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Introduction: Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is correlated with timing of menopause. Accordingly, women with higher AMH levels become menopausal at a higher age. Previous research suggests that a higher age at menopause is associated with a decreased risk of type 2 diabetes (T2D). In contrast, AMH levels are increased in women with polycystic ovary syndrome (PCOS), who have a higher risk of insulin resistance and T2D than women without PCOS. However, it is not clear yet whether AMH actually plays a role in the development of T2D. We aimed to investigate whether plasma AMH levels and age-related AMH trajectories are associated with risk of T2D in women. Hypothesis: Higher age-specific plasma AMH levels are associated with a decreased risk of T2D. Methods: We analyzed longitudinal data from 3104 female participants, aged 20-60 years at recruitment, in the population-based Doetinchem Cohort Study. In total, we analyzed 12460 plasma AMH measurements. We calculated age-specific AMH tertiles, to account for the strong AMH-age correlation. Cox Proportional hazards models adjusted for known risk factors for diabetes were used to assess the relation between age-specific AMH tertiles and T2D. We applied linear mixed models to compare age-related AMH trajectories between T2D cases and non-cases. Results: After a median follow-up of 20 years, 163 incident T2D cases were identified. Higher age-specific AMH levels were associated with a lower risk of T2D (hazard ratio (HR) T2vsT1 = 0.77, 95%CI: 0.53-1.11; HR T3vsT1 =0.62, 95%CI: 0.40-0.94; p for trend = 0.02). These findings were supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages and declined at a slower rate in women who were diagnosed with T2D compared to women who were not. However, differences in trajectories between T2D cases and non-cases were not statistically significant. Conclusions: We observed that women with higher age-specific AMH levels were at a lower risk of T2D. In addition, our longitudinal analyses may suggest that AMH is lower in women who develop T2D compared to women who do not. These findings are in line with previous studies that observed that a higher age at menopause was associated with a decreased risk of T2D.

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Background: Vitamin K has been associated with various health outcomes, including non-fatal cardiovascular diseases and cancer. However, little is known about the association between vitamin K intake and all-cause and cause specific mortality. Objective: To investigate the association between vitamin K intake and all-cause and cause specific mortality. Methods: This prospective cohort study included 33,289 participants, aged 21-70 years from the EPIC-NL cohort. Participants were recruited between 1993 and 1997 and the follow-up is complete until December 2012. Dietary intake was assessed at baseline with a 178-item validated food frequency questionnaire and intakes of total vitamin K intake and its sub forms, phylloquinone, menaquinones (MK), short-chain menaquinones (SMK) and long-chain menaquinones (LMK) were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazard regression, adjusted for risk factors for chronic diseases (gender, age, BMI, physical activity, smoking status, education level) and nutrient intake. Results: During a median follow-up of 16.8 years, 2,863 deaths occurred, including 625 from CVD (256 CHD specific), 1,346 from cancer and 894 from other causes. After multivariable adjustment, vitamin K intake was not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of phylloquinone and menaquinone intake of 1.04 (0.93-1.17) and 0.94 (0.82-1.07) respectively. Phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. Higher intake of LMK was borderline significantly associated (p trend = 0.06) with lower CHD mortality with a HR per 10 μg of 0.87 (0.75-1.01). None of the forms of vitamin K intake were associated with cancer mortality or mortality from other causes. Conclusions: Vitamin K intake was not associated with all-cause mortality, cancer mortality and mortality from other causes. A higher intake of LMK tended to be associated with a lower risk of CHD mortality.

Background: Matrix Gla protein (MGP) is a vitamin K dependent protein and a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP) is a marker for vitamin K status with high dp-ucMGP concentration reflecting a low vitamin K status. High dp-ucMGP concentrations are thought to be associated with an increased risk of cardiovascular disease, but this has never been investigated in the general population. Objective: This study aimed to investigate the association of dp-ucMGP with incident coronary heart disease (CHD) or stroke in the general population. Design and Methods: A prospective case-cohort study with a representative baseline sample of 1406 participants and 1154 and 380 incident cases of CHD and stroke, respectively, was nested within the EPIC-NL study. Dp-ucMGP concentrations were measured by ELISA technique in baseline plasma samples. The incidence of fatal and non-fatal CHD and stroke was obtained by linkage to national registers. Cox proportional hazard models adapted for the case-cohort design were used to calculate hazard ratios (HRs) per standard deviation (SD) and per quartile of circulating dp-ucMGP levels, adjusted for cardiovascular risk factors. Results: This case-cohort study had an average follow-up of 11.5 years. Circulating dp-ucMGP levels were not associated with CHD risk with a HR per SD of 1.00 (95% CI: 0.93-1.07) and a HR Q4 vs Q1 of 0.94 (95% CI: 0.79-1.13) after multivariate adjustment. Circulating dp-ucMGP was not associated with stroke risk with a HR per SD of 0.98 (95% CI: 0.90-1.08) and a HR Q4 vs Q1 of 1.09 (95% CI: 0.78-1.51). Conclusion: This study does not support the hypothesis that high dp-ucMGP levels, reflecting a poor vitamin K status, are associated with increased CHD or stroke risk.