

Tomsk

Научно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук; Сибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian FederationНаучно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук; Сибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical UniversityRussian Federation202306032023271717Copyright © Брагина Е.Ю., Пузырёв В.П., 20232023Брагина Е.Ю., Пузырёв В.П.Bragina E.Y., Puzyrev V.P.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3627

Структура заболеваний у человека неоднородна, характеризуется различными вариантами сочетаний болезней, включая сопутствующие патологии, связанные общим патогенетическим механизмом, а также болезни, редко проявляющиеся совместно на фенотипическом уровне. В последнее время отмечается рост интереса к изучению закономерностей развития не отдельных болезней, а целых семейств, связанных общими патогенетическими механизмами и общими генами, вовлеченными в их развитие. В результате установлен существенный генетический компонент, контролирующий образование конгломератов болезней сложным образом, через функционально взаимодействующие модули отдельных генов в генных сетях. Аналитический обзор исследований по проблематике разных аспектов сочетания болезней и является целью настоящей работы. В обзоре использована метафора герменевтического круга для познания структуры закономерных связей между болезнями, приведены концептуальные рамки, связанные с множественностью заболеваний у индивида. Рассмотрена существующая терминология применительно к ним, среди которых мультиморбидность, полипатии, коморбидность, конгломераты, семейства, «вторые болезни», синтропия и другие. Приведены ключевые результаты, чрезвычайно полезные, прежде всего, для описания генетической архитектуры болезней многофакторной природы. Обобщения по проблеме исследования феномена сочетания болезней позволяют приблизиться к систематизации и естественной классификации болезней. С точки зрения практического здравоохранения описание феномена сочетания болезней имеет решающее значение для расширения интерпретационного горизонта клинициста и выхода за пределы узких, ориентированных на конкретную болезнь терапевтических решений.

The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest together. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analytical review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The review uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is considered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, “second diseases”, syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic architecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician’s interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions.

феномен сочетания болезнейсинтропиядистропиякоморбидностьгерменевтикаdiseases connection phenomenonsyntropydystropycomorbidityhermeneuticsThis study was carried out within the framework of the State Task of the Ministry of Science and Higher Education, No. 122020300041-7.ReferencesAzaïs B., Bowis J., Wismar M. Facing the challenge of multimorbidity. J. Comorb. 2016;6(1):1-3. DOI 10.15256/joc.2016.6.71.Azaïs B., Bowis J., Wismar M. Facing the challenge of multimorbidity. J. Comorb. 2016;6(1):1-3. DOI 10.15256/joc.2016.6.71.Barabási A.L., Gulbahce N., Loscalzo J. Network medicine: a networkbased approach to human disease. Nat. Rev. Genet. 2011;12(1):56-68. DOI 10.1038/nrg2918.Barabási A.L., Gulbahce N., Loscalzo J. Network medicine: a networkbased approach to human disease. Nat. Rev. Genet. 2011;12(1):56-68. DOI 10.1038/nrg2918.Biesecker L.G. Lumping and splitting: molecular biology in the genetics clinic. Clin. Genet. 1998;53(1):3-7. DOI 10.1034/j.1399-0004.1998.531530102.x.Biesecker L.G. Lumping and splitting: molecular biology in the genetics clinic. Clin. Genet. 1998;53(1):3-7. DOI 10.1034/j.1399-0004.1998.531530102.x.Blair D.R., Lyttle C.S., Mortensen J.M., Bearden C.F., Jensen A.B., Khiabanian H., Melamed R., Rabadan R., Bernstam E.V., Brunak S., Jensen L.J., Nicolae D., Shah N.H., Grossman R.L., Cox N.J., White K.P., Rzhetsky A. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell. 2013;155(1):70-80. DOI 10.1016/j.cell.2013.08.030.Blair D.R., Lyttle C.S., Mortensen J.M., Bearden C.F., Jensen A.B., Khiabanian H., Melamed R., Rabadan R., Bernstam E.V., Brunak S., Jensen L.J., Nicolae D., Shah N.H., Grossman R.L., Cox N.J., White K.P., Rzhetsky A. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell. 2013;155(1):70-80. DOI 10.1016/j.cell.2013.08.030.Bosch L., Bosch B., De Boeck K., Nawrot T., Meyts I., Vanneste D., Le Bourlegat C.A., Croda J., da Silva Filho L.V.R.F. Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory. BMC Infect. Dis. 2017;17(1):340. DOI 10.1186/s12879-017-2448-z.Bosch L., Bosch B., De Boeck K., Nawrot T., Meyts I., Vanneste D., Le Bourlegat C.A., Croda J., da Silva Filho L.V.R.F. Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory. BMC Infect. Dis. 2017;17(1):340. DOI 10.1186/s12879-017-2448-z.Boyle E.A., Li Y.I., Pritchard J.K. An expanded view of complex traits: from polygenic to omnigenic. Cell. 2017;169(7):1177-1186. DOI 10.1016/j.cell.2017.05.038.Boyle E.A., Li Y.I., Pritchard J.K. An expanded view of complex traits: from polygenic to omnigenic. Cell. 2017;169(7):1177-1186. DOI 10.1016/j.cell.2017.05.038.Bragina E.Y., Goncharova I.A., Garaeva A.F., Nemerov E.V., Babovskaya A.A., Karpov A.B., Semenova Y.V., Zhalsanova I.Z., Gomboeva D.E., Saik O.V., Zolotareva O.I., Ivanisenko V.A., Dosenko V.E., Hofestaedt R., Freidin M.B. Molecular relationships between bronchial asthma and hypertension as comorbid diseases. J. Integr. Bioinform. 2018;15(4):20180052. DOI 10.1515/jib-2018-0052.Bragina E.Y., Goncharova I.A., Garaeva A.F., Nemerov E.V., Babovskaya A.A., Karpov A.B., Semenova Y.V., Zhalsanova I.Z., Gomboeva D.E., Saik O.V., Zolotareva O.I., Ivanisenko V.A., Dosenko V.E., Hofestaedt R., Freidin M.B. Molecular relationships between bronchial asthma and hypertension as comorbid diseases. J. Integr. Bioinform. 2018;15(4):20180052. DOI 10.1515/jib-2018-0052.Bragina E.Yu., Goncharova I.A., Zhalsanova I.Z., Nemerov E.V., Nazarenko M.S., Freidin M.B., Puzyrev V.P. Genetic comorbidity of hypertension and bronchial asthma. Arterial’naya Gipertenziya = Arterial Hypertension. 2022;28(1):87-95. DOI 10.18705/1607-419X- 2022-28-1-87-95. (in Russian)Bragina E.Yu., Goncharova I.A., Zhalsanova I.Z., Nemerov E.V., Nazarenko M.S., Freidin M.B., Puzyrev V.P. Genetic comorbidity of hypertension and bronchial asthma. Arterial’naya Gipertenziya = Arterial Hypertension. 2022;28(1):87-95. DOI 10.18705/1607-419X- 2022-28-1-87-95. (in Russian)Branigan G.L., Soto M., Neumayer L., Rodgers K., Brinton R.D. Association between hormone-modulating breast cancer therapies and incidence of neurodegenerative outcomes for women with breast cancer. JAMA Netw. Open. 2020;3(3):e201541. DOI 10.1001/jamanetworkopen.2020.1541.Branigan G.L., Soto M., Neumayer L., Rodgers K., Brinton R.D. Association between hormone-modulating breast cancer therapies and incidence of neurodegenerative outcomes for women with breast cancer. JAMA Netw. Open. 2020;3(3):e201541. DOI 10.1001/jamanetworkopen.2020.1541.Brown M.S., Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34-47. DOI 10.1126/science.3513311.Brown M.S., Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34-47. DOI 10.1126/science.3513311.Brunner H.G., van Driel M.A. From syndrome families to functional genomics. Nat. Rev. Genet. 2004;5(7):545-551. DOI 10.1038/nrg1383.Brunner H.G., van Driel M.A. From syndrome families to functional genomics. Nat. Rev. Genet. 2004;5(7):545-551. DOI 10.1038/nrg1383.Catalá-López F., Suárez-Pinilla M., Suárez-Pinilla P., Valderas J.M., Gómez-Beneyto M., Martinez S., Balanzá-Martínez V., Climent J., Valencia A., McGrath J., Crespo-Facorro B., Sanchez-Moreno J., Vieta E., Tabarés-Seisdedos R. Inverse and direct cancer comorbidity in people with central nervous system disorders: a metaanalysis of cancer incidence in 577,013 participants of 50 observational studies. Psychother. Psychosom. 2014;83(2):89-105. DOI 10.1159/000356498.Catalá-López F., Suárez-Pinilla M., Suárez-Pinilla P., Valderas J.M., Gómez-Beneyto M., Martinez S., Balanzá-Martínez V., Climent J., Valencia A., McGrath J., Crespo-Facorro B., Sanchez-Moreno J., Vieta E., Tabarés-Seisdedos R. Inverse and direct cancer comorbidity in people with central nervous system disorders: a metaanalysis of cancer incidence in 577,013 participants of 50 observational studies. Psychother. Psychosom. 2014;83(2):89-105. DOI 10.1159/000356498.Cohen J., Pertsemlidis A., Kotowski I.K., Graham R., Garcia C.K., Hobbs H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 2005;37(2):161-165. DOI 10.1038/ng1509.Cohen J., Pertsemlidis A., Kotowski I.K., Graham R., Garcia C.K., Hobbs H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 2005;37(2):161-165. DOI 10.1038/ng1509.Crespi B.J., Go M.C. Diametrical diseases reflect evolutionary-genetic tradeoffs: evidence from psychiatry, neurology, rheumatology, oncology and immunology. Evol. Med. Public. Health. 2015;2015(1): 216-253. DOI 10.1093/emph/eov021.Crespi B.J., Go M.C. Diametrical diseases reflect evolutionary-genetic tradeoffs: evidence from psychiatry, neurology, rheumatology, oncology and immunology. Evol. Med. Public. Health. 2015;2015(1): 216-253. DOI 10.1093/emph/eov021.Davidenkov S.N. Evolutionary Genetic Problems in Neuropathology. Leningrad: GIDUV Publ., 1947. (in Russian)Davidenkov S.N. Evolutionary Genetic Problems in Neuropathology. Leningrad: GIDUV Publ., 1947. (in Russian)Dilman V.M. Aging, Menopause, Cancer. Moscow, 1968. (in Russian)Dilman V.M. Aging, Menopause, Cancer. Moscow, 1968. (in Russian)Diss G., Lehner B. The genetic landscape of a physical interaction. eLife. 2018;7:e32472. DOI 10.7554/eLife.32472.Diss G., Lehner B. The genetic landscape of a physical interaction. eLife. 2018;7:e32472. DOI 10.7554/eLife.32472.Divac A., Nikolic A., Mitic-Milikic M., Nagorni-Obradovic L., Petrovic-Stanojevic N., Dopudja-Pantic V., Nadaskic R., Savic A., Radojkovic D. High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease. J. Cyst. Fibros. 2004;3(3):189-191. DOI 10.1016/j.jcf.2004.05.049.Divac A., Nikolic A., Mitic-Milikic M., Nagorni-Obradovic L., Petrovic-Stanojevic N., Dopudja-Pantic V., Nadaskic R., Savic A., Radojkovic D. High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease. J. Cyst. Fibros. 2004;3(3):189-191. DOI 10.1016/j.jcf.2004.05.049.Dong G., Feng J., Sun F., Chen J., Zhao X.M. A global overview of genetically interpretable multimorbidities among common diseases in the UK Biobank. Genome Med. 2021;13(1):110. DOI 10.1186/s13073-021-00927-6.Dong G., Feng J., Sun F., Chen J., Zhao X.M. A global overview of genetically interpretable multimorbidities among common diseases in the UK Biobank. Genome Med. 2021;13(1):110. DOI 10.1186/s13073-021-00927-6.Dzau V.J., Antman E.M., Black H.R., Hayes D.L., Manson J.E., Plutzky J., Popma J.J., Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. Part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114(25):2850-2870. DOI 10.1161/CIRCULATIONAHA.106.655688.Dzau V.J., Antman E.M., Black H.R., Hayes D.L., Manson J.E., Plutzky J., Popma J.J., Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. Part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114(25):2850-2870. DOI 10.1161/CIRCULATIONAHA.106.655688.Feinstein A.R. The pre-therapeutic classification of co-morbidity in chronic disease. J. Chronic Dis. 1970;23(7):455-468. DOI 10.1016/0021-9681(70)90054-8.Feinstein A.R. The pre-therapeutic classification of co-morbidity in chronic disease. J. Chronic Dis. 1970;23(7):455-468. DOI 10.1016/0021-9681(70)90054-8.Ferreira M.A., Matheson M.C., Tang C.S., Granell R., Ang W., Hui J., Kiefer A.K., Duffy D.L., Baltic S., Danoy P., Bui M., Price L., Sly P.D., Eriksson N., Madden P.A., Abramson M.J., Holt P.G., Heath A.C., Hunter M., Musk B., Robertson C.F., Le Souëf P., Montgomery G.W., Henderson A.J., Tung J.Y., Dharmage S.C., Brown M.A., James A., Thompson P.J., Pennell C., Martin N.G., Evans D.M., Hinds D.A., Hopper J.L., Australian Asthma Genetics Consortium Collaborators. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J. Allergy Clin. Immunol. 2014;133(6):1564-1571. DOI 10.1016/j.jaci.2013.10.030.Ferreira M.A., Matheson M.C., Tang C.S., Granell R., Ang W., Hui J., Kiefer A.K., Duffy D.L., Baltic S., Danoy P., Bui M., Price L., Sly P.D., Eriksson N., Madden P.A., Abramson M.J., Holt P.G., Heath A.C., Hunter M., Musk B., Robertson C.F., Le Souëf P., Montgomery G.W., Henderson A.J., Tung J.Y., Dharmage S.C., Brown M.A., James A., Thompson P.J., Pennell C., Martin N.G., Evans D.M., Hinds D.A., Hopper J.L., Australian Asthma Genetics Consortium Collaborators. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J. Allergy Clin. Immunol. 2014;133(6):1564-1571. DOI 10.1016/j.jaci.2013.10.030.Ferreira M.A., Vonk J.M., Baurecht H., Marenholz I., Tian C., Hoffman J.D., Helmer Q., Tillander A., Ullemar V., van Dongen J., … Jorgenson E., Lee Y.A., Boomsma D.I., Almqvist C., Karlsson R., Koppelman G.H., Paternoster L. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat. Genet. 2017;49(12):1752-1757. DOI 10.1038/ng.3985.Ferreira M.A., Vonk J.M., Baurecht H., Marenholz I., Tian C., Hoffman J.D., Helmer Q., Tillander A., Ullemar V., van Dongen J., … Jorgenson E., Lee Y.A., Boomsma D.I., Almqvist C., Karlsson R., Koppelman G.H., Paternoster L. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat. Genet. 2017;49(12):1752-1757. DOI 10.1038/ng.3985.Flannick J., Thorleifsson G., Beer N.L., Jacobs S.B., Grarup N., Burtt N.P., Mahajan A., Fuchsberger C., Atzmon G., Benediktsson R., … Pedersen O., Go-T2D Consortium, T2D-GENES Consortium, Groop L., Cox D.R., Stefansson K., Altshuler D. Loss-offunction mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 2014;46(4):357-363. DOI 10.1038/ng.2915.Flannick J., Thorleifsson G., Beer N.L., Jacobs S.B., Grarup N., Burtt N.P., Mahajan A., Fuchsberger C., Atzmon G., Benediktsson R., … Pedersen O., Go-T2D Consortium, T2D-GENES Consortium, Groop L., Cox D.R., Stefansson K., Altshuler D. Loss-offunction mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 2014;46(4):357-363. DOI 10.1038/ng.2915.Forés-Martos J., Boullosa C., Rodrigo-Domínguez D., Sánchez-Valle J., Suay-García B., Climent J., Falcó A., Valencia A., Puig-Butillé J.A., Puig S., Tabarés-Seisdedos R. Transcriptomic and genetic associations between Alzheimer’s disease, Parkinson’s disease, and cancer. Cancers (Basel). 2021;13(12):2990. DOI 10.3390/cancers13122990.Forés-Martos J., Boullosa C., Rodrigo-Domínguez D., Sánchez-Valle J., Suay-García B., Climent J., Falcó A., Valencia A., Puig-Butillé J.A., Puig S., Tabarés-Seisdedos R. Transcriptomic and genetic associations between Alzheimer’s disease, Parkinson’s disease, and cancer. Cancers (Basel). 2021;13(12):2990. DOI 10.3390/cancers13122990.Freydin M.B., Ogorodova L.M., Puzyrev V.P. Pathogenetics of Allergic Diseases. Novosibirsk, 2015. (in Russian)Freydin M.B., Ogorodova L.M., Puzyrev V.P. Pathogenetics of Allergic Diseases. Novosibirsk, 2015. (in Russian)Gadamer G.-G. On the Circle of Understanding. The Relevance of Beauty. Moscow, 2010. (in Russian)Gadamer G.-G. On the Circle of Understanding. The Relevance of Beauty. Moscow, 2010. (in Russian)Goh K.I., Cusick M.E., Valle D., Childs B., Vidal M., Barabási A.L. The human disease network. Proc. Natl. Acad. Sci. USA. 2007; 104(21):8685-8690. DOI 10.1073/pnas.0701361104.Goh K.I., Cusick M.E., Valle D., Childs B., Vidal M., Barabási A.L. The human disease network. Proc. Natl. Acad. Sci. USA. 2007; 104(21):8685-8690. DOI 10.1073/pnas.0701361104.Golubovsky M.D. Commentary on the Dialogue on Systematics. Nadezhda Mandelstam and Lyubishchev. Priroda = Nature. 2006;6: 77-80. (in Russian)Golubovsky M.D. Commentary on the Dialogue on Systematics. Nadezhda Mandelstam and Lyubishchev. Priroda = Nature. 2006;6: 77-80. (in Russian)Gomboeva D.E., Bragina E.Y., Nazarenko M.S., Puzyrev V.P. The inverse comorbidity between oncological diseases and Huntington’s disease: review of epidemiological and biological evidence. Russ. J. Genet. 2020;56(3):269-279. DOI 10.1134/S1022795420030059.Gomboeva D.E., Bragina E.Y., Nazarenko M.S., Puzyrev V.P. The inverse comorbidity between oncological diseases and Huntington’s disease: review of epidemiological and biological evidence. Russ. J. Genet. 2020;56(3):269-279. DOI 10.1134/S1022795420030059.Guglielmotto M., Manassero G., Vasciaveo V., Venezia M., Tabaton M., Tamagno E. Estrogens inhibit amyloid-β-mediated paired helical filament-like conformation of tau through antioxidant activity and miRNA 218 regulation in hTau mice. J. Alzheimers Dis. 2020;77(3):1339-1351. DOI 10.3233/JAD-200707.Guglielmotto M., Manassero G., Vasciaveo V., Venezia M., Tabaton M., Tamagno E. Estrogens inhibit amyloid-β-mediated paired helical filament-like conformation of tau through antioxidant activity and miRNA 218 regulation in hTau mice. J. Alzheimers Dis. 2020;77(3):1339-1351. DOI 10.3233/JAD-200707.Holodkovsky N.A. Lamarckism and Geoffreyism. Priroda = Nature. 1915;4:533-542. (in Russian)Holodkovsky N.A. Lamarckism and Geoffreyism. Priroda = Nature. 1915;4:533-542. (in Russian)Ibáñez K., Boullosa C., Tabarés-Seisdedos R., Baudot A., Valencia A. Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic metaanalyses. PLoS Genet. 2014;10(2):e1004173. DOI 10.1371/journal.pgen.1004173.Ibáñez K., Boullosa C., Tabarés-Seisdedos R., Baudot A., Valencia A. Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic metaanalyses. PLoS Genet. 2014;10(2):e1004173. DOI 10.1371/journal.pgen.1004173.Jia G., Zhong X., Im H.K., Schoettler N., Pividori M., Hogarth D.K., Sperling A.I., White S.R., Naureckas E.T., Lyttle C.S., Terao C., Kamatani Y., Akiyama M., Matsuda K., Kubo M., Cox N.J., Ober C., Rzhetsky A., Solway J. Discerning asthma endotypes through comorbidity mapping. Nat. Commun. 2022;13(1):6712. DOI 10.1038/s41467-022-33628-8.Jia G., Zhong X., Im H.K., Schoettler N., Pividori M., Hogarth D.K., Sperling A.I., White S.R., Naureckas E.T., Lyttle C.S., Terao C., Kamatani Y., Akiyama M., Matsuda K., Kubo M., Cox N.J., Ober C., Rzhetsky A., Solway J. Discerning asthma endotypes through comorbidity mapping. Nat. Commun. 2022;13(1):6712. DOI 10.1038/s41467-022-33628-8.Jones K.L. Hereditary Syndromes According to David Smith. Atlasreference book. Moscow: Praktika Publ., 2011. (in Russian)Jones K.L. Hereditary Syndromes According to David Smith. Atlasreference book. Moscow: Praktika Publ., 2011. (in Russian)Kathiresan S., Willer C.J., Peloso G.M., Demissie S., Musunuru K., Schadt E.E., Kaplan L., Bennett D., Li Y., Tanaka T., … Peltonen L., Orho-Melander M., Ordovas J.M., Boehnke M., Abecasis G.R., Mohlke K.L., Cupples L.A. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 2009;41(1):56-65. DOI 10.1038/ng.291.Kathiresan S., Willer C.J., Peloso G.M., Demissie S., Musunuru K., Schadt E.E., Kaplan L., Bennett D., Li Y., Tanaka T., … Peltonen L., Orho-Melander M., Ordovas J.M., Boehnke M., Abecasis G.R., Mohlke K.L., Cupples L.A. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 2009;41(1):56-65. DOI 10.1038/ng.291.Kaznacheev V.P. Modern Aspects of Adaptation. Novosibirsk, 1980. (in Russian)Kaznacheev V.P. Modern Aspects of Adaptation. Novosibirsk, 1980. (in Russian)Kingston A., Robinson L., Booth H., Knapp M., Jagger C., MODEM project. Projections of multi-morbidity in the older population in England to 2035: estimates from the Population Ageing and Care Simulation (PACSim) model. Age Ageing. 2018;47(3):374-380. DOI 10.1093/ageing/afx201.Kingston A., Robinson L., Booth H., Knapp M., Jagger C., MODEM project. Projections of multi-morbidity in the older population in England to 2035: estimates from the Population Ageing and Care Simulation (PACSim) model. Age Ageing. 2018;47(3):374-380. DOI 10.1093/ageing/afx201.Kolchanov N.A., Ignatieva E.V., Podkolodnaya O.A., Lihoschvai V.A. Gene networks. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2013;17(4-2):833-850. (in Russian)Kolchanov N.A., Ignatieva E.V., Podkolodnaya O.A., Lihoschvai V.A. Gene networks. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2013;17(4-2):833-850. (in Russian)Krylov A.A. To the problem of compatibility of diseases. Klinicheskaya Meditsyna = Clinical Medicine. 2000;78(1):56-58. (in Russian)Krylov A.A. To the problem of compatibility of diseases. Klinicheskaya Meditsyna = Clinical Medicine. 2000;78(1):56-58. (in Russian)Lazarevic-Pasti T., Leskovac A., Momic T., Petrovic S., Vasic V. Modulators of acetylcholinesterase activity: from Alzheimer’s disease to anti-cancer drugs. Curr. Med. Chem. 2017;24(30):3283-3309. DOI 10.2174/0929867324666170705123509.Lazarevic-Pasti T., Leskovac A., Momic T., Petrovic S., Vasic V. Modulators of acetylcholinesterase activity: from Alzheimer’s disease to anti-cancer drugs. Curr. Med. Chem. 2017;24(30):3283-3309. DOI 10.2174/0929867324666170705123509.Liu X., Li Y.I., Pritchard J.K. Trans effects on gene expression can drive omnigenic inheritance. Cell. 2019;177(4):1022-1034.e6. DOI 10.1016/j.cell.2019.04.014.Liu X., Li Y.I., Pritchard J.K. Trans effects on gene expression can drive omnigenic inheritance. Cell. 2019;177(4):1022-1034.e6. DOI 10.1016/j.cell.2019.04.014.Lupski J.R., Belmont J.W., Boerwinkle E., Gibbs R.A. Clan genomics and the complex architecture of human disease. Cell. 2011;147(1): 32-43. DOI 10.1016/j.cell.2011.09.008.Lupski J.R., Belmont J.W., Boerwinkle E., Gibbs R.A. Clan genomics and the complex architecture of human disease. Cell. 2011;147(1): 32-43. DOI 10.1016/j.cell.2011.09.008.Manolio T.A. Bringing genome-wide association findings into clinical use. Nat. Rev. Genet. 2013;14(8):549-558. DOI 10.1038/nrg3523.Manolio T.A. Bringing genome-wide association findings into clinical use. Nat. Rev. Genet. 2013;14(8):549-558. DOI 10.1038/nrg3523.Mauro A.A., Ghalambor C.K. Trade-offs, pleiotropy, and shared molecular pathways: a unified view of constraints on adaptation. Integr. Comp. Biol. 2020;60(2):332-347. DOI 10.1093/icb/icaa056.Mauro A.A., Ghalambor C.K. Trade-offs, pleiotropy, and shared molecular pathways: a unified view of constraints on adaptation. Integr. Comp. Biol. 2020;60(2):332-347. DOI 10.1093/icb/icaa056.McKusick V.A. Some principles of medical genetics. In: Bartalos M. (Ed.) Genetics in Medical Practice. London: Pitman Medical, 1968;43-54.McKusick V.A. Some principles of medical genetics. In: Bartalos M. (Ed.) Genetics in Medical Practice. London: Pitman Medical, 1968;43-54.McKusick V.A. On lumpers and splitters, or the nosology of genetic disease. Perspect. Biol. Med. 1969;12(2):298-312. DOI 10.1353/pbm.1969.0039.McKusick V.A. On lumpers and splitters, or the nosology of genetic disease. Perspect. Biol. Med. 1969;12(2):298-312. DOI 10.1353/pbm.1969.0039.Murmann A.E., Gao Q.Q., Putzbach W.E., Patel M., Bartom E.T., Law C.Y., Bridgeman B., Chen S., McMahon K.M., Thaxton C.S., Peter M.E. Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells. EMBO Rep. 2018;19(3): e45336. DOI 10.15252/embr.201745336.Murmann A.E., Gao Q.Q., Putzbach W.E., Patel M., Bartom E.T., Law C.Y., Bridgeman B., Chen S., McMahon K.M., Thaxton C.S., Peter M.E. Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells. EMBO Rep. 2018;19(3): e45336. DOI 10.15252/embr.201745336.Navickas R., Petric V.K., Feigl A.B., Seychell M. Multimorbidity: what do we know? What should we do? J. Comorb. 2016;6(1):4-11. DOI 10.15256/joc.2016.6.72.Navickas R., Petric V.K., Feigl A.B., Seychell M. Multimorbidity: what do we know? What should we do? J. Comorb. 2016;6(1):4-11. DOI 10.15256/joc.2016.6.72.Nazarenko M.S., Slepcov A.A., Puzyrev V.P. “Mendelian code” in the genetic structure of complex diseases. Genetics. 2022;58(10):1101-1111. DOI 10.31857/S0016675822100058. (in Russian)Nazarenko M.S., Slepcov A.A., Puzyrev V.P. “Mendelian code” in the genetic structure of complex diseases. Genetics. 2022;58(10):1101-1111. DOI 10.31857/S0016675822100058. (in Russian)Opitz J.M., Neri G. Historical perspective on developmental concepts and terminology. Am. J. Med. Genet. A. 2013;161A(11):2711-2725. DOI 10.1002/ajmg.a.36244.Opitz J.M., Neri G. Historical perspective on developmental concepts and terminology. Am. J. Med. Genet. A. 2013;161A(11):2711-2725. DOI 10.1002/ajmg.a.36244.Paigen K., Eppig J.T. A mouse phenome project. Mamm. Genome. 2000;11(9):715-717. DOI 10.1007/s003350010152.Paigen K., Eppig J.T. A mouse phenome project. Mamm. Genome. 2000;11(9):715-717. DOI 10.1007/s003350010152.Palmer C.N., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H., Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J., O’Regan G.M., Watson R.M., Cecil J.E., Bale S.J., Compton J.G., DiGiovanna J.J., Fleckman P., Lewis-Jones S., Arseculeratne G., Sergeant A., Munro C.S., El Houate B., McElreavey K., Halkjaer L.B., Bisgaard H., Mukhopadhyay S., McLean W.H. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 2006;38(4):441-446. DOI 10.1038/ng1767.Palmer C.N., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H., Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J., O’Regan G.M., Watson R.M., Cecil J.E., Bale S.J., Compton J.G., DiGiovanna J.J., Fleckman P., Lewis-Jones S., Arseculeratne G., Sergeant A., Munro C.S., El Houate B., McElreavey K., Halkjaer L.B., Bisgaard H., Mukhopadhyay S., McLean W.H. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 2006;38(4):441-446. DOI 10.1038/ng1767.Pepe P., Vatrano S., Cannarella R., Calogero A.E., Marchese G., Ravo M., Fraggetta F., Pepe L., Pennisi M., Romano C., Ferri R., Salemi M. A study of gene expression by RNA-seq in patients with prostate cancer and in patients with Parkinson disease: an example of inverse comorbidity. Mol. Biol. Rep. 2021;48(11):7627-7631. DOI 10.1007/s11033-021-06723-0.Pepe P., Vatrano S., Cannarella R., Calogero A.E., Marchese G., Ravo M., Fraggetta F., Pepe L., Pennisi M., Romano C., Ferri R., Salemi M. A study of gene expression by RNA-seq in patients with prostate cancer and in patients with Parkinson disease: an example of inverse comorbidity. Mol. Biol. Rep. 2021;48(11):7627-7631. DOI 10.1007/s11033-021-06723-0.Pfaundler M., Seht L.V. Über Syntropie von Krankheitszuständen. Z. Kinder-Heilk. 1921;30:100-120. DOI 10.1007/BF02222706. Piro R.M. Network medicine: linking disorders. Hum. Genet. 2012; 131(12):1811-1820. DOI 10.1007/s00439-012-1206-y.Pfaundler M., Seht L.V. Über Syntropie von Krankheitszuständen. Z. Kinder-Heilk. 1921;30:100-120. DOI 10.1007/BF02222706. Piro R.M. Network medicine: linking disorders. Hum. Genet. 2012; 131(12):1811-1820. DOI 10.1007/s00439-012-1206-y.Puzyrev V.P. Genetic bases of human comorbidity. Russ. J. Genet. 2015;51(4):408-417. DOI 10.1134/S1022795415040092.Puzyrev V.P. Genetic bases of human comorbidity. Russ. J. Genet. 2015;51(4):408-417. DOI 10.1134/S1022795415040092.Puzyrev V.P., Makeeva O.A., Freidin M.B. Syntropy, genetic testing and personalized medicine. Per. Med. 2010;7(4):399-405. DOI 10.2217/pme.10.35.Puzyrev V.P., Makeeva O.A., Freidin M.B. Syntropy, genetic testing and personalized medicine. Per. Med. 2010;7(4):399-405. DOI 10.2217/pme.10.35.Puzyryov V.P. Liberties of genome and medical pathogenetics. Byulleten Sibirskoy Meditsiny = Bulletin of Siberian Medicine. 2002;1(2): 16-29. DOI 10.20538/1682-0363-2002-2-16-29. (in Russian)Puzyryov V.P. Liberties of genome and medical pathogenetics. Byulleten Sibirskoy Meditsiny = Bulletin of Siberian Medicine. 2002;1(2): 16-29. DOI 10.20538/1682-0363-2002-2-16-29. (in Russian)Quick C.R., Conway K.P., Swendsen J., Stapp E.K., Cui L., Merikangas K.R. Comorbidity and coaggregation of major depressive disorder and bipolar disorder and cannabis use disorder in a controlled family study. JAMA Psychiatry. 2022;79(7):727-735. DOI 10.1001/jamapsychiatry.2022.1338.Quick C.R., Conway K.P., Swendsen J., Stapp E.K., Cui L., Merikangas K.R. Comorbidity and coaggregation of major depressive disorder and bipolar disorder and cannabis use disorder in a controlled family study. JAMA Psychiatry. 2022;79(7):727-735. DOI 10.1001/jamapsychiatry.2022.1338.Reaven G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-1607. DOI 10.2337/diab.37.12.1595.Reaven G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-1607. DOI 10.2337/diab.37.12.1595.Reynolds R.J., Irvin M.R., Bridges S.L., Kim H., Merriman T.R., Arnett D.K., Singh J.A., Sumpter N.A., Lupi A.S., Vazquez A.I. Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities. Eur. J. Hum. Genet. 2021;29(9):1438-1445. DOI 10.1038/s41431-021-00830-z.Reynolds R.J., Irvin M.R., Bridges S.L., Kim H., Merriman T.R., Arnett D.K., Singh J.A., Sumpter N.A., Lupi A.S., Vazquez A.I. Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities. Eur. J. Hum. Genet. 2021;29(9):1438-1445. DOI 10.1038/s41431-021-00830-z.Rijken M., Hujala A., van Ginneken E., Melchiorre M.G., Groenewegen P., Schellevis F. Managing multimorbidity: profiles of integrated care approaches targeting people with multiple chronic conditions in Europe. Health Policy. 2018;122(1):44-52. DOI 10.1016/j.healthpol.2017.10.002.Rijken M., Hujala A., van Ginneken E., Melchiorre M.G., Groenewegen P., Schellevis F. Managing multimorbidity: profiles of integrated care approaches targeting people with multiple chronic conditions in Europe. Health Policy. 2018;122(1):44-52. DOI 10.1016/j.healthpol.2017.10.002.Rubio-Perez C., Guney E., Aguilar D., Piñero J., Garcia-Garcia J., Iadarola B., Sanz F., Fernandez-Fuentes N., Furlong L.I., Oliva B. Genetic and functional characterization of disease associations explains comorbidity. Sci. Rep. 2017;7(1):6207. DOI 10.1038/s41598-017-04939-4.Rubio-Perez C., Guney E., Aguilar D., Piñero J., Garcia-Garcia J., Iadarola B., Sanz F., Fernandez-Fuentes N., Furlong L.I., Oliva B. Genetic and functional characterization of disease associations explains comorbidity. Sci. Rep. 2017;7(1):6207. DOI 10.1038/s41598-017-04939-4.Ryu I., Ryu M.J., Han J., Kim S.J., Lee M.J., Ju X., Yoo B.H., Lee Y.L., Jang Y., Song I.C., Chung W., Oh E., Heo J.Y., Kweon G.R. L-Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration. Oncol. Rep. 2018;40(6):3869-3878. DOI 10.3892/or.2018.6753.Ryu I., Ryu M.J., Han J., Kim S.J., Lee M.J., Ju X., Yoo B.H., Lee Y.L., Jang Y., Song I.C., Chung W., Oh E., Heo J.Y., Kweon G.R. L-Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration. Oncol. Rep. 2018;40(6):3869-3878. DOI 10.3892/or.2018.6753.Rzhetsky A., Wajngurt D., Park N., Zheng T. Probing genetic overlap among complex human phenotypes. Proc. Natl. Acad. Sci. USA. 2007;104(28):11694-11699. DOI 10.1073/pnas.0704820104.Rzhetsky A., Wajngurt D., Park N., Zheng T. Probing genetic overlap among complex human phenotypes. Proc. Natl. Acad. Sci. USA. 2007;104(28):11694-11699. DOI 10.1073/pnas.0704820104.Sandilands A., Terron-Kwiatkowski A., Hull P.R., O’Regan G.M., Clayton T.H., Watson R.M., Carrick T., Evans A.T., Liao H., Zhao Y., Campbell L.E., Schmuth M., Gruber R., Janecke A.R., Elias P.M., van Steensel M.A., Nagtzaam I., van Geel M., Steijlen P.M., Munro C.S., Bradley D.G., Palmer C.N., Smith F.J., McLean W.H., Irvine A.D. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 2007;39(5):650-654. DOI 10.1038/ng2020.Sandilands A., Terron-Kwiatkowski A., Hull P.R., O’Regan G.M., Clayton T.H., Watson R.M., Carrick T., Evans A.T., Liao H., Zhao Y., Campbell L.E., Schmuth M., Gruber R., Janecke A.R., Elias P.M., van Steensel M.A., Nagtzaam I., van Geel M., Steijlen P.M., Munro C.S., Bradley D.G., Palmer C.N., Smith F.J., McLean W.H., Irvine A.D. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 2007;39(5):650-654. DOI 10.1038/ng2020.Serebrovskiy A.S. Some Problems of Organic Evolution. Moscow, 1973. (in Russian)Serebrovskiy A.S. Some Problems of Organic Evolution. Moscow, 1973. (in Russian)Shadrina A.S., Sharapov S.Z., Shashkova T.I., Tsepilov Y.A. Varicose veins of lower extremities: insights from the first large-scale genetic study. PLoS Genet. 2019;15(4):e1008110. DOI 10.1371/journal.pgen.1008110.Shadrina A.S., Sharapov S.Z., Shashkova T.I., Tsepilov Y.A. Varicose veins of lower extremities: insights from the first large-scale genetic study. PLoS Genet. 2019;15(4):e1008110. DOI 10.1371/journal.pgen.1008110.Shnayder N.A., Novitsky M.A., Neznanov N.G., Limankin O.V., Asadullin A.R., Petrov A.V., Dmitrenko D.V., Narodova E.A., Popenko N.V., Nasyrova R.F. Genetic predisposition to schizophrenia and depressive disorder comorbidity. Genes (Basel). 2022;13(3):457. DOI 10.3390/genes13030457.Shnayder N.A., Novitsky M.A., Neznanov N.G., Limankin O.V., Asadullin A.R., Petrov A.V., Dmitrenko D.V., Narodova E.A., Popenko N.V., Nasyrova R.F. Genetic predisposition to schizophrenia and depressive disorder comorbidity. Genes (Basel). 2022;13(3):457. DOI 10.3390/genes13030457.Sidransky E., Nalls M.A., Aasly J.O., Aharon-Peretz J., Annesi G., Barbosa E.R., Bar-Shira A., Berg D., Bras J., Brice A., … Tsuji S., Wittstock M., Wolfsberg T.G., Wu Y.R., Zabetian C.P., Zhao Y., Ziegler S.G. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 2009; 361(17):1651-1661. DOI 10.1056/NEJMoa0901281.Sidransky E., Nalls M.A., Aasly J.O., Aharon-Peretz J., Annesi G., Barbosa E.R., Bar-Shira A., Berg D., Bras J., Brice A., … Tsuji S., Wittstock M., Wolfsberg T.G., Wu Y.R., Zabetian C.P., Zhao Y., Ziegler S.G. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 2009; 361(17):1651-1661. DOI 10.1056/NEJMoa0901281.Spataro N., Rodríguez J.A., Navarro A., Bosch E. Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology. Hum. Mol. Genet. 2017;26(3):489-500. DOI 10.1093/hmg/ddw405.Spataro N., Rodríguez J.A., Navarro A., Bosch E. Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology. Hum. Mol. Genet. 2017;26(3):489-500. DOI 10.1093/hmg/ddw405.Stein O., Stein Y. Smooth muscle cells and atherosclerosis. Curr. Opin. Lipidol. 1995;6(5):269-274. DOI 10.1097/00041433-199510000-00005.Stein O., Stein Y. Smooth muscle cells and atherosclerosis. Curr. Opin. Lipidol. 1995;6(5):269-274. DOI 10.1097/00041433-199510000-00005.Stephens Z.D., Lee S.Y., Faghri F., Campbell R.H., Zhai C., Efron M.J., Iyer R., Schatz M.C., Sinha S., Robinson G.E. Big data: astronomical or genomical? PLoS Biol. 2015;13(7):e1002195. DOI 10.1371/journal.pbio.1002195.Stephens Z.D., Lee S.Y., Faghri F., Campbell R.H., Zhai C., Efron M.J., Iyer R., Schatz M.C., Sinha S., Robinson G.E. Big data: astronomical or genomical? PLoS Biol. 2015;13(7):e1002195. DOI 10.1371/journal.pbio.1002195.Vertkin A.L. Comorbid Patient. Moscow, 2015. (in Russian)Vertkin A.L. Comorbid Patient. Moscow, 2015. (in Russian)Vertkin A.L., Rumyantsev M.A., Skotnikov A.S. Comorbidity. Klinicheskaya Meditsyna = Clinical Medicine. 2012;90(10):4-11. (in Russian)Vertkin A.L., Rumyantsev M.A., Skotnikov A.S. Comorbidity. Klinicheskaya Meditsyna = Clinical Medicine. 2012;90(10):4-11. (in Russian)Vilenkin A. Many Worlds in One. The Search for Other Universes. Moscow: Astrel Publ., 2010. (in Russian)Vilenkin A. Many Worlds in One. The Search for Other Universes. Moscow: Astrel Publ., 2010. (in Russian)Vyatkin V.B. About application of the term “syntropy” in scientific research. Nauchnoye Obozreniye. Referativnyy Zhurnal = Scientific Review. Abstract Journal. 2016;3:81-84. (in Russian)Vyatkin V.B. About application of the term “syntropy” in scientific research. Nauchnoye Obozreniye. Referativnyy Zhurnal = Scientific Review. Abstract Journal. 2016;3:81-84. (in Russian)Wagner G.P., Kenney-Hunt J.P., Pavlicev M., Peck J.R., Waxman D., Cheverud J.M. Pleiotropic scaling of gene effects and the ‘cost of complexity’. Nature. 2008;452(7186):470-472. DOI 10.1038/nature06756.Wagner G.P., Kenney-Hunt J.P., Pavlicev M., Peck J.R., Waxman D., Cheverud J.M. Pleiotropic scaling of gene effects and the ‘cost of complexity’. Nature. 2008;452(7186):470-472. DOI 10.1038/nature06756.Wang M., Tang S., Yang X., Xie X., Luo Y., He S., Li X., Feng X. Identification of key genes and pathways in chronic rhinosinusitis with nasal polyps and asthma comorbidity using bioinformatics approaches. Front. Immunol. 2022;13:941547. DOI 10.3389/fimmu.2022.941547.Wang M., Tang S., Yang X., Xie X., Luo Y., He S., Li X., Feng X. Identification of key genes and pathways in chronic rhinosinusitis with nasal polyps and asthma comorbidity using bioinformatics approaches. Front. Immunol. 2022;13:941547. DOI 10.3389/fimmu.2022.941547.Weiss F.U., Simon P., Bogdanova N., Mayerle J., Dworniczak B., Horst J., Lerch M.M. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005;54(10):1456-1460. DOI 10.1136/gut.2005.064808.Weiss F.U., Simon P., Bogdanova N., Mayerle J., Dworniczak B., Horst J., Lerch M.M. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005;54(10):1456-1460. DOI 10.1136/gut.2005.064808.Werner H., Sarfstein R., Nagaraj K., Laron Z. Laron syndrome research paves the way for new insights in oncological investigation. Cells. 2020;9(11):2446. DOI 10.3390/cells9112446.Werner H., Sarfstein R., Nagaraj K., Laron Z. Laron syndrome research paves the way for new insights in oncological investigation. Cells. 2020;9(11):2446. DOI 10.3390/cells9112446.Woese C.R., Goldenfeld N. How the microbial world saved evolution from the scylla of molecular biology and the charybdis of the modern synthesis. Microbiol. Mol. Biol. Rev. 2009;73(1):14-21. DOI 10.1128/MMBR.00002-09.Woese C.R., Goldenfeld N. How the microbial world saved evolution from the scylla of molecular biology and the charybdis of the modern synthesis. Microbiol. Mol. Biol. Rev. 2009;73(1):14-21. DOI 10.1128/MMBR.00002-09.Wray N.R., Goddard M.E., Visscher P.M. Prediction of individual genetic risk of complex disease. Curr. Opin. Genet. Dev. 2008;18(3): 257-263. DOI 10.1016/j.gde.2008.07.006.Wray N.R., Goddard M.E., Visscher P.M. Prediction of individual genetic risk of complex disease. Curr. Opin. Genet. Dev. 2008;18(3): 257-263. DOI 10.1016/j.gde.2008.07.006.Zhao R., Choi B.Y., Lee M.H., Bode A.M., Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine. 2016;8:30-39. DOI 10.1016/j.ebiom.2016.04.017.Zhao R., Choi B.Y., Lee M.H., Bode A.M., Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine. 2016;8:30-39. DOI 10.1016/j.ebiom.2016.04.017.Zolotareva O., Saik O.V., Königs C., Bragina E.Y., Goncharova I.A., Freidin M.B., Dosenko V.E., Ivanisenko V.A., Hofestädt R. Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects. Sci. Rep. 2019;9(1):16302. DOI 10.1038/s41598-019-52762-w.Zolotareva O., Saik O.V., Königs C., Bragina E.Y., Goncharova I.A., Freidin M.B., Dosenko V.E., Ivanisenko V.A., Hofestädt R. Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects. Sci. Rep. 2019;9(1):16302. DOI 10.1038/s41598-019-52762-w.

The authors declare that there are no conflicts of interest present.