Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.

BACKGROUND: Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. RESULTS: We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. CONCLUSIONS: We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels.

Association of calcium and dairy product consumption with childhood obesity and the presence of a Brain Derived Neurotropic Factor-Antisense (BDNF-AS) polymorphism.

BACKGROUND & AIMS: Calcium and dairy products have multiple health benefits. The objective of this work was to evaluate the association between calcium/dairy intake, blood pressure, the BDNF-AS rs925946 polymorphism and nutritional status in a group of schoolchildren. METHODS: As part of the GENYAL study to childhood obesity prevention, 221 children belonging to different areas of the Community of Madrid were enrolled. Anthropometric and dietary data were collected, and children were genotyped according to the rs925946 polymorphism. Adjusted logistic and linear models were used to describe the data. RESULTS: A significantly lower consumption of calcium in overweight versus normal weight children was observed (811.0 ± 174.1; 859.0 ± 195.9; 954.0 ± 223.1 mg; for obesity, overweight and normal weight, respectively, p = 0.010). Moreover, an inverse association between blood pressures and calcium intake was detected (ß = -0.006 (-0.011, -3e-4)), p = 0.040. The number of dairy servings/day showed a protective effect against overweight (OR = 0.48 (0.29, 0.75), p = 0.001). Finally, common homozygous children (GG) showed an inverse association between the calcium intake and the BMI (ß = -0.003 (-0.006, -0.001), p = 0.004), which was not observed in children carrying the T allele (ß = -1.3e-4 (-0.0022, 0.0024), p = 0.93). CONCLUSION: Calcium and dairy were strongly associated with the nutritional status and blood pressure. The identification of differential effects of calcium/dairy consumption on the nutritional status according to genetics may contribute to the personalization of future nutritional advice. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.govNCT03419520.