LEPR rs3790433 GG homozygotes had increased MetS risk (OR 1.65) compared with the minor A allele carriers, which may be accounted for by their increased risk of elevated insulin concentrations (OR 2.40) and insulin resistance (OR 2.15). Low (less than median) plasma (n-3) and high (n-6) PUFA status exacerbated the genetic risk conferred by GG homozygosity to hyperinsulinemia (OR 2.92–2.94) and insulin resistance (OR 3.40–3.47). These associations were abolished against a high (n-3) or low (n-6) PUFA background. Here, LEPR is linked to hyperinsulinism.