Malezya'daki Malaylar Arasında İrritabl Bağırsak Sendromu (IBS) ile ilişkili Tek Nükleotid Polimorfizmlerinin Genotip ve Alel Frekansları

Abstract

Amaç: Kronik veya tekrarlayan karın ağrısı veya rahatsızlığı ve bağırsak alışkanlıklarında değişiklik ile tanımlanan irritabl bağırsak sendromu (irritable bowel syndrome, IBS), en sık görülen fonksiyonel gastrointestinal bozukluktur. Çalışmalar, genlerdeki polimorfizmlerin, IBS'de altta yatan anahtar rollerden biri olduğunu kanıtlamıştır. Bu çalışmada, Malezya'nın ilişkisiz, sağlıklı Malaylarında, GNB3 (rs54443) ve SCN5A (rs8015124) genlerinden, IBS ile ilişkili tek nükleotid polimorfizminin (single nucleotide polymorphism, SNP) genotiplerinin ve alel frekanslarının araştırılması amaçlanmıştır. Gereç ve Yöntemler: Toplam 404 katılımcının genomik DNA'sı, yukarıda belirtilen SNP'leri belirlemek için yuvalanmış, multipleks ve alele özgü polimeraz zincir reaksiyonu (polymerase chain reaction, PCR) ile analiz edildi. PCR sonuçları, Sanger sıralama analizi ile doğrulandı. Bulgular: Malaylar, rs5443'te %56,3’e karşı %43,7 ile mutant (T) alellerinden biraz daha yüksek bir yabanıl (C) alel frekansına sahipti. Bununla birlikte, alellerin frekansları Malay kadınlar alt grubunda eşitti (C-%50, T-%50). rs1805124 için, Malayların sadece %18,6'sı mutant alel G'yi taşıyordu ve 10'dan az katılımcı homozigot mutant GG taşıyıcılarıydı. Aynı zamanda, çalışmadaki SNP Hardy-Weinberg dengesinden de sapmamıştı. Sonuç: İBS, kişinin yaşam kalitesini önemli ölçüde düşüren ve toplumlara ekonomik yük haline gelen yaygın bir gastrointestinal sorunudur. Mutant alellerin oldukça düşük olmasına rağmen, IBS ile ilişkili polimorfizmlerin, rs5443 ve rs1805124'ün Malaylarda yaygın olarak bulunduğu kaydedildi. rs5443 ve rs1805124 polimorfizmleri ile sendromun ilişkisini doğrulamak için yerel IBS hastaları üzerinde daha fazla araştırma yapılması önerilir.

Keywords

• Genetik popülasyon
• irritabl bağırsak sendromu
• Malayca
• rs5443
• rs1805124

Project Number

Lab Material (LABMAT) Research Grant (Project code no.: UniSZA/LABMAT/2018/03, R0044-R003)

Genotype and Allele Frequencies of Irritable Bowel Syndrome (IBS)-associated Single Nucleotide Polymorphisms among Malays in Malaysia

Abstract

Aim: Irritable bowel syndrome (IBS) defined by chronic or recurrent abdominal pain or discomfort and changes in bowel habits, is the most common functional gastrointestinal disorder. Studies proved that polymorphisms in the genes were one of the key roles in the underlying IBS. This study aimed to investigate the genotypes and allele frequencies of the IBS-associated single nucleotide polymorphism (SNP) from the genes GNB3 (rs54443) and SCN5A (rs8015124) in unrelated, healthy Malays of Malaysia. Material and Methods: The genomic DNA of 404 subjects was set to nested, multiplex, and allele-specific PCR to determine the aforementioned SNPs. The PCR results were validated through the Sanger sequencing analysis. Results: Malays possessed a slightly higher frequency of wild (C) than mutant (T) alleles in the rs5443 with 56.3 vs 43.7%. However, the frequencies of the alleles were equivalent in the subset of Malay females (C-50%, T-50%). For rs1805124, only 18.6% of Malays carried the mutant allele G with less than 10 subjects being homozygous mutant GG carriers. Concurrently, the Hardy-Weinberg equilibrium of the SNPs in the study was not deviated. Conclusion: IBS is a common gastrointestinal problem that has significantly reduced the life quality of oneself and become an economic burden to societies. Though the mutant alleles were rather low, the IBS-associated polymorphisms, rs5443 and rs1805124 were noted to be commonly present in the Malays. Further research on the local IBS patients is recommended to affirm the association of rs5443 and rs1805124 polymorphisms and the syndrome.

Keywords

• Genetic population
• irritable bowel syndrome
• Malay
• rs5443
• rs1805124

Supporting Institution

Universiti Sultan Zainal Abidin

Project Number

Lab Material (LABMAT) Research Grant (Project code no.: UniSZA/LABMAT/2018/03, R0044-R003)

Thanks

This study was supported by the Lab Material (LABMAT) Research Grant from Universiti Sultan Zainal Abidin (Project code no.: UniSZA/LABMAT/2018/03, R0044-R003). The authors would like to thank all healthy volunteers from the Development of Ethno-pharmacogenetics Relatedness and Personalized Medicine project (Grant no: 1001/PSK/8620013) for the blood samples in this study.

References

1. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol. 2016;1(2):133-46.
2. Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: A clinical review. JAMA. 2015;313(9):949-58.
3. Katsumata R, Shiotani A, Murao T, Ishii M, Fujita M, Matsumoto H, et al. The TPH1 rs211105 gene polymorphism affects abdominal symptoms and quality of life of diarrhea-predominant irritable bowel syndrome. J Clin Biochem Nutr. 2018;62(3):270-6.
4. Mohammadi M, Tahmasebi Abdar H, Mollaei HR, Hajghani H, Baneshi MR, Hayatbakhsh MM. Serotonin transporter gene (SLC6A4) polymorphism and mucosal serotonin levels in southeastern Iranian patients with irritable bowel syndrome. Middle East J Dig Dis. 2017;9(1):26-32.
5. Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut. 2004;53(10):1452-8.
6. Jiang D, Huang D, Cai W, Li T, Wang Y, Chen H, et al. G protein beta 3 (GNβ3) C825T polymorphism and irritable bowel syndrome susceptibility: An updated meta-analysis based on eleven case-control studies. Oncotarget. 2017;9(2):2770-81.
7. Xiao QY, Fang XC, Li XQ, Fei GJ. Ethnic differences in genetic polymorphism associated with irritable bowel syndrome. World J Gastroenterol. 2020;26(17):2049-63.
8. Pyvovar SM, Rudyk YS, Lozyk TV, Galchinska VY. Polymorphism of C825T (rs5443) G-protein β3-subunit gene and the long-term prognosis for patients with heart failure. World Med Biol. 2019;15(67):88-93.

9. Mărginean C, Mărginean CO, Bănescu C, Meliţ LE, Tripon F, Iancu M. The relationship among GNB3 rs5443, PNPLA3 rs738409, GCKR rs780094 gene polymorphisms, type of maternal gestational weight gain and neonatal outcomes (STROBE-compliant article). Medicine (Baltimore). 2019;98(28):e16414.
10. Ruiz JR, Eynon N, Meckel Y, Fiuza-Luces C, Santiago C, Gómez-Gallego F, et al. GNB3 C825T polymorphism and elite athletic status: A replication study with two ethnic groups. Int J Sports Med. 2011;32(2):151-3.
11. Iyer A, Yaghmoor S, Hagras M, Hettari Y, Kumosani T. Association of GNB3 C825T polymorphism with obesity in Saudi population. Life Sci J. 2014;11(6):680-4.
12. Kim HG, Lee KJ, Lim SG, Jung JY, Cho SW. G-Protein beta3 subunit C825T polymorphism in patients with overlap syndrome of functional dyspepsia and irritable bowel syndrome. J Neurogastroenterol Motil. 2012;18(2):205-10.
13. Park CS, Uhm JH. Polymorphisms of the serotonin transporter gene and G-protein β3 subunit gene in Korean children with irritable bowel syndrome and functional dyspepsia. Gut Liver. 2012;6(2):223-8.
14. Zhu S, Wang B, Jia Q, Duan L. Candidate single nucleotide polymorphisms of irritable bowel syndrome: A systemic review and meta-analysis. BMC Gastroenterol. 2019;19(1):165.
15. Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, et al. Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation. Circ Arrhythmia Electrophysiol. 2009;2(3):268-75.
16. Braak B, Klooker TK, Scholvinck S, Hofman N, Wilde A, Boeckxstaens GE. Abdominal symptoms in patients with long QT syndrome and a “gain of function” mutation in the Nav1.5 sodium channel. Gastroenterology. 2008;134(W1337):688-94.
17. Beyder A, Mazzone A, Strege PR, Tester DJ, Saito YA, Bernard CE, et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014;146(7):1659-68.
18. Kimura L, Angeli CB, Auricchio MT, Fernandes GR, Pereira AC, Vicente JP, et al. Multilocus family-based association analysis of seven candidate polymorphisms with essential hypertension in an African-derived semi-isolated Brazilian population. Int J Hypertens. 2012;2012:859219.
19. Faruque MU, Millis RM, Dunston GM, Kwagyan J, Bond V Jr, Rotimi CN, et al. Association of GNB3 C825T polymorphism with peak oxygen consumption. Int J Sports Med. 2009;30(5):315-9.
20. Ma J, Wang L, Yang Y, Qiao Z, Fang D, Qiu X, et al. GNB3 and CREB1 gene polymorphisms combined with negative life events increase susceptibility to major depression in a Chinese Han population. PLoS One. 2017;12(2):e0170994.
21. Feng Y, Jiang CD, Chang AM, Shi Y, Gao J, Zhu L, et al. Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus. J Matern Neonatal Med. 2019;32(2):339-47.
22. Yvert T, Miyamoto-Mikami E, Murakami H, Miyachi M, Kawahara T, Fuku N. Lack of replication of associations between multiple genetic polymorphisms and endurance athlete status in Japanese population. Physiol Rep. 2016;4(20):e13003.
23. Triantafyllou K, Kourikou A, Gazouli M, Karamanolis GP, Dimitriadis GD. Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms in the Greek population. Neurogastroenterol Motil. 2016;29(1):e12913.
24. Chen JY, Liu JH, Wu HDI, Lin KH, Chang KC, Liou YM. Transforming growth factor-β1 T869C gene polymorphism is associated with acquired sick sinus syndrome via linking a higher serum protein level. PLoS One. 2016;11(7):e0158676.
25. Hsiao TJ, Hwang Y, Liu CH, Chang HM, Lin E. Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population. Genes Nutr. 2013;8(1):137-44.
26. Chen L, Zhang W, Fang C, Jiang S, Shu C, Cheng H, et al. Polymorphism H558R in the human cardiac sodium channel SCN5A gene is associated with atrial fibrillation. J Int Med Res. 2011;39(5):1908-16.
27. Chen LY, Ballew JD, Herron KJ, Rodeheffer RJ, Olson TM. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther. 2007;81(1):35-41.
28. Tounsi N, Labro AJ, Kerkeni E, Grissa MH, Trabelsi I, Gannoun I, et al. Relevance of KCNE1, SCN5A and eNOS polymorphisms in Tunisian atrial fibrillation patients. Int J Clin Exp Med. 2018;11(6):6009-18.
29. Marjamaa A, Newton-Cheh C, Porthan K, Reunanen A, Lahermo P, Väänänen H, et al. Common candidate gene variants are associated with QT interval duration in the general population. J Intern Med. 2009;265(4):448-58.
30. Tu E, Bagnall RD, Duflou J, Lynch M, Twigg SM, Semsarian C. Post-mortem pathologic and genetic studies in “dead in bed syndrome” cases in type 1 diabetes mellitus. Hum Pathol. 2010;41(3):392-400.
31. Jiang S, Li FL, Dong Q, Liu HW, Fang CF, Shu C, et al. H558R polymorphism in SCN5A is associated with Keshan disease and QRS prolongation in Keshan disease patients. Genet Mol Res. 2014;13(3):6569-76.
32. Moselhy SS, Alhetari YA, Iyer A, Huwait EA, Al-Ghamdi MA, Al-Ghamdi S, et al. Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects. Afr Health Sci. 2017;17(4):1059-69.
33. Sydorchuk A, Sydorchuk L. The severity of essential hypertension in terms of blood pressure values does not depend on NOS3 (rs2070744) and GNB3 (rs5443) genes polymorphisms in the West-Ukrainian population. J Educ Health Sport. 2021;11(10):332-41.
34. Panoulas VF, Smith JP, Stavropoulos-Kalinoglou A, Douglas KM, Nightingale P, Kitas GD. Lack of an association of GNB3 C825T polymorphism and blood pressure in patients with rheumatoid arthritis. Clin Exp Hypertens. 2009;31(5):428-39.
35. Costa B, Pini S, Baldwin DS, Silove D, Manicavasagar V, Abelli M, et al. Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety. J Affect Disord. 2017;218:365-73.
36. El Din Hemimi NS, Mansour AA, Abdelsalam MM. Prediction of the risk for essential hypertension among carriers of C825T genetic polymorphism of G protein β3 (GNB3) gene. Biomark Insights. 2016;11:69-75.
37. Bondarenko EA, Shadrina MI, Grishkina MN, Druzhkova TA, Akzhigitov RG, Gulyaeva NV, et al. Genetic analysis of BDNF, GNB3, MTHFR, ACE and APOE variants in major and recurrent depressive disorders in Russia. Int J Med Sci. 2016;13(12):977-83.
38. Zhang Y, Chang B, Hu S, Wang D, Fang Q, Huang X, et al. Single nucleotide polymorphisms and haplotype of four genes encoding cardiac ion channels in Chinese and their association with arrhythmia. Ann Noninvasive Electrocardiol. 2008;13(2):180-90.
39. Mazzaccara C, Limongelli G, Petretta M, Vastarella R, Pacileo G, Bonaduce D, et al. A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy. J Cardiovasc Med (Hagerstown). 2018;19(7):344-50.
40. Nikulina SY, Chernova AA, Shulman VA, Maksimov VN, Gavrilyuk OA, Tretyakova SS, et al. An investigation of the association of the H558R polymorphism of the SCN5A gene with idiopathic cardiac conduction disorders. Genet Test Mol Biomarkers. 2015;19(6):1288-94.
41. He Y, Yang H, Geng T, Feng T, Yuan D, Kang L, et al. Genetic polymorphisms of pharmacogenomic VIP variants in the Ihoba population of southwest China. Int J Clin Exp Pathol. 2015;8(10):13293-303.
42. Jin T, Aikemu A, Zhang M, Geng T, Feng T, Kang L, et al. Genetic polymorphisms analysis of pharmacogenomic VIP variants in Miao ethnic group of southwest China. Med Sci Monit. 2015;21:3769-76.
43. Chen W, Ding H, Cheng Y, Li Q, Dai R, Yang X, et al. Genetic polymorphisms analysis of pharmacogenomic VIP variants in Bai ethnic group from China. Mol Genet Genomic Med. 2019;7(9):e884.
44. AL-Eitan LN. Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations. Gene. 2020;737:144408.