The relationship between genetic variants associated with primary ovarian insufficiency and lipid profile in women recruited from MASHAD cohort study

Background and aim Primary Ovarian Insufficiency (POI) is defined by the occurrence of menopause before the age of 40 years. It is often associated with cardiovascular disease (CVD). The purpose of this study was to explore the relationship between POI-associated genotypes cardiometabolic disorder risk factors. Methods One hundred seventeen women with POI and one hundred eighty-three healthy women without POI were recruited in this study. DNA was extracted and analyzed using ASO-PCR or Tetra ARMS-PCR. Lipid profiles were also assessed. Results Multivariate logistic regression analysis showed that individuals with GG vs. TT genotype of the rs1046089 SNP were more likely to have a higher serum LDL (p = 0.03) compared to the control group. There was also a significant association between low serum HDL and rs2303369 and rs4806660 SNP genotypes in the POI group. In the POI group, the percentage of those with high total cholesterol was lower in those with a CC genotype compared to those with a TT genotype (p = 0.03). Conclusion Some SNPs reported to be associated with POI appear to be independently associated with dyslipidemia. These results may be helpful to identify subjects with POI who may be susceptible to CVD.

Abstract P113: Genotypic Effect Of Foxo3 On Lifespan Is Confined To Men With A Cardiometabolic Disorder (hypertension Or Coronary Heart Disease Or Diabetes)

FOXO3 is a prominent human longevity gene. To date, no-one has examined whether longevity-associated genetic variants of FOXO3 protect against mortality in all individuals, or whether they protect against mortality only in individuals with aging-related diseases. Here, we examined this issue for the first time. We tested 9 representative longevity associated single nucleotide polymorphisms (SNPs) located within a haplotype block of FOXO3 for association with mortality in 3,584 elderly American men of Japanese ancestry. At baseline (1991-1993), 2,512 had either diabetes (n=1,010), coronary heart disease (CHD; n=738), or hypertension (n=1,919), and 1,072 lacked any of these cardiometabolic disorders (CMDs). The men were followed from baseline until Dec 31, 2019. The longevity-associated (minor) alleles of all 9 SNPs were strongly associated with longer lifespan in individuals who had a CMD (covariate-adjusted hazard ratios [HRs] for each SNP: 0.82-0.95 [ P =0.00008 to 0.020]; covariate adjusted haplotype analysis HR=0.81, P =0.0003). For just diabetes, just hypertension, and just CHD, haplotype HRs were 0.77, 0.82 and 0.83 ( P =0.007, 0.0003 and 0.10), respectively. Reduced mortality was strongest for carriers of the minor ( G ) allele of SNP rs2802292 (covariate adjusted HR=0.82, 95% CI 0.75-0.90; P= 0.00008), as were survival curve differences (covariate adjusted Cox proportional hazard model difference, P =0.0002). As expected, men without a CMD outlived men with a CMD (Kaplan-Meier Log-rank chi-squared=24.8, P =0.0001). There was, however, no genotypic difference in lifespan of men who did not have a CMD (haplotype HR 1.02, P = 0.74). We propose that in individuals with a cardiometabolic disorder, longevity-associated genetic variants of FOXO3 enhance resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs, thereby allowing CMD-affected men to live longer than men without the protective variants.