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Association Between Rs2303861 Polymorphism in CD82 Gene and Non-Alcoholic Fatty Liver Disease: a Preliminary Case-Control Study

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Association Between Rs2303861 Polymorphism in CD82 Gene and Non-Alcoholic Fatty Liver Disease: a Preliminary Case-Control Study RESEARCH ARTICLE 361 Croat Med J. 2019;60:361-8 https://doi.org/10.3325/cmj.2019.60.361 Association between Parham Habibzadeh1, Behnam Honarvar2, rs2303861 polymorphism Mohammad Silawi3, Shima Bahramjahan3, Azar in CD82 gene and non- Kazemi4, Mohammad alcoholic fatty liver disease: a Ali Faghihi3,5, Kamran Lankarani2 preliminary case-control study 1Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran 2Health Policy Research Center, Institute of Health, Shiraz University Aim To investigate the genetic factors involved in the de- of Medical Sciences, Shiraz, Iran velopment of non-alcoholic fatty liver disease (NAFLD) and 3Persian BayanGene Research and its sequelae in a Middle Eastern population. Training Center, Shiraz, Iran Methods This genetic case-control association study, con- 4Transplant Research Center, Shiraz ducted in 2018, enrolled 30 patients with NAFLD and 30 University of Medical Sciences, Shiraz, Iran control individuals matched for age, sex, and body mass index. After quality control measures, entire exonic regions 5Center for Therapeutic Innovation, of 3654 genes associated with human diseases were se- Department of Psychiatry and Behavioral Sciences, University of quenced. Allelic association test and enrichment analysis Miami Miller School of Medicine, of the significant genetic variants were performed. Miami, FL, USA Results The association analysis was conducted on 27 NAFLD patients and 28 controls. When Bonferroni cor- rection was applied, NAFLD was significantly associ- ated with rs2303861, a variant located in the CD82 gene (P = 2.49 × 10−7, adjusted P = 0.0059). When we used Ben- jamini-Hochberg adjustment for correction, NAFLD was significantly associated with six more variants. Enrich- ment analysis of the genes corresponding to all the seven variants showed significant enrichment for miR-193b-5p (P = 0.00004, adjusted P = 0.00922). Conclusion A variant on CD82 gene and a miR-193b ex- pression dysregulation may have a role in the develop- ment and progression of NAFLD and its sequelae. Received: December 5, 2018 Accepted: June 28, 2019 Correspondence to: Kamran B Lankarani Health Policy Research Center Institute of Health Shiraz University of Medical Sciences Shiraz, Iran P.O. BOX 7134845794 [email protected] www.cmj.hr 362 RESEARCH ARTICLE Croat Med J. 2019;60:361-8 Non-alcoholic fatty liver disease (NAFLD) is the most com- factors, we investigated the underlying genetic factors in- mon liver disease in many parts of the world and an im- volved in the development of NAFLD and its sequelae in portant global health concern (1-4). As a hepatic manifes- an Iranian population. tation of metabolic syndrome, it is closely associated with obesity, insulin resistance, and dyslipidemia (5). NAFLD MATERIALS AND METHODS prevalence is steadily on the rise due to a global increasing trend in obesity incidence (5,6) and within the next decade Study population NAFLD is predicted to replace hepatitis C as the leading in- dication for liver transplantation in the United States (1). The study included 30 patients with NAFLD (17 female) and 30 healthy controls (17 female) matched for age, sex, The main causes of mortality among patients with NAFLD and body mass index (BMI), who were randomly selected are malignancies and cardiovascular diseases (7,8). The (with a random number generator) from participants of condition is an independent risk factor for hepatocellu- a cross-sectional population-based study previously con- lar carcinoma (HCC), which was previously thought to re- ducted in Shiraz (23). Briefly, the previous study had en- quire liver cirrhosis as its precursor but has been recently rolled 542 adult unrelated participants randomly selected described in patients with simple hepatic steatosis and no from the general population through a proportional clus- sign of inflammation or fibrosis (9,10). NAFLD is also close- ter random sampling. They had been interviewed to ob- ly associated with an increased risk of colorectal cancer tain demographic information and physically examined by (11,12), as well as with myocardial remodeling, thus play- a medical doctor. Participants with alcohol consumption, ing an important role in the development of heart failure participants serologically positive for hepatitis B or hepa- (13,14). The observed association between NAFLD, HCC, titis C, and those identified through the interview to have colorectal cancer, and heart failure implies that there is hepatic steatosis due to other competing etiologies (eg, a possible underpinning defect in cellular processes that drugs, bariatric surgery, etc) had been excluded. NAFLD link cell metabolism to cell division and metabolite traf- had been ultrasonographically diagnosed by an experi- ficking. enced radiologist unaware of the patients’ clinical informa- tion according to a validated protocol (24). The underlying risk factors for NAFLD (eg, obesity and diabetes mellitus) are associated with numerous genetic The current study included only patients with confirmed polymorphisms (15-17). Genetic factors could also in part moderate-to-severe hepatic steatosis. The absence of he- explain the extreme variation in the worldwide NAFLD patic steatosis in the control group was also documented prevalence (6) and considerable inter-individual variabili- by ultrasonography. ty in disease severity, morbidity, and mortality (18). NAFLD was found to be significantly associated with SNP rs738409 This study was conducted in compliance with the Decla- (I148M) in PNPLA3 gene on chromosome 22, encoding an ration of Helsinki. Written informed consent was obtained enzyme responsible for the hydrolysis of triacylglycerols from all study participants who had been assured that in adipocytes; individuals homozygous for this allele had their data would be kept confidential. The study was ap- more than twice as much hepatic fat content as non-carri- proved by the Research Ethics Committee of Health Policy ers (19). Variants in other genes (eg, MBOAT7, TM6SF2, etc) Research Center affiliated to Shiraz University of Medical (20), as well as dysregulated expression of several micro- Sciences Ethics Committee. RNAs (miRNAs), were also found to contribute to NAFLD pathogenesis (21). For instance, miR-33a/b modulates the Clinical and laboratory evaluation risk of metabolic syndrome by regulating various metabol- ic pathways (22). Weight, height, waist circumference, hip circumference, and blood pressure had been measured and BMI was cal- To the best of our knowledge, no genetic case-control as- culated (23). Fasting venous blood samples were obtained, sociation study has so far been conducted on NAFLD in serum was separated, and fasting glucose, aspartate amin- the Middle Eastern population, despite the fact that the otransferase (AST), alanine aminotransferase (ALT), triacyl- underlying genetic factors of NAFLD and their relative glycerols, high-density lipoprotein cholesterol, low-densi- contributions might differ from those in other popula- ty lipoprotein cholesterol, hepatitis B surface antigen, and tions. Therefore, after controlling for traditional risk hepatitis C virus antibodies were measured with an auto- www.cmj.hr Habibzadeh et al: rs2303861 polymorphism and NAFLD 363 mated analyzer (CS-1200 Auto-Chemistry Analyzer, DIRUI BMI. Genotypes for SNPs with significant P values were re- Industrial Co, Changchun, China). coded as 0, 1, or 2, according to the number of alterna- tive alleles present. Multiple linear regression analysis, per- DNA preparation, genotyping, and quality control formed in SPSS, assessed the effect of the SNP’s alternative alleles that were found significant in allelic association test Genomic DNA was extracted from EDTA-anticoagulated on clinical and biochemical parameters after adjustment peripheral whole blood collected from each individual for age, sex, and BMI. False discovery rate for each associa- with QIAamp DNA isolation mini kit (QIAGEN, Hilden, Ger- tion was calculated with the Benjamini-Hochberg method many) by salting out technique. The quality of isolated (28). SNPs with a false discovery rate <0.05 were included DNA specimens was assessed by QUBIT 3.0 fluorometer in the enrichment analysis. Information about overlapping (Thermo Fisher Scientific, Waltham, MA, USA). The entire or nearest gene corresponding to the associated SNPs exonic regions of 3654 genes associated with human dis- was obtained by an SNP annotation tool (29). Enrichment eases (inherited disease panel, Agilent Technologies, Santa analysis was carried out with Enrichr on miRTarBase data- Clara, CS, USA) were sequenced above 70 × coverage on base (30,31). Significantly enriched miRNAs were identified an Illumina NextSeq 500 platform (Illumina, San Diego, CA, from the list of genes corresponding to the SNPs that were USA). A total of 54 100 variants located in genomic loci of found to be significantly different between patients and these genes were identified. Target Enrichment for Illumina controls with the Fisher exact test in Enrichr. Multiplexed sequencing protocol (v. D0, November 2015) with SureSelectQXT (Agilent Technologies) was used for indi- RESULTS vidual library preparation and sample pooling. The follow- ing quality control measures were performed in PLINK, v. After quality control, 55 individuals – 27 patients with NA- 1.07 (Free Software Foundation Inc., Boston, MA, USA) (25): FLD and 28 controls – and 23 732 SNPs were included in single nucleotide polymorphisms (SNPs) with minor allele the association analysis. Patients
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