Background. Type 2 diabetes mellitus (T2DM) is a multifactorial disease where both genetic and environmental factors contribute to its pathogenesis. The PvuII and XbaI polymorphisms of the estrogen receptor 1(ESR1) gene have been variably associated with T2DM in several populations. This association has not been studied in the Palestinian population. Therefore, the aim of this study was to investigate the association between the PvuII and XbaI variants in the ESR1 and T2DM and its related metabolic traits among Palestinian women. Methods. This case-control study included 102 T2DM and 112 controls in which PvuII and XbaI variants of the ESR1 gene were genotyped using amplicon based next generation sequencing (NGS). Results. Allele frequencies of both PvuII and XbaI variants were not significantly different between patients and control subjects (P>0.05). In logestic regression analysis adjusted for age and BMI, the ESR1 PvuII variant was associated with risk of T2DM in three genotypic models (P< 0.025) but the strongest association was observed under over-dominant model (TT+CC versus TC) (OR=2.32, CI=1.18-4.55 adjusted P=0.013). A similar but nonsignificant trend was also observed for the ESR1 XbaI variant under the over-dominant model (AA+GG versus AG) (OR=2.03, CI=1.05-3.95; adjusted P=0.035). The frequencies of the four haplotypes (TA, CG, CA, TG) were not significantly different in the T2DM patients compared with control group (P>0.025). Among diabetic group, an inverse trend with risk of CVD was shown in carriers of CG haplotype compared to those with TA haplotype (OR=0.28, CI=0.09 -0.90; adjusted P=0.035). Further, stratified analyses based on ESR1 PvuII and XbaI genotypes revealed no evidence for association with lipid levels (TC, TG, HDL, LDL). Conclusions. This is the first Palestinian study to conclude that ESR1 PuvII and XbaI variants may contribute to diabetes susceptibility in Palestinian women. Identification of genetic risk markers can be used in defining high risk subjects and in prevention trials. PeerJ reviewing PDF | Manuscript to be reviewed 25 Abstract 26 Background. Type 2 diabetes mellitus (T2DM) is a multifactorial disease where both genetic and 27 environmental factors contribute to its pathogenesis. The PvuII and XbaI polymorphisms of the 28 estrogen receptor 1(ESR1) gene have been variably associated with T2DM in several populations. 29 This association has not been studied in the Palestinian population. Therefore, the aim of this study 30 was to investigate the association between the PvuII and XbaI variants in the ESR1 and T2DM 31 and its related metabolic traits among Palestinian women. 32 Methods. This case-control study included 102 T2DM and 112 controls in which PvuII and XbaI 33 variants of the ESR1 gene were genotyped using amplicon based next generation sequencing 34 (NGS). Results. Allele frequencies of both PvuII and XbaI variants were not significantly different 35 between patients and control subjects (P>0.05). In logestic regression analysis adjusted for age and 36 BMI, the ...