Candidate gene and genome-wide association studies for circulating leptin levels reveal population and sex-specific association in high cardiovascular Mediterranean subjects

Authors: ORTEGA-AZORIN, CAROLINA - University Of Valencia; COLTELL, OSCAR - University Jaume I Of Castellon; ASENSIO, EVA - University Of Valencia; SORLI, JOSE - University Of Valencia; GONZALEZ, JOSE - University Of Valencia; PORTOLES, OLGA - University Of Valencia; SAIZ, CARMEN - University Of Valencia; ESTRUCH, RAMON - Instituto De Salud Carlos Iii; RAMIREZ-SABIO, JUDITH - Sagunto Hospital; PEREZ-FIDALGO, ALEJANDRO - University Of Valencia; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CORELLA, DOLORES - University Of Valencia

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/9/2019
Publication Date: 11/13/2019
Citation: Ortega-Azorin, C., Coltell, O., Asensio, E.M., Sorli, J.V., Gonzalez, J.I., Portoles, O., Saiz, C., Estruch, R., Ramirez-Sabio, J.B., Perez-Fidalgo, A., Ordovas, J.M., Corella, D. 2019. Candidate gene and genome-wide association studies for circulating leptin levels reveal population and sex-specific association in high cardiovascular Mediterranean subjects. Nutrients. 11(11):2751. https://doi.org/10.3390/nu11112751.
DOI: https://doi.org/10.3390/nu11112751

Interpretive Summary: The regulation of appetite in humans is complex and a better understanding of its genetic and environmental drivers will be key to fight the epidemy of obesity and related disorders. In this regard, leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its circulating levels in blood are still not well known. Our aim was to identify and investigate the genes and gene variants most associated with blood leptin concentrations in a high-cardiovascular-risk Mediterranean population. For this purpose, we measured plasma leptin and analyzed genetic factors in 1011 men and women. We did not find any statistically significant associations between previously reported genetic variants and plasma leptin in this population. However, an extensive screening of other gene variants in those genes revealed more associations and heterogeneity of the effects by sex. The gene most associated with plasma leptin levels was the FTO gene in men and the LEPR in women. When we analyzed the entire genome, we found several new associations, including one in the CHN2 SNP, as well as a gene by sex interaction involving the SLIT3 gene. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.

Technical Abstract: Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p < 1x10^-5 level, among them with the rs245908-CHN2 SNP (p = 1.6x10^-6). We also detected a SNP-sex interaction at the GWAS significance level (p < 5x10^-8), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.