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Cardiovascular disease (CVD) risk factors, and particularly decreased high density lipoprotein cholesterol (HDL-C) dyslipidemia are prevalent in Assam, India. This study was undertaken to investigate whether Apolipoprotein A-I (APOA1) gene polymorphisms (G-75A and C+83T) were associated with i) the risk for decreased HDL-C, and ii) other CVD risk factors, viz. serum lipids, atherogenic indices, obesity, and blood pressure (BP). A total of 649 subjects were screened, from which 200 eligible individuals, classified as case group with decreased HDL-C levels (100 subjects) and control group with normal HDL-C levels (100 subjects) were enrolled and genotyped using polymersase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Lipid fractions [HDL-C, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), triglycerides (TG)] and atherogenic indices [Castelli’s Risk Indices-I and -II (CRI-I and -II), non-HDL-C fraction, atherogenic index of plasma (AIP), atherogenic coefficient (AC)] were estimated. The G-75A and C+83T loci were not associated with decreased HDL-C risk. This was confirmed across different genetic models (dominant, recessive, additive and allelic). Association was also absent with BP and obesity. However, the G-75A locus was associated with LDL-C, whereas the C+83T locus was associated with TG and VLDL-C. Furthermore, these sites had effects on atherogenic indices. The rare A allele at the G-75A locus was associated with adverse CRI-I, CRI-II, non-HDL-C and AC values, while the major C allele at the C+83T locus was associated with adverse AIP values. Thus, the pro-atherogenic G-75A polymorphism and the anti-atherogenic C+83T polymorphism represent important genetic loci that modulate CVD risk factors in subjects from Assam.