 |
 |
 |
 |
 |
 |
Sains Malaysiana 52(3)(2023): 851-862
http://doi.org/10.17576/jsm-2023-5203-13
Investigation
of Gene Variation among Non-Alcoholic Fatty Liver Disease Patients in Gaza
Strip: A Preliminary Study
(Kajian Variasi Gen dalam Kalangan Pesakit Hati Berlemak Bukan Alkohol di Semenanjung Gaza: Suatu Kajian Awal)
ABEER
AL-QATATI 1, ALI AL-BELTAJI2 & MAZEN
ALZAHARNA2,*
1Clinical Laboratory Sciences Department, Faculty of
Science, The University of Jordan, Amman, Jordan
2Medical Laboratory Sciences Dept., Faculty of Health
Sciences, Islamic University of Gaza, P.O. Box 108, Gaza city, Palestine
Received:
18 October 2022/Accepted: 7 February 2023
Abstract
The
prevalent hepatic presentation of the metabolic syndrome is a non-alcoholic
fatty liver disease (NAFLD), one of the most common types of chronic liver
illnesses. Patients with NAFLD may develop liver damage depending on their
genetic heritage. In this preliminary study, our main aim was to detect the
genetic association of p85α (Met326Ile), PNPLA3 (C>G), IL28B275
(A>G), and IL28B860 (C>T) single nucleotide polymorphisms (SNPs) with
steatosis and NASH in patients from Gaza Strip. We performed an SNP analysis by
RFLP-PCR in 33 cases of steatosis and 28 cases of non-alcoholic steatohepatitis (NASH), in addition to 29 age- and
sex-matched controls. We found that only the mutant T allele of IL28B860 was
significantly associated with an increased risk of steatosis (P = 0.04). The
other studied alleles and genotypes were not significantly associated with increased
or decreased risk of steatosis, NASH, or combined steatosis or NASH groups.
Among all of the studied variables (age, sex, diabetes, and BMI), only BMI was
significantly associated with an increased risk of steatosis as well as NASH. A
linkage disequilibrium analysis showed that the association between the two
SNPs of IL28B860 and IL28B275 was significant. Having the TG haplotype
increased the risk of steatosis by 2.97 fold and the risk of combined steatosis
or NASH by 2.44 fold. This haplotype increased the risk of NASH, but the effect
was not significant.
Keywords:
NAFLD; NASH; preliminary study; single nucleotide polymorphism; steatosis
Abstrak
Persembahan hati yang lazim bagi sindrom metabolik ialah penyakit hati berlemak bukan alkohol (NAFLD), salah satu jenis penyakit hati kronik yang paling biasa. Pesakit dengan NAFLD mungkin mengalami kerosakan hati bergantung kepada warisan genetik mereka. Dalam kajian awal ini, matlamat utama kami adalah untuk mengesan perkaitan genetik p85α
(Met326Ile), PNPLA3 (C> G), IL28B275 (A> G) dan IL28B860 (C> T) polimorfisme nukleotida tunggal (SNP) dengan steatosis dan NASH pada pesakit dari Semenanjung Gaza. Kami menjalankan analisis SNP dengan RFLP-PCR dalam 33 kes steatosis dan 28 kes steatohepatitis bukan alkohol (NASH), sebagai tambahan kepada 29 kawalan padanan umur dan jantina. Kami mendapati bahawa hanya alel T mutan IL28B860 dikaitkan dengan peningkatan risiko steatosis (P = 0.04). Kajian lain Alel dan genotip tidak dikaitkan dengan peningkatan atau penurunan risiko steatosis, NASH, atau gabungan steatosis atau kumpulan NASH. Antara semua pemboleh ubah yang dikaji (umur, jantina,
diabetes dan BMI), hanya BMI dikaitkan dengan peningkatan risiko steatosis serta NASH. Analisis ketidakseimbangan kaitan menunjukkan bahawa perkaitan antara dua SNP IL28B860 dan IL28B275 adalah signifikan. Mempunyai haplotip TG meningkatkan risiko steatosis sebanyak 2.97 kali ganda dan risiko gabungan steatosis atau NASH sebanyak 2.44 kali ganda. Haplotip ini meningkatkan risiko NASH, tetapi kesannya tidak ketara.
Kata kunci: Kajian awal; NAFLD; NASH; polimorfisme nukleotida tunggal; steatosis
REFERENCES
Abe,
H., Ochi, H., Maekawa, T., Hayes, C.N., Tsuge, M., Miki, D., Mitsui, F.,
Hiraga, N., Imamura, M. & Takahashi, S. 2010. Common variation of IL28
affects gamma-GTP levels and inflammation of the liver in chronically infected
hepatitis C virus patients. Journal of
Hepatology 53(3): 439-443.
Agundez, J.A., Garcia-Martin, E.,
Maestro, M.L., Cuenca, F., Martinez, C., Ortega, L., Carballo, M., Vidaurreta,
M., Agreda, M. & Diaz-Zelaya, G. 2012. Relation of IL28B gene polymorphism
with biochemical and histological features in hepatitis C virus-induced liver
disease. PLoS ONE 7(5): e37998.
Anstee, Q.M. & Day, C.P. 2015.
The genetics of nonalcoholic fatty liver disease: Spotlight on PNPLA3 and
TM6SF2. Seminars in Liver Disease 35(3): 270-290.
Baier, L.J., Wiedrich, C., Hanson,
R.L. & Bogardus, C. 1998. Variant in the regulatory subunit of
phosphatidylinositol 3-kinase (p85alpha): Preliminary evidence indicates a
potential role of this variant in the acute insulin response and type 2
diabetes in Pima women. Diabetes 47(6): 973-975.
Chen, S., Yan, W., Huang, J., Ge,
D., Yao, Z. & Gu, D. 2005. Association analysis of the variant in the
regulatory subunit of phosphoinositide 3‐kinase (p85α) with Type 2
diabetes mellitus and hypertension in the Chinese Han population. Diabetic Medicine 22(6): 737-743.
Clark, P.J., Thompson, A.J., Zhu,
M., Vock, D.M., Zhu, Q., Ge, D., Patel, K., Harrison, S.A., Urban, T.J. &
Naggie, S. 2012. Interleukin 28B polymorphisms are the only common genetic
variants associated with low‐density lipoprotein cholesterol (LDL‐C)
in genotype‐1 chronic hepatitis C and determine the association between
LDL‐C and treatment response. Journal
of Viral Hepatitis 19(5): 332-340.
Clark, P.J., Thompson, A.J., Zhu,
Q., Vock, D.M., Zhu, M., Patel, K., Harrison, S.A., Naggie, S., Ge, D.,
Tillmann, H.L., Urban, T.J., Shianna, K., Fellay, J., Goodman, Z., Noviello,
S., Pedicone, L.D., Afdhal, N., Sulkowski, M., Albrecht, J.K., Goldstein, D.B.,
McHutchison, J.G. & Muir, A.J. 2012. The association of genetic variants
with hepatic steatosis in patients with genotype 1 chronic hepatitis C
infection. Digestive Diseases and
Sciences 57(8): 2213-2221.
Dutta, A.K. 2011. A new PCR-RFLP
method for diagnosing PNPLA3 RS738409 polymorphism.
Engwa, G.A., Nwalo, F.N., Chiezey,
V.O., Unachukwu, M.N., Ojo, O.O. & Ubi, B.E. 2018. Assessment of the
Pro12Ala polymorphism in the PPAR-γ2 gene among type 2 diabetes patients
in a Nigerian population. Journal of
Clinical Medicine 7(4): 69.
Ficarella, R., Laviola, L. &
Giorgino, F. 2015. Lipodystrophic diabetes mellitus: A lesson for other forms
of diabetes? Current Diabetes Reports 15(3): 1-10.
Fruman, D.A., Meyers, R.E. &
Cantley, L.C. 1998. Phosphoinositide kinases. Annual Review of Biochemistry 67: 481.
Ge, D., Fellay, J., Thompson, A.J.,
Simon, J.S., Shianna, K.V., Urban, T.J., Heinzen, E.L., Qiu, P., Bertelsen,
A.H. & Muir, A.J. 2009. Genetic variation in IL28B predicts hepatitis C
treatment-induced viral clearance. Nature
Biotechnology 461(7262): 399-401.
Hansen, L., Zethelius, B.,
Berglund, L., Reneland, R., Hansen, T., Berne, C., Lithell, H., Hemmings, B.A.
& Pedersen, O. 2001. In vitro and in vivo studies of a
naturally occurring variant of the human p85α regulatory subunit of the
phosphoinositide 3-kinase: Inhibition of protein kinase B and relationships
with type 2 diabetes, insulin secretion, glucose disappearance constant, and
insulin sensitivity. Diabetes and
Metabolism 50(3): 690-693.
Hansen, T., Andersen, C.B.,
Echwald, S.M., Urhammer, S.A., Clausen, J.O., Vestergaard, H., Owens, D.,
Hansen, L. & Pedersen, O. 1997. Identification of a common amino acid
polymorphism in the p85α regulatory subunit of phosphatidylinositol
3-kinase: Effects on glucose disappearance constant, glucose effectiveness, and
the insulin sensitivity index. Diabetes 46(3): 494-501.
Honda, M., Sakai, A., Yamashita,
T., Nakamoto, Y., Mizukoshi, E., Sakai, Y., Yamashita, T., Nakamura, M.,
Shirasaki, T. & Horimoto, K. 2010. Hepatic ISG expression is associated
with genetic variation in interleukin 28B and the outcome of IFN therapy for
chronic hepatitis C. Gastroenterology 139(2): 499-509.
Kawanishi, M., Tamori, Y., Masugi,
J., Mori, H., Ito, C., Hansen, T., Andersen, C.B., Pedersen, O. & Kasuga,
M. 1997. Prevalence of a polymorphism of the phosphatidylinositol 3-Kinase
p85α regulatory subunit (Codon 326Met→ ile) in Japanese NIDDM
patients. Diabetes Care 20(6): 1043.
Lankarani, K.B., Ghaffarpasand, F.,
Mahmoodi, M., Lotfi, M., Zamiri, N., Heydari, S.T., Fallahzadeh, M.K.,
Maharlouei, N., Babaeinejad, M. & Mehravar, S. 2013. Non alcoholic fatty
liver disease in southern Iran: A population based study. Hepatitis Monthly 13(5): e9248.
Li, J.H., Lao, X.Q., Tillmann,
H.L., Rowell, J., Patel, K., Thompson, A., Suchindran, S., Muir, A.J., Guyton,
J.R. & Gardner, S.D., McHutchison, J.G. & McCarthy, J.J. 2010. Interferon‐lambda
genotype and low serum low‐density lipoprotein cholesterol levels in
patients with chronic hepatitis C infection. Hepatology 51(6): 1904-1911.
Li, L., Liu, D‐W., Yan,
H‐Y., Wang, Z‐Y., Zhao, S‐H. & Wang, B. 2016. Obesity is
an independent risk factor for non‐alcoholic fatty liver disease:
Evidence from a meta‐analysis of 21 cohort studies. Obesity Reviews 17(6): 510-519.
Ludwig, J., Viggiano, T.R., Mcgill,
D.B. & Oh, B.J. 1980. Nonalcoholic steatohepatitis: Mayo clinic experiences
with a hitherto unnamed disease. Mayo Clinic Proceedings 55(7): 434-438.
Matsuda, S., Kobayashi, M. &
Kitagishi, Y. 2013. Roles for PI3K/AKT/PTEN pathway in cell signaling of
nonalcoholic fatty liver disease. International
Scholarly Research Notices 2013: Article ID. 472432.
Petta, S., Grimaudo, S., Cammà, C.,
Cabibi, D., Marco, V.D., Licata, G., Pipitone, R.M. & Craxì, A. 2012. IL28B
and PNPLA3 polymorphisms affect histological liver damage in patients with
non-alcoholic fatty liver disease. Journal
of Hepatology 56(6): 1356-1362.
Pirazzi, C., Adiels, M., Burza,
M.A., Mancina, R.M., Levin, M., Ståhlman, M., Taskinen, M-R., Orho-Melander,
M., Perman, J. & Pujia, A. 2012. Patatin-like phospholipase
domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in
humans and in vitro. Journal of
Hepatology 57(6): 1276-1282.
Rüstemoğlu, A., Yalcin, D.,
Günal, Ö., Çelik, B., Barut, Ş. & Ateş, Ö. 2016. Interleukin 28B
rs12979860 CT, rs12980275 GA, rs8099917 GT and TT genotypes are the predictors
of rapid viral response in hepatitis C virus-infected patients. Viral Hepat. J. 22(3): 97-102.
Schreuder, T.C.M.A., Verwer, B.J.,
van Nieuwkerk, C.M.J. & Mulder, C.J.J. 2008. Nonalcoholic fatty liver
disease: An overview of current insights in pathogenesis, diagnosis and
treatment. World Journal of
Gastroenterology: WJG 14(16): 2474-2486.
Schwimmer, J.B., Celedon, M.A.,
Lavine, J.E., Salem, R., Campbell, N., Schork, N.J., Shiehmorteza, M., Yokoo,
T., Chavez, A. & Middleton, M.S. 2009. Heritability of nonalcoholic fatty
liver disease. Gastroenterology 136(5): 1585-1592.
Shibata, M., Kihara, Y., Taguchi,
M., Tashiro, M. & Otsuki, M. 2007. Nonalcoholic fatty liver disease is a
risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 30(11): 2940-2944.
Sookoian, S. & Pirola, C.J.
2011. Meta‐analysis of the influence of I148M variant of
patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the
susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53(6): 1883-1894.
Tai, C-M., Huang, C-K., Tu, H-P.,
Hwang, J-C., Chang, C-Y. & Yu, M-L. 2015. PNPLA3 genotype increases
susceptibility of nonalcoholic steatohepatitis among obese patients with
nonalcoholic fatty liver disease. Surgery
for Obesity and Related Diseases 11(4): 888-894.
Tanase, D.M., Gosav, E.M., Costea,
C.F., Ciocoiu, M., Lacatusu, C.M., Maranduca, M.A., Ouatu, A. & Floria, M.
2020. The intricate relationship between type 2 diabetes mellitus (T2DM),
insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD). Journal of Diabetes Research 2020:
3920196.
Thompson, A.J., Clark, P.J., Zhu,
M., Zhu, Q., Ge, D., Sulkowski, M.S., Muir, A.J., Tillmann, H.L., Patel, K.
& Naggie, S. 2010. Genome wide-association study identifies IL28B
polymorphism to be associated with baseline ALT and hepatic necro-inflammatory
activity in chronic hepatitis C patients enrolled in the IDEAL study. Hepatology 52(4): 1220A-1221A.
Tilg, H. & Moschen, A. 2010.
Update on nonalcoholic fatty liver disease: Genes involved in nonalcoholic
fatty liver disease and associated inflammation. Current Opinion in Clinical Nutrition Metabolic Care 13(4):
391-396.
Tillmann, H.L., Patel, K., Muir,
A.J., Guy, C.D., Li, J.H., Lao, X.Q., Thompson, A., Clark, P.J., Gardner, S.D.
& McHutchison, J.G. 2011. Beneficial IL28B genotype associated with lower
frequency of hepatic steatosis in patients with chronic hepatitis C. Journal of Hepatology 55(6): 1195-1200.
Xia, M-F., Lin, H-D., Chen, L-Y.,
Wu, L., Ma, H., Li, Q., Aleteng, Q., Hu, Y., He, W-Y. & Gao, J. 2019. The
PNPLA3 rs738409 C> G variant interacts with changes in body weight over time
to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes. Diabetologia 62(4): 644-654.
Xu, R., Tao, A., Zhang, S., Deng,
Y. & Chen, G. 2015. Association between patatin-like phospholipase domain
containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease:
A HuGE review and meta-analysis. Scientific
Reports 5(1): 1-11.
Younes, R. & Bugianesi, E.
2019. NASH in lean individuals. Seminars in Liver Disease 39(1): 86-95.
Zhang, L., You, W., Zhang, H.,
Peng, R., Zhu, Q., Yao, A., Li, X., Zhou, Y., Wang, X. & Pu, L. 2015.
PNPLA3 polymorphisms (rs738409) and non‐alcoholic fatty liver disease
risk and related phenotypes: A meta‐analysis. Journal of Gastroenterology and Hepatology 30(5): 821-829.
*Corresponding author; email: mzaharna@iugaza.edu.ps
|
|||
|
