ERV3-1/ZNF117: rs67047829 association with substantial protection against obesity

Abstract

Abstract There is now substantial evidence that zinc finger proteins are implicated in adiposity. High-frequency pretermination codons (PTCs) confer near-neutral selection. Aims were to datamine for high-frequency-PTC single nucleotide polymorphisms (SNPs; n = 141; one linked with ERV3-1/ZNF117) from a database with > 550 000 variants and analyze possible association with obesity in a large Polish sample (n = 5757). Body mass index (BMI) was regressed (males/females together or separately) against genetic models. Stringent regression for rs67047829 uncovered an interaction-independent significant association between this high-frequency PTC-SNP and BMI with both sexes together: mean BMI ± standard deviation (n): GG, 25.4 ± 4.59 (3650), GA, 25.0 ± 4.28 (731); AA, 23.4 ± 3.60 (44); additive model adjusted for age and sex: p = 4.08x10− 5; beta: -0.0458, 95% confidence interval (CI): -0.0732:-0.0183; surviving Bonferroni correction; and with males: GG, 24.8 ± 4.94 (1878); GA, 24.2 ± 4.31 (386); AA, 22.4 ± 3.69 (23); p = 4.20x10− 4; beta: -0.0573, CI: -0.0947:-0.0199. For average-height males the difference between GG and AA genotypes would correspond to ~ 6 kg, suggesting considerable protection against obesity. rs67047829 is a PTC-SNP in ERV3-1 which lies upstream of, and shares an exonic region and possibly a promoter with, ZNF117, previously associated with adiposity and type 2 diabetes. As this result occurs in a near-neutral Mendelian setting, a drug target involving ERV3-1/ZNF117 potentially might provide considerable benefits with minimal side-effects. This result needs to be replicated, followed by analysis of splice-variant mRNA and protein expression.