Apolipoprotein E gene polymorphism, blood lipids and clinical-biochemical values in gallstone disease with T2DM women

Aim. To study the clinical-biochemical parameters, APOE gene polymorphism in women with gallstone disease (GSD) with/without type 2 diabetes mellitus (T2DM). Materials and methods. In the open, single-stage, single-center, observational, cross-sectional, uncontrolled case-series study, 137 women with GSD were examined, including 71 patients with GSD and T2DM (Group 1), 66 patients – GSD without T2DM (Group 2) comparable age and BMI. The inspection included clinical examination, biochemical blood tests, including lipid profile, APOE gene polymorphism identification by PCR. Results. In group 1 met more often than in group 2 pain in the right hypochondrium (97.2 % vs. 86.4 %), in the left hypochondrium (42.3 % vs. 22.7 %), belching (88.7 % vs. 59.1 %), heartburn (78.9 % vs. 50.0 %), bitterness in the mouth (87.3 % vs. 57.6 %), stool disorders (83.1 % vs. 48.5 %, p < 0.05 in all cases). In group 1 were significantly higher than in group 2, TG (1.9 [1.5; 2.6] vs. 1.4 [1.0; 2.0] mmol/l), atherogenic coefficient (AC) (3.9 [3.1; 4.5] vs. 3.4 [2.5; 4.4] units), HDL-C – significantly lower (1.1 [1.0; 1.3] vs. 1.2 [1.1; 1.6] mmol/l). HypoHDL-C (69.0 % vs. 45.5 %) and hyperTG (66. 2% vs. 36.4 %) significantly more often observed in group 1. Systolic (140,0 [130,0; 150,0] and 130,0 [120,0; 130,0] mmHg, р < 0,001), diastolic blood pressure (SBP, DBP) (90,0 [80,0; 90,0] and 80,0 [80,0; 90,0] mmHg, р < 0,001), in group 1 higher than in group 2. APOE gene alleles frequency in group 1 and 2 is similar. There were no differences in the lipidogram in carriers of different alleles of the APOE gene in group 1. Conclusions. The presence of GSD and T2DM in group 1, both with cholecystolithiasis and after cholecystectomy, is associated with more conspicuous gastroenterological symptoms, lipid metabolism disorders, SBP, DBP increase, compared to group 2. There were no differences in the frequency of the alleles of the AРOE in groups 1 and 2, as well as in the lipidogram of carriers of different alleles of the AРOE in group 1.

1. Григорьева И.Н., Рагино Ю.И., Шахтшнейдер Е.В., Рябиков А.Н., Веревкин Е.Г., Воевода М.И. Желчнокаменная болезнь: результаты собственных 20-летних исследований (×. 1. Эпидемиология, липиды крови и желчи, полиморфизм аполипопротеина Е). Дневник Казанской медицинской школы, 2016; 2 (12): 18–23. [Grigor’eva I.N., Ragino Yu.I., Shakhtshneider E.V., Ryabikov A.N., Verevkin E.G., Voevoda M.I. Gallstone disease: results of our 20-year studies (P. 1: Epidemiology, lipids of blood serum and bile, apolipoprotein E polymorphism). Diary of the Kazan Medical School, 2016; 2 (12): 18–23. (In Russ.)].

2. Григорьева И.Н., Нотова Т.Е., Суворова Т.С., ×икинев Ю.В., Толстых Г.Н., Непомнящих Д.Л., Тов Н.Л., Романова Т.И. Характеристики артериальной гипертензии у больных желчнокаменной болезнью в сочетании с сахарным диабетом 2 типа. Атеросклероз, 2023; 19 (3): 203–205. doi: 10.52727/2078-256X-2023-19-3-203-205. [Grigor’eva I.N., Notova T.E., Suvorova T.S., Chikinev Yu.V., Tolstykh G.N., Nepomnyashchikh D.L., Tov N.L., Romanova T.I. Characteristics of arterial hypertension in patients with cholelithiasis combined with type 2 diabetes mellitus. Ateroskleroz, 023; 19 (3): 203–205. (In Russ.)]. doi: 10.52727/2078-256X-2023-19-3-203-205

3. Kockx M., Traini M., Kritharides L. Cell-specific production, secretion, and function of apolipoprotein E. J. Mol. Med. (Berl), 2018; 96 (5): 361–371. doi: 10.1007/s00109-018-1632-y

4. Bertomeu A., Ros E., Zambуn D., Vela M., PérezAyuso R.M., Targarona E., Trías M., Sanllehy C., Casals E., Ribó J.M. Apolipoprotein E polymorphism and gallstones. Gastroenterology, 1996; 111 (6): 1603– 1610. doi: 10.1016/s0016-5085(96)70023-9

5. Juvonen T., Kervinen K., Kairaluoma M.I., Lajunen L.H., Kesäniemi Y.A. Gallstone cholesterol content is related to apolipoprotein E polymorphism. Gastroenterology, 1993; 104 (6): 1806–1813. doi: 10.1016/0016-5085(93)90662-v

6. van Erpecum K.J., van Berge-henegouwen G.P., Eckhardt E.R., Portincasa P., van de Heijning B.J., Dallinga-Thie G.M., Groen A.K. Cholesterol crystallization in human gallbladder bile: relation to gallstone number, bile composition, and apolipoprotein E4 isoform. Hepatology, 1998; 27 (6): 1508–1516. doi: 10.1002/hep.510270607

7. Fischer S., Dolu M.H., Zündt B., Meyer G., Geisler S., Jüngst D. Apolipoprotein E polymorphism and lithogenic factors in gallbladder bile. Eur. J. Clin. Invest., 2001; 31 (9): 789–795. doi: 10.1046/j.1365-2362.2001.00874.x

8. Martinez-Lopez E., Curiel-Lopez F., HernandezNazara A., Moreno-Luna L.E., Ramos-Marquez M.E., Roman S., Panduro A. Influence of ApoE and FABP2 polymorphisms and environmental factors in the susceptibility to gallstone disease. Ann. Hepatol., 2015; 14 (4): 515–523.

9. Sánchez-Cuén J., Aguilar-Medina M., ArámbulaMeraz E., Romero-Navarro J., Granados J., SicairosMedina L., Ramos-Payán R. ApoB-100, ApoE and CYP7A1 gene polymorphisms in Mexican patients with cholesterol gallstone disease. World J. Gastroenterol., 2010; 16 (37): 4685–4690. doi: 10.3748/wjg.v16.i37.4685

10. Chen D.W., Shi J.K., Li Y., Yang Y., Ren S.P. Association between ApoE Polymorphism and Type 2 diabetes: a meta-analysis of 59 studies. Biomed. Environ. Sci., 2019; 32 (11): 823–838. doi: 10.3967/bes2019.104

11. Srirojnopkun C., Kietrungwilaikul K., Boonsong K., Thongpoonkaew J., Jeenduang N. Association of APOE and CETP TaqIB Polymorphisms with Type 2 diabetes mellitus. Arch. Med. Res., 2018; 49 (7): 479–485. doi: 10.1016/j.arcmed.2019.02.005

12. Ratheesh R., Ulrich M.T., Ghozy S., Al-Jaboori M., Nayak S.S. The association between diabetes and gallstones: a nationwide population-based cohort study. Prz. Gastroenterol., 2023; 18 (3): 292–299. doi: 10.5114/pg.2023.131395

13. Bodmer M., Brauchli Y.B., Jick S.S., Meier C.R. Diabetes mellitus and the risk of cholecystectomy. Dig. Liver Dis., 2011; 43 (9): 742–747. doi: 10.1016/j.dld.2011.04.014

14. Ежов М.В., Кухарчук В.В., Сергиенко И.В., Алиева А.С., Анциферов М.Б., Аншелес А.А., Арабидзе Г.Г., Аронов Д.М., Арутюнов Г.П., Ахмеджанов Н.М., Балахонова Т.В., Барбараш О.Л., Бойцов С.А., Бубнова М. Г., Воевода М.И., Галстян Г.Р., Галявич А.С., Горнякова Н.Б., Гуревич В.С., Дедов И.И., Драпкина О.М., Дупляков Д.В., Ерегин С.Я., Ершова А.И., Иртюга О.Б., Карпов Р.С., Карпов Ю.А., Качковский М.А., Кобалава Ж.Д., Козиолова Н.А., Коновалов Г.А., Константинов В.О., Космачева Е.Д., Котовская Ю.В., Мартынов А.И., Мешков А.Н., Небиеридзе Д.В., Недогода С.В., Обрезан А.Г., Олейников В.Э., Покровский С.Н., Рагино Ю.И., Ротарь О.П., Скибицкий В.В., Смоленская О.Г., Соколов А.А., Сумароков А.Б., Ткачева О.Н., Филиппов А.Е., Халимов Ю.Ш., ×азова И.Е., Шапошник И.И., Шестакова М.В., Якушин С.С., Шляхто Е.В. Нарушения липидного обмена. Клинические рекомендации 2023. Рос. кардиол. журн., 2023; 28 (5): 5471. doi: 10.15829/1560-4071-20235471 [Ezhov M.V., Kukharchuk V.V., Sergienko I.V., Alieva A.S ., Antsiferov M.B., Ansheles A.A., Arabidze G.G., Aronov D.M., Arutyunov G.P., Akhmedzhanov N.M., Balakhonova T.V., Barbarash O.L., Boytsov S.A., Bubnova M.G., Voevoda M.I., Galstyan G.R., Galyavich A.S., Gornyakova N.B., Gurevich V.S., Dedov I.I., Drapkina O.M., Duplyakov D.V., Eregin S.Ya., Ershova A.I., Irtyuga O.B., Karpov R.S., Karpov Yu.A., Kachkovsky M.A., Kobalava Zh.D., Koziolova N.A., Konovalov G.A., Konstantinov V.O., Kosmacheva E.D., Kotovskaya Yu.V., Martynov A.I., Meshkov A.N., Nebieridze D.V., Nedogoda S.V., Obrezan A.G., Oleinikov V.E., Pokrovsky S.N., Ragino Yu.I., Rotar O.P., Skibitsky V.V., Smolenskaya O.G., Sokolov A.A., Sumarokov A.B., Tkacheva O.N., Filippov A.E., Halimov Yu.Sh., Chazova I.E., Shaposhnik I.I., Shestakova M.V., Yakushin S.S., Shlyakhto E.V. Disorders of lipid metabolism. Clinical Guidelines 2023. Russian Journal of Cardiology, 2023; 28 (5): 5471. (In Russ.)]. doi: 10.15829/1560-4071-2023-5471

15. Latenstein C.S.S., de Reuver P.R. Tailoring diagnosis and treatment in symptomatic gallstone disease. Br. J. Surg., 2022; 109 (9): 832–838. doi: 10.1093/bjs/znac154

16. di Ciaula A., Molina-Molina E., Bonfrate L., Wang D.Q., Dumitrascu D.L., Portincasa P. Gastrointestinal defects in gallstone and cholecystectomized patients. Eur. J. Clin. Invest., 2019; 49 (3): e13066. doi: 10.1111/eci.13066

17. Agoons D.D., Musani S.K., Correa A., Golden S.H., Bertoni A.G., Echouffo-Tcheugui J.B. High-density lipoprotein-cholesterol and incident type 2 diabetes mellitus among African Americans: The Jackson Heart Study. Diabet Med., 2022; 39 (8): e14895. doi: 10.1111/dme.14895

18. Zhang M., Mao M., Zhang C., Hu F., Cui P., Li G., Shi J., Wang X., Shan X. Blood lipid metabolism and the risk of gallstone disease: a multi-center study and meta-analysis. Lipids Health Dis., 2022; 21 (1): 26. doi: 10.1186/s12944-022-01635-9

19. Charoensri S., Turnsaket S., Pongchaiyakul C. Hypertriglyceridemia as an Independent Predictor for TenYear Incidence of Diabetes in Thais. Vasc. Health. Risk. Manag., 2021; 17: 519–525. doi: 10.2147/VHRM.S326500

20. The epidemiology of gallstone disease in Rome, Italy. Part II. Factors associated with the disease. The Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO). Hepatology, 1988; 8 (4): 907–913.

21. Shabanzadeh D.M., Sørensen L.T., Jørgensen T. Determinants for gallstone formation – a new data cohort study and a systematic review with meta-analysis. Scand. J. Gastroenterol., 2016; 51 (10): 1239–1248. doi: 10.1080/00365521.2016.1182583

22. Григорьева И.Н., Никитенко Т.М., Романова Т.И., Осипенко М.Ф., Егошина М.А., Сединина Е.В., Венжина Ю.Ю., Шахтшнейдер Е.В., Куликов И.В., Максимов В.Н., Усов С.А., Мироненко Т.В., Данильчева Т.В., Иванова М.В., Потапова Т.А., Ромащенко А.Г., Малютина С.К., Воевода М.И. Полиморфизм гена аполипопротеина Е, желчнокаменная болезнь и панкреатит. Бюллетень Сибирского отделения Российской академии медицинских наук, 2006; 26 (4): 80–87. [Grigor’eva I.N., Nikitenko T.M., Romanova T.I., Osipenko M.F., Egoshina M.A., Sedinina E.V., Venzhina Yu.Yu., Shakhtshneider E.V., Kulikov I.V., Maksimov V.N., Usov S.A., Mironenko T.V., Danilcheva T.V., Ivanova M.V., Potapova T.A., Romashchenko A.G., Malyutina S.K., Voevoda M.I. Apolipoprotein e polymorphism, gallstone disease and pancreatitis. Bulletin of Siberian Branch of Russian Academy of Medical Sciences, 2006; 26 (4): 80–87. (In Russ.)].

23. Шахтшнейдер Е.В., Воевода М.И., Огарков М.Ю., Барбараш О.Л., Поликутина О.М., Казачек Я.В., Баум В.А., Юдин Н.С., Кобзев В.Ф., Ромащенко А.Г. Полиморфизм гена аполипопротеина Е в популяции коренных жителей Горной Шории и его ассоциация с параметрами углеводного обмена. Атеросклероз, 2009; 5 (1): 28–32. [Shakhtshneider E.V., Voevoda M.I., Ogarkov M.Yu., Barbarash O.L., Polikutina O.M., Kazachek Ya.V., Baum V.A., Yudin N.S., Kobzev V.F., Romashchenko A.G. Apolipoprotein E gene рolymorphism in the population of indigenous inhabitants of Gornaya Shoria and its association with parameters of carbohydrate metabolism. Atherosclerosis, 2009; 5 (1): 28–32. (In Russ.)].

24. Yang L.G., March Z.M., Stephenson R.A., Narayan P.S. Apolipoprotein E in lipid metabolism and neurodegenerative disease. Trends Endocrinol Metab., 2023; 34 (8): 430–445. doi: 10.1016/j.tem.2023.05.002

25. Григорьева И.Н., Нотова Т.Е. Полиморфизм гена аполипопротеина Е, желчнокаменная болезнь, сахарный диабет 2 типа и нарушения липидного обмена. Атеросклероз, 2023; 19 (1): 479–488. doi: 10.52727/2078-256X-2023-19-1-47-56 [Grigor’eva I.N., Notova T.E. Apolypoprotein E gene polymorphism, gallstone disease, diabetes 2 type and lipid metabolism disorders. Ateroskleroz, 2023; 19 (1): 479–488. (In Russ.)]. doi: 10.52727/2078-256X-202319-1-47-56

26. Mella J.G., Schirin-Sokhan R., Rigotti A., Pimentel F., Villarroel L., Wasmuth H.E., Sauerbruch T., Nervi F., Lammert F., Miquel J.F. Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations. J. Lipid. Res., 2007; 48(6): 1378–1385. doi: 10.1194/jlr.M700059-JLR200

27. Hasegawa K., Terada S., Kubota K., Itakura H., Imamura H., Ohnishi S., Aoki T., Ijichi M., Saiura A., Makuuchi M. Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone. Am. J. Gastroenterol., 2003; 98 (7): 1605–1609. doi: 10.1111/j.1572-0241.2003.07527