Genetics of «atopic march» syntropy

The study of the phenomenon of a combination of several diseases at the same time in an individual, actualized in the second half of the 19th century, is being actively analyzed 150 years later using genetic approaches. We present an overview of the results of such studies in relation to allergic diseases, in particular, a special variant, the so-called «atopic march», the sequential development of eczema, allergic rhinitis and asthma («atopic march» syntropy). The data of genetic and epidemiological studies were summarized, the analysis of genome-wide associative studies was carried out, and the role of mutations in the filaggrin gene (FLG) in the development of the «atopic march» syntropy was considered.

1. Feinstein A.R. Pre-therapeutic classification of co-morbidity in chronic disease. J Chron Dis. 1970; 23 (7): 455-468. doi: 10.1016/0021-9681(70)90054-8
2. Pfaundler M., Seht L.V. Über Syntropie von Krankheitszuständen. Z. Kinder-Heilk. 1921; 30: 100–120. doi.org/10.1007/BF02222706
3. Puzyrev V.P., Freidin M.B. Genetic view the phenomenon of combined diseases in man. Acta Naturae. 2009; 1 (3): 52-57.
4. Vyatkin V.P. On the use of the term "syntropy" in scientific research. Nauchnoye obozreniye = Scientific review. 2016; 3: 81–84. [In Russian].
5. Agache I., Cojanu C., Laculiceanu A., Rogozea L. Critical points on the use of biologicals in allergic diseases and asthma. Allergy Asthma Immunol. Res. 2020; 12 (1): 24-41.  doi: 10.4168/aair.2020.12.1.24
6. Pascal M., Perez-Gordo M., Caballero T., Escribese M.M., Lopez Longo M.N., Luengo O., Manso L., Matheu V., Seoane E., Zamorano M., Labrador M., Mayorga C. Microbiome and allergic diseases. Front. Immunol. 2018; 9: 1584.  doi: 10.3389/fimmu.2018.01584
7. Ortiz R.A., Barnes K.C. Genetics of allergic diseases. Immunol Allergy Clin. North Am. 2015; 35 (1): 19-44.  doi: 10.1016/j.iac.2014.09.014
8. Spergel J.M., Paller A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 2003; 112 (6): 118-127. doi: 10.1016/j.jaci.2003.09.033
9. Dharmage S.C., Lowe A.J., Matheson M.C., Burgess J.A., Allen K.J., Abramson M.J. Atopic dermatitis and the atopic march revisited. Allergy. 2014; 69 (1): 17-27. doi: 10.1111/all.12268
10. Almqvist C., Li Q., Britton W.J., Kemp A.S. Xuan W., Tovey E.R, Marks G.B. Early predictors for developing allergic disease and asthma: examining separate steps in the 'allergic march'. Clin. Exp. Allergy. 2007; 37 (9): 1296-1302.  doi: 10.1111/j.1365-2222.2007.02796.x
11. Punekar Y.S., Sheikh A. Establishing the sequential progression of multiple allergic diagnoses in a UK birth cohort using the General Practice Research Database. Clin. Exp. Allergy. 2009; 39 (12): 1889-1895. doi: 10.1111/j.1365-2222.2009.03366.x
12. Chernyak B.A., Vorozhaeva I.I. Comorbid diseases in allergic rhinitis. Astma i allergiya = Asthma and allergy. 2017; (1): 3-7. [In Russian].
13. Ivanova N.A. Comorbidity of allergic rhinitis and bronchial asthma in children. Meditsinskiy sovet = Medical Council. 2014; 6: 54-58. [In Russian].
14. Freidin M.B., Puzyrev V.P. Syntropic genes of allergic diseases. Russ. J. Genet. 2010; 46 (2): 224–229. doi: 10.1134/S1022795410020134
15. Davidson W.F., Leung D.Y.M., Beck L.A., Berin C.M., Boguniewicz M., Busse W.W., Chatila T.A., Geha R.S., Gern J.E., Guttman-Yassky E., Irvine A.D., Kim B.S., Kong H.H., Lack G., Nadeau K.C., Schwaninger J., Simpson A., Simpson E.L., Spergel J.M., Togias A., Wahn U., Wood R.A., Woodfolk J.A., Ziegler S.F., Plaut M. Report from the National Institute of Allergy and Infectious Diseases workshop on "Atopic dermatitis and the atopic march: Mechanisms and interventions". J. Allergy Clin. Immunol. 2019; 143 (3): 894-913. doi: 10.1016/j.jaci.2019.01.003
16. Elmose C., Thomsen S.F. Twin studies of atopic dermatitis: Interpretations and applications in the filaggrin era. J. Allergy (Cairo). 2015: 902359. doi: 10.1155/2015/902359
17. Lichtenstein P., Svartengren M. Genes, environments, and sex: factors of importance in atopic diseases in 7-9-year-old Swedish twins. Allergy. 1997; 52 (11): 1079-1086. doi: 10.1111/j.1398-9995.1997.tb00179.x
18. Thomsen S.F., Ulrik C.S., Kyvik K.O., Skadhauge L.R., Steffensen I., Backer V. Findings on the atopic triad from a Danish twin registry. Int. J. Tuberc. Lung Dis. 2006; 10 (11): 1268-1272.
19. Van Beijsterveldt C.E., Boomsma D.I. Genetics of parentally reported asthma, eczema and rhinitis in 5-yr-old twins. Eur. Respir. J. 2007; 29 (3): 516-521. doi: 10.1183/09031936.00065706
20. Heinzmann A., Deichmann K.A. Genes for atopy and asthma. Curr. Opin. Allergy Clin. Immunol. 2001; 1 (5): 387-392.  doi: 10.1097/01.all.0000011050.36626.ec
21. Freidin M.B., Ogorodova L.M., Puzyrev V.P. Pathogenetics of allergic diseases. Novosibirsk, 2015. 149 p.
22. Buniello A., MacArthur J.A.L., Cerezo M., Harris L.W., Hayhurst J., Malangone C., McMahon A., Morales J., Mountjoy E., Sollis E., Suveges D., Vrousgou O., Whetzel P.L., Amode R., Guillen J.A., Riat H.S., Trevanion S.J., Hall P., Junkins H., Flicek P., Burdett T., Hindorff L.A., Cunningham F., Parkinson H. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics. Nucleic Acids Res. 2019; 47 (D1): D1005-D1012. doi: 10.1093/nar/gky1120
23. Moffatt M.F., Gut I.G., Demenais F., Strachan D.P., Bouzigon E., Heath S., von Mutius E., Farrall M., Lathrop M., Cookson W., & GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 2010; 363 (13): 1211-1221. doi: 10.1056/NEJMoa0906312
24. Marenholz I., Bauerfeind A., Esparza-Gordillo J., Kerscher T., Granell R., Nickel R., Lau S., Henderson J., Lee Y.A. The eczema risk variant on chromosome 11q13 (rs7927894) in the population-based ALSPAC cohort: a novel susceptibility factor for asthma and hay fever. Hum. Mol. Genet. 2011; 20 (12): 2443-2449. doi: 10.1093/hmg/ddr117
25. Ferreira M.A.R., 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. 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
26. Marenholz  I., Esparza-Gordillo J., Rüschendorf F., Bauerfeind A., Strachan D.P., Spycher B.D., Baurecht H., Margaritte-Jeannin P., Sääf A., Kerkhof M., … Lee Y.A. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat. Commun. 2015; 6: 8804. doi: 10.1038/ncomms9804
27. Ferreira M.A., Vonk J.M., Baurecht H., Marenholz I., Tian C., Hoffman J.D., Helmer Q., Tillander A., Ullemar V., van Dongen J., … 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
28. Zhu Z., Lee P.H., Chaffin M.D., Chung W., Loh P.R., Lu Q., Christiani D.C., Liang L. A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat. Genet. 2018; 50 (6): 857-864. doi: 10.1038/s41588-018-0121-0
29. Johansson Å., Rask-Andersen M., Karlsson T., Ek W.E. Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema. Hum. Mol. Genet. 2019; 28 (23): 4022-4041. doi: 10.1093/hmg/ddz175
30. Melén E., Granell R., Kogevinas M, Strachan D., Gonzalez J.R., Wjst M., Jarvis D., Ege M., Braun-Fahrländer C., Genuneit J., … Lasky-Su J. Genome-wide association study of body mass index in 23 000 individuals with and without asthma. Clin. Exp. Allergy. 2013; 43 (4): 463-474.  doi: 10.1111/cea.12054
31. Barrett J.C., Hansoul S., Nicolae D.L., Cho J.H., Duerr R.H., Rioux J.D., Brant S.R., Silverberg M.S., Taylor K.D., Barmada M.M., … Daly M.J. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's diseases. Nat. Genet. 2008; 40 (8): 955-962. doi: 10.1038/ng.175
32. Probst-Kepper M., Balling R., Buer J. FOXP3: required but not sufficient. the role of GARP (LRRC32) as a safeguard of the regulatory phenotype. Curr. Mol. Med. 2010; 10 (6): 533-539. doi: 10.2174/1566524011009060533
33. Trehearne A. Genetics, lifestyle and environment. UK Biobank is an open access resource following the lives of 500,000 participants to improve the health of future generations. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2016; 59 (3): 361-367. doi: 10.1007/s00103-015-2297-0
34. Zhu Y., Tazearslan C., Suh Y. Challenges and progress in interpretation of non-coding genetic variants associated with human disease. Exp. Biol. Med. (Maywood). 2017; 242 (13): 1325-1334.  doi: 10.1177/1535370217713750
35. Schaub M.A., Boyle A.P., Kundaje A., Batzoglou S., Snyder M. Linking disease associations with regulatory information in the human genome. Genome Res. 2012; 22 (9): 1748-1759.  doi: 10.1101/gr.136127.111
36. Maurano M.T., Humbert R., Rynes E., Thurman R.E., Haugen E., Wang H., Reynolds A.P., Sandstrom R., Qu H., Brody J., Shafer A., Neri F., Lee K., Kutyavin T., Stehling-Sun S., Johnson A.K., Canfield T.K., Giste E., Diegel M., Bates D., Hansen R.S., Neph S., Sabo P.J., Heimfeld S., Raubitschek A., Ziegler S., Cotsapas C., Sotoodehnia N., Glass I., Sunyaev S.R., Kaul R., Stamatoyannopoulos J.A. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012; 337 (6099): 1190-1195. doi: 10.1126/science.1222794
37. Igartua C., Myers R.A., Mathias R.A., Pino-Yanes M., Eng C., Graves P.E., Levin A.M., Del-Rio-Navarro B.E., Jackson D.J., Livne O.E., Rafaels N., Edlund C.K., Yang J.J., Huntsman S., Salam M.T., Romieu I., Mourad R., Gern J.E., Lemanske R.F., Wyss A., Hoppin J.A., Barnes K.C., Burchard E.G., Gauderman W.J., Martinez F.D., Raby B.A., Weiss S.T., Williams L.K., London S.J., Gilliland F.D., Nicolae D.L., Ober C. Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nat. Commun. 2015; 6: 5965. doi: 10.1038/ncomms6965
38. Demenais F., Margaritte-Jeannin P., Barnes K.C., Cookson W.O.C., Altmüller J., Ang W., Barr R.G., Beaty T.H., Becker A.B., Beilby J., … Nicolae D.L. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat. Genet. 2018; 50 (1): 42–53. doi: 10.1038/s41588-017-0014-7
39. Kabesch M., Tost J. Recent findings in the genetics and epigenetics of asthma and allergy. Semin. Immunopathol. 2020; 42 (1): 43-60. doi: 10.1007/s00281-019-00777-w
40. Das S., Miller M., Broide D.H. Chromosome 17q21 genes ORMDL3 and GSDMB in asthma and immune diseases. Adv. Immunol. 2017; 135: 1-52.  doi: 10.1016/bs.ai.2017.06.001
41. 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
42. Bragina E.Yu., Goncharova I.A., Freidin M.B., Zhalsanova I.Zh., Gomboeva D.E., Nemerov E.V., Puzyrev V.P. Analysis of haplotypes of CAT, TLR4, and IL10 genes in bronchial asthma patients comorbid with arterial hypertension. Sibirskiy nauchnyy meditsinskiy zhurnal = Siberian Scientific Medical Journal. 2019; 39 (6): 55–64. [In Russian]. doi: 10.15372/SSMJ20190607
43. Saik O.V., Demenkov P.S., Ivanisenko T.V., Bragina E.Y., Freidin M.B., Goncharova I.A., Dosenko V.E., Zolotareva O.I., Hofestaedt R., Lavrik I.N., Rogaev E.I., Ivanisenko V.A. Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks. BMC Med. Genomics. 2018; 11 (1): 15. doi: 10.1186/s12920-018-0331-4
44. Drevytska T., Morhachov R., Tumanovska L., Portnichenko G., Nagibin V., Boldyriev O., Lapikova-Bryhinska T., Gurianova V., Donskoi B., Freidin M., Ivanisenko V., Bragina E.Y., Hofestädt R., Dosenko V. shRNA-induced knockdown of a bioinformatically predicted target IL10 influences functional parameters in spontaneously hypertensive rats with asthma. J. Integr. Bioinform. 2018; 15 (4): 20180053.  doi: 10.1515/jib-2018-0053
45. 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: 16302. doi.org/10.1038/s41598-019-52762-w
46. Lemonnier N., Melén E., Jiang Y., Joly S., Ménard C., Aguilar D., Acosta-Perez E., Bergström A., Boutaoui N., Bustamante M., Canino G., Forno E., Ramon González J., Garcia‐Aymerich J., Gruzieva O., Guerra S., Heinrich J., Kull I., Ibarluzea Maurolagoitia J., Santa‐Marina Rodriguez L., Thiering E., Wickman M., Akdis C., Akdis M., Chen W., Keil T., Koppelman G.H., Siroux V., Xu C.J., Hainaut P., Standl M., Sunyer J., Celedón J.C., Maria Antó J., Bousquet J. A novel whole blood gene expression signature for asthma, dermatitis and rhinitis multimorbidity in children and adolescents. Allergy. 2020. Available at: https://onlinelibrary.wiley.com/doi/full/10.1111/all.14314
47. Lee J., Kim B., Chu H., Zhang K., Kim H., Kim J.H., Kim S.H., Pan Y., Noh J.Y., Sun Z., Lee J., Jeong K.Y., Park K.H., Park J.-W., Kupper T.S., Park C.O., Lee K.H. FABP5 as a possible biomarker in atopic march: FABP5-induced Th17 polarization, both in mouse model and human samples. EBioMedicine. 2020; 58: 102879. doi: 10.1016/j.ebiom.2020.102879
48. Glatz J.F., van der Vusse G.J. Cellular fatty acid-binding proteins: their function and physiological significance. Prog. Lipid Res. 1996; 35 (3): 243-282. doi: 10.1016/s0163-7827(96)00006-9
49. Ziyab A.H., Hankinson J., Ewart S., Schauberger E., Kopec-Harding K., Zhang H., Custovic A., Arshad H., Simpson A., Karmaus W.J. Epistasis between FLG and IL4R genes on the risk of allergic sensitization: results from two population-based birth cohort studies. Sci. Rep. 2018; 8 (1): 3221. doi: 10.1038/s41598-018-21459-x
50. Freĭdin M.B., Bragina E.Iu., Saltykova I.V., Deeva E.V., Deeva E.V., Ogorodova L.M., Puzyrev V.P. Effect of additional disease (comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant. Russ. J. Genet. 2013; 49 (4): 473-475. doi: 10.1134/S1022795413040054
51. Engebretsen K.A., Bandier J., Kezic S., Riethmüller C., Heegaard N.H.H., Carlsen B.C., Linneberg A., Johansen J.D., Thyssen J.P. Concentration of filaggrin monomers, its metabolites and corneocyte surface texture in individuals with a history of atopic dermatitis and controls. J. Eur. Acad. Dermatol. Venereol. 2018; 32 (5): 796-804.  doi: 10.1111/jdv.14801
52. Osawa R., Akiyama M., Shimizu H. Filaggrin gene defects and the risk of developing allergic disorders. Allergol. Int. 2011; 60 (1): 1-9.  doi: 10.2332/allergolint.10-RAI-0270
53. Smith F.J.D., Irvine A.D., Terron-Kwiatkowski A., Sandilands A., Campbell L.E., Zhao Y., Liao H., Evans A.T., Goudie D.R., Lewis-Jones S., Arseculeratne G., Munro C.S., Sergeant A., O'Regan G., Bale S.J., Compton J.G., DiGiovanna J.J., Presland R.B., Fleckman P., McLean W.H.I. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 2006; 38 (3): 337-342.  doi: 10.1038/ng1743
54. Palmer C.N.A., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H., Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J.D., 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.I. 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
55. Osawa R., Akiyama M., Shimizu H. Filaggrin gene defects and the risk of developing allergic disorders. Allergol. Int. 2011; 60 (1): 1-9.  doi: 10.2332/allergolint.10-RAI-0270
56. Smieszek S.P., Welsh S., Xiao C., Wang J., Polymeropoulos C., Birznieks G., Polymeropoulos M.H. Correlation of age-of-onset of atopic dermatitis with filaggrin loss-of-function variant status. Sci. Rep. 2020; 10 (1): 2721. doi: 10.1038/s41598-020-59627-7
57. Chan A., Terry W., Zhang H., Karmaus W., Ewart S., Holloway J.W., Roberts G., Kurukulaaratchy R., Arshad S.H. Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization. Clin. Exp. Allergy. 2018; 48 (2): 147-155. doi: 10.1111/cea.13077
58. Watanabe K., Stringer S., Frei O., Mirkov M.U., de Leeuw C., Polderman T.J.C., van der Sluis S., Andreassen O.A., Neale B.M., Posthuma D. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 2019; 51 (9): 1339-1348. doi: 10.1038/s41588-019-0481-0
59. Løset M., Brown S.J., Saunes M., Hveem K. Genetics of atopic dermatitis: from DNA sequence to clinical relevance. Dermatology. 2019; 235 (5): 355-364.  doi: 10.1159/000500402
60. Oyoshi M.K., Murphy G.F., Geha R.S. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen. J. Allergy Clin. Immunol. 2009; 124 (3): 485-493. doi: 10.1016/j.jaci.2009.05.042
61. Rasheed Z., Zedan K., Saif G.B., Salama R.H., Salem T., Ahmed A.A., El-Moniem A.A., Elkholy M., Al Robaee A.A., Alzolibani A.A. Markers of atopic dermatitis, allergic rhinitis and bronchial asthma in pediatric patients: correlation with filaggrin, eosinophil major basic protein and immunoglobulin E. Clin. Mol. Allergy. 2018; 16: 23. doi: 10.1186/s12948-018-0102-y
62. Fallon P.G., Sasaki T., Sandilands A., Campbell L.E., Saunders S.P., Mangan N.E., Callanan J.J., Kawasaki H., Shiohama A., Kubo A., Sundberg J.P., Presland R.B., Fleckman P., Shimizu N., Kudoh J., Irvine A.D., Amagai M., McLean W.H.I. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat. Genet. 2009; 41 (5): 602-608. doi: 10.1038/ng.358
63. Langkilde A., Olsen L.C., Sætrom P., Drabløs F., Besenbacher S., Raaby L., Johansen C., Iversen L. Pathway analysis of skin from psoriasis patients after adalimumab treatment reveals new early events in the anti-inflammatory mechanism of anti-TNF-α. PLoS One. 2016; 11 (12): e0167437. doi: 10.1371/journal.pone.0167437
64. Sunryd J.C., Cheon B., Graham J.B., Giorda K.M., Fissore R.A., Hebert D.N. TMTC1 and TMTC2 are novel endoplasmic reticulum tetratricopeptide repeat-containing adapter proteins involved in calcium homeostasis. J. Biol. Chem. 2014; 289 (23): 16085–16099. doi: 10.1074/jbc.M114.554071
65. Ober C., Yao T.C. The genetics of asthma and allergic disease: a 21st century perspective. Immunol. Rev. 2011; 242 (1): 10-30.  doi: 10.1111/j.1600-065X.2011.01029.x
66. Ullemar V., Magnusson P.K., Lundholm C., Zettergren A., Melén E., Lichtenstein P., Almqvist C. Heritability and confirmation of genetic association studies for childhood asthma in twins. Allergy. 2016; 71 (2): 230-238.  doi: 10.1111/all.12783
67. Bataille V., Lens M., Spector T.D. The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data. J. Eur. Acad. Dermatol. Venereol. 2012; 26 (9): 1067-1073.  doi: 10.1111/j.1468-3083.2011.04444.x
68. Blair David R., Lyttle Christopher S., Mortensen Jonathan M., Bearden Charles F., Jensen Anders B., Khiabanian H., Melamed R., Rabadan R., Bernstam Elmer V., Brunak S., Jensen Lars J., Nicolae D., Shah Nigam H., Grossman Robert L., Cox Nancy J., White Kevin 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
69. Kerner G., Ramirez-Alejo N., Seeleuthner Y., Yang R., Ogishi M., Cobat A., Patin E., Quintana-Murci L., Boisson-Dupuis S., Casanova J.L., Abel L. Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry. Proc. Natl. Acad. Sci. USA. 2019; 116 (21): 10430-10434. doi: 10.1073/pnas.1903561116
70. Guardamagna O., Restagno G., Rolfo E., Pederiva C., Martini S., Abello F., Baracco V., Pisciotta L., Pino E., Calandra S., Bertolini S. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J. Pediatr. 2009; 155 (2): 199-204.e2. doi: 10.1016/j.jpeds.2009.02.022
71. Abramycheva N.Yu., Fedotova E.Yu., Bagieva G.K., Klyushnikov S.A., Ivanova-Smolenskaya I.A., Illarioshkin S.N. Mutations of the GBA gene in Parkinson's disease. Meditsinskaya genetika = Medical Genetics. 2011; 107 (5): 22-27. [In Russian].
72. 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.Yu., e-mail: elena.bragina72@gmail.com