To date, the genes associated with susceptibility to Atopic Eczema (AE) are mainly implicated in immunity, inflammation, and maintenance of skin barrier. Little is known about the possible relationship between genes modulating Extra-Cellular Matrix (ECM) and AE etiopathogenesis. In this regard, the primary objective of the present study has been the investigation of susceptibility biomarkers localized within genes encoding collagen proteins. Several studies have shown that polymorphisms within the genes encoding such proteins may generate abnormal connective tissues, making them more susceptible to mechanical stress, loss of epidermal integrity, and aging. We therefore decided to investigate three polymorphisms located in , and as potential susceptibility biomarkers for AE in a cohort of 1470 subjects of Mediterranean origin. The genes of interest have been selected considering that the ECM and immune/inflammatory response are strongly dysregulated in AE and other complex disorders. The study confirmed that the susceptibility to AE depends on a complex interaction between latitude, geographical localization, and the differential distribution of genetic variants among populations exposed to similar environmental factors.