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High Genetic Risk Scores of ASIC2, MACROD2, CHRM3, and C2orf83 Genetic Variants Associated with Polycystic Ovary Syndrome Impair Insulin Sensitivity and Interact with Energy Intake in Korean Women

Background: We explored the genetic variants that were associated with polycystic ovary syndrome (PCOS) by genome-wide association study (GWAS) and evaluated the association of genetic risk scores (GRS) of the selected genetic variants with insulin resistance and the interaction of the GRS with nutrient intake to develop insulin resistance. Methods: The 6 genetic variants involved in brain and nervous system (acid sensing ion channel subunit 2 rs8071961, rs1988598, and rs16589, macro domain containing 2 rs7262810 CHRM3 rs1867265 and chromosome 2 open reading frame 83 rs11889798) were selected from a GWAS of the PCOS study. GRS of the 6 single nucleotide polymorphisms was calculated in 3,723 Korean women in the Ansan/Ansung cohort of KARE study. Results: Fasting serum insulin and C-reactive protein (CRP) levels, homeostasis model assessment of insulin resistance (HOMA-IR), and psychological stress levels were significantly higher in the high-GRS group than the low-GRS group. However, serum-free T4 levels were significantly lower in the high-GRS group. HOMA-IR and CRP were higher OR (1.129 and 1.382) in the high-GRS group than the low-GRS group after adjusted for covariates. There was a significant interaction between GRS and daily energy intake (p = 0.004). The OR (1.233) for HOMA-IR was higher in the high-GRS group than the low-GRS group only in the group with lower energy intakes based on estimated energy requirement. Conclusion: Women with high-GRS for PCOS had increased risk of insulin resistance and low energy intake did not protect against the elevation of insulin resistance in women with high GRS. Low energy intake might be protective against PCOS in carriers with low and medium GRS.