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.