HOW THE PAST SHAPES CURRENT STORIES: (EPI)GENETIC EPIDEMIOLOGICAL PROFILES OF METABOLIC SYNDROME IN BRAZILIAN MENNONITES

Abstract

Mennonites present cc. 500 years genetic isolation and three bottleneck events that reducedtheir genetic diversity. In order to identify (epi)genetic markers for metabolic syndrome (MS),we used a modified version of the Brazilian National Health Survey to interview 762Mennonites from three settlements, between 2016-2023. We compared 63 vs. 127 exomes(Illumina HiSeq) from Mennonites with/without metabolic syndrome (MS) and genotypedcandidate variants in regulatory regions with mass spectrometry (iPLEX) and sequence-specific amplification (PCR-SSP). We also evaluated DNA methylation of the NR3C1 andFKBP5 genes in peripheral blood mononuclear cells (PBMCs) of up to 66 and 141 individualswith/without MS. MS prevalence was 14.02%, less than half the one reported forNeobrazilians (34.8%, P<0.00001), being paralleled by a three times lower prevalence ofacute myocardial infarction (AMI). Among independent MS risk factors, we found lowermaternal warmth in infancy (OR=1.59, P=0.019) and a higher susceptibility to AMI with theharshest migratory route to Brazil (OR=1.57, P=0.001). Thirty-nine variants of 34 genes wereassociated with MS (p<0.02), 41% create/disrupt CpG sites and 12 were associated withvisceral adipose and/or cardiovascular tissue expression. There were no methylationdifferences between individuals with and without MS in PBMCs with the NR3C1 and FKBP5genes, pointing to other epigenetic causal effects. In conclusion, Mennonites have a peculiarepidemiological profile marked by (epi)genetic founder effects that also affect theirmetabolism, calling for urgent action for prevention and to alleviate the burden ofcomorbidities due to late diagnosis.