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Are IL18RAP Gene Polymorphisms Associated with Body Mass Regulation? a Cross-Sectional Study

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Are IL18RAP Gene Polymorphisms Associated with Body Mass Regulation? a Cross-Sectional Study Open Access Research BMJ Open: first published as 10.1136/bmjopen-2017-017875 on 15 November 2017. Downloaded from Are IL18RAP gene polymorphisms associated with body mass regulation? A cross-sectional study Vanesa Martínez-Barquero,1,2 Griselda de Marco,2 Sergio Martínez-Hervas,1,3,4 Victoria Adam-Felici,2 Cristina Pérez-Soriano,2 Verónica Gonzalez-Albert,2 Gemma Rojo,3,5 Juan Francisco Ascaso,1,3,4 José Tomás Real,1,3,4 Ana Barbara Garcia-Garcia,2,3 Juan Carlos Martín-Escudero,6 Raquel Cortes,2 Felipe Javier Chaves2,3 To cite: Martínez-Barquero V, ABSTRACT Strengths and limitations of this study Marco Gde, Martínez-Hervas S, Objectives To investigate the association between et al. Are IL18RAP gene IL18RAP and body mass index (BMI) and obesity ► Our study was carried out in two Spanish polymorphisms associated with and to verify the effect of a polymorphism in the body mass regulation? A cross- populations from different regions with noticeably microRNA136 (MIR136) IL18RAP binding region. sectional study. BMJ Open distinct characteristics, although the results were Design We analysed samples from two Spanish 2017;7:e017875. doi:10.1136/ similar for both. cross-sectional studies, VALCAR (Spanish bmjopen-2017-017875 ► The number of individuals included in this study was Mediterranean coast) and Hortega (Spanish centre). limited, but its statistical power was sufficient for ► Prepublication history for These studies aimed at analysing cardiovascular risk the reduced number of polymorphisms we analysed. this paper is available online. and development of cardiovascular disease in the To view please visit the journal ► We did not exhaustively study genetic variability in general population. Both populations correspond to online (http:// dx. doi. org/ 10. this gene because this gene region has too many regions with different characteristics. 1136/ bmjopen- 2017- 017875). variations, and would have required the study of Setting Five single nucleotide IL18RAP more polymorphisms. Received 22 May 2017 polymorphisms were selected using the SYSNPs web ► Our results should be confirmed by other studies, Revised 8 September 2017 tool and analysed by oligonucleotide ligation assay which include analyses of different populations and Accepted 22 September 2017 (SNPlex). For the MIR136 functional study, cells with larger sample sizes. were transfected with plasmids containing different rs7559479 polymorphism alleles and analysed by http://bmjopen.bmj.com/ luciferase reporter assays. Participants 1970 individuals (Caucasian, both INTRODUCTION genders): VALCAR (468) and Hortega (1502). 1Department of Medicine, Obesity is a state in which excess energy Results rs2293225, rs2272127 and rs7559479 University of Valencia, Valencia, accumulates in corporal adipose tissue due Spain showed the following associations: rs7559479 G to a chronic imbalance between energy 2Department of Genomic and allele correlated with a higher obesity risk (P=0.01; intake and energy expenditure1; individ- OR=1.82; 95% CI 1.15 to 2.87 for the VALCAR group; Genetic Diagnosis Unit, Hospital uals respond differently to this imbalance Clínico Research Foundation P=0.033; OR=1.35; 95% CI 1.03 to 1.79 for the because of their differing genetic back- on September 24, 2021 by guest. Protected copyright. (INCLIVA), Valencia, Spain Hortega population) and higher body mass index (BMI) 2 3CIBER of Diabetes and values (P=0.0045; P=0.1 for VALCAR and Hortega, grounds. Over the past 20 years there has Associated Metabolic Diseases respectively); a significant association with obesity been an alarming increase in the number (CIBERDEM), Madrid, Spain of overweight and obese individuals. This is 4 (P=0.0024, OR=1.44, 95% CI 1.14 to 1.82) and Department of Endocrinology increased BMI values (P=0.008) was found when especially worrying because obesity signifi- and Nutrition Service, Hospital considering both populations together. rs2293225 Clínico Universitario de Valencia, cantly increases the risk of chronic diseases, Valencia, Spain T allele was associated with lower obesity risk such as type 2 diabetes, cardiovascular 5Department of Endocrinology (P=0.036; OR=0.60; 95% CI 0.35 to 0.96) and lower disease, non-alcoholic fatty liver disease, and Nutrition Service, Hospital BMI values (P=0.0038; OR=1.41) while the rs2272127 colon cancer and obstructive sleep apnoea.3 Regional Universitario, Instituto G allele was associated with lower obesity risk Obesity is defined as a low-grade inflam- de Biomedicina de Málaga (P=0.028; OR=0.66; 95% CI 0.44 to 0.97) only in the matory state characterised by increased (IBIMA), Malaga, Spain VALCAR population. A reporter assay showed that the 4 6 cytokine production. Interleukin-18 Department of Internal presence of the A allele in rs7559479 was associated Medicine, Rio Hortega Hospital, (IL-18) concentration increases in obesity, with increased MIR136 binding to IL18RAP. University of Valladolid, Conclusions Our results suggest that polymorphisms suggesting it is involved in obesity and Valladolid, Spain in IL18RAP influence susceptibility to obesity. metabolic syndrome by increasing adipo- 5 Correspondence to We demonstrated that the A allele in rs7559479 genesis. IL-18 is a member of the IL-1 cyto- Dr Ana Barbara Garcia-Garcia; increases MIR136 binding, which regulates IL-18 kine superfamily. It regulates the immune a. barbara. garcia@ ext. uv. es system activity. response and is expressed in cells involved Martínez-Barquero V, et al. BMJ Open 2017;7:e017875. doi:10.1136/bmjopen-2017-017875 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2017-017875 on 15 November 2017. Downloaded from in chronic inflammation, autoimmune diseases and procedures. The presence of obesity, hypertension several cancers and infectious diseases: macrophages, (HTN) and type 2 diabetes (as defined by the WHO dendritic cells, Kupffer cells, keratinocytes, osteoblasts, criteria; http://www. who. int) was recorded and the adrenal cortex cells, intestinal epithelial cells, microg- BMI (kg/m2) was calculated. Briefly, obesity was diag- lial cells and synovial fibroblasts.6–14 IL-18 signalling is nosed when the BMI was ≥30 kg/m2, HTN was diag- induced by binding of this cytokine to a heterodimeric nosed when systolic and diastolic blood pressure receptor called IL-18R. IL-18R is formed of two chains, values were >140 and/or >90 mm Hg, respectively, and IL-18R1 (with a binding role) and IL18RAP (receptor diabetes was defined as a fasting plasma glucose level accessory protein, with a signal-transducing role). >7.0 mmol/L (126 mg/dL) or a 2-hour plasma glucose The interaction of both IL-18R chains is mandatory to level >11.1 mmol/L (200 mg/dL). A previous diagnosis induce IL-18 signalling.15–17 of type 2 diabetes or HTN and detection of the disease Some polymorphisms can modulate gene activity via at the time of sample collection was also recorded. different mechanisms, such as modifying the binding The general characteristics of the samples analysed are or action of specific microRNAs (miRNAs). They are shown in table 1. small non-coding RNAs which modulate expression of The exclusion criteria were the same in both popula- thousands of genes, and studies performed over the tions: the presence of serious physical conditions which past decade suggested their involvement in disease prevented the subject from responding to the survey regulation.18 19 Several miRNAS have been described or donating the samples required, disorders that might as biomarkers for cancers, cardiovascular disease influence the collection of reliable information, or any and type 2 diabetes.18 20–22 Furthermore, it has been mental or social condition which might complicate or suggested that a failure in miRNA regulation plays a prevent the subject’s participation in the study. The deci- part in obesity.23 These facts support the use of miRNA sion to exclude patients was made on an individual basis as biomarkers for the early diagnosis of chronic diseases by the clinician. and as therapeutic targets.24 Many studies have reported on IL-18 and IL18R1, SNP selection and genotyping but few specifically discussed IL18RAP; therefore, we Venous blood samples were collected in tubes containing investigated, for the first time, the possible association EDTA in order to obtain genomic DNA using the between IL18RAP, body mass index (BMI) and obesity. Chemagic system (Chemagen, Baesweiler, Germany). To do this, we verified the effect of polymorphism DNA was quantified and diluted to a final concentra- rs7559479 located in the MIR136 binding site in the tion of 100 ng ⁄µL. The IL18RAP single nuclear polymor- mRNA of IL18RAP and the mRNA levels of this gene. phisms (SNPs) were selected for genotyping based on the conjunction of several parameters selected in the 25 SYSNPs web tool : heterozygosity in a Caucasian popula- http://bmjopen.bmj.com/ MatERIALS AND METHODS tion (>10% for the minor allele frequency), position and Population samples spacing along the gene and a possible functional effect We analysed two general-population-based study (http://www. ensembl. org/ index. html). Five SNPs in the samples (a total of 1970 people) from two different IL18RAP gene were selected (table 2) and were genotyped regions of Spain: the VALCAR study, with 468 subjects using an oligonucleotide ligation assay (SNPlex; Applied from the Valencian region and the Hortega study, with Biosystems, Foster City, California, USA), according to 1502 subjects from the province of Valladolid. Both the the manufacturer’s guidelines. The genomic
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