Date Published: June 29, 2017
Publisher: Public Library of Science
Author(s): Marta Sobalska-Kwapis, Aleksandra Suchanecka, Marcin Słomka, Anna Siewierska-Górska, Ewa Kępka, Dominik Strapagiel, Tuan Van Nguyen.
Genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI) in many different populations. Variants in the FTO locus are reported to be one of the strongest genetic predictors of obesity. Recent publications pointed also to a topologically associated domain (TAD) which is identified as a novel region affecting BMI. The TAD area encompasses the IRXB cluster (IRX3, IRX5, IRX6), FTO and RPGRIP1L genes.
In this study, we investigated the relationship between variation of the FTO and IRX genes and obesity in Poles. We presented a case—control association analysis (normal versus overweight and/or obesity group) of Polish adult individuals (N = 5418). We determined whether or not the chromosomal region 16:53 500 000–55 500 000 contains polymorphic variants which are correlated with BMI in Polish population, including sex and age stratified analysis.
The obtained results showed that the problem of weight-height abnormalities differently affects populations of Polish women and men (χ2 = 187.1; p<0.0001). From 353 SNPs enrolled to this study, 86 were statistically significant (highest χ2 = 15.72; p = 7.35E-05 observed for rs1558902). Linkage disequilibrium (LD) analysis revealed 61 blocks in the tested region of chromosome 16, with 24 SNPs located within the same block (block 8) of approximately 40 kb, in almost complete LD (|D’|>0.98, r2>0.80). We confirmed presence of the genetic susceptibility loci located in intron 1 of the FTO gene, which were correlated with BMI in our study group. For the first time, our analyses revealed strong association of FTO intronic variants (block 8) with overweight in group of men only. We have also identified association of the IRX region with overweight and/or obesity in Polish individuals.
Our study demonstrated how tested SNPs make differential contributions to obesity and overweight risk. We revealed sex dependent differences in the distribution of tested loci which are associated with BMI in the population of Poles.
Obesity is one of the biggest health care problems worldwide. It is the most common nutritional disorder in developed countries, and it increases risk for hypertension, cardiovascular disease, and type 2 diabetes [1, 2]. It is a complex, multifactorial medical condition, affected by genetic and environmental risk factors [3–5]. According to the World Health Organization (2014) there are around 2 billion overweight adults, of those 670 million are considered to be affected by obesity (BMI ≥30 kg/m2) and 98 million severely affected by obesity (BMI ≥35 kg/m2). In Poland the current prevalence of overweight and obesity among the Polish population have been estimated to 36.54 and 13.34%, respectively (WHO websitehttp://www.who.int/bmi).
In our study, we tested the genetic variation of 2 Mb region of chromosome 16, encompassing region of FTO, RPGRIP1L, AKTIP, RBL2, IRX3, IRX5 and, IRX6 genes. It was the first study with representation of individuals from each geographical region of Poland (N = 5418) focusing on this topic. Case—control association analysis was performed for 262 SNPs located in the tested region. Obtained results revealed that FTO SNPs rs1558902, rs1421085, rs12149832, rs9930506, rs9939609 had the strongest influence on obesity phenotype in our study group which is consistent with other studies [8–10, 27, 43–50]. These SNPs were in almost perfect LD (|D’|>0.98) with other 19 SNPs in block 8 located in non-coding sequence of intron 1. The haplotype analysis exhibited that the strongest obesity associated haplotype (χ2 = 11.474, p = 0.0007) which contained the minor alleles for SNPs distributed across a 45-kb stretch of intron 1 of FTO, was in block 8 and occurred at a frequency of 0.46 in the case group and 0.41 in controls. This region identified in our cohort was previously described by Hotta et al. as the 45 kb obesity associated region of high LD encompassing introns 1 and 2 of the FTO .