Habitual dietary intake of flavonoids and all-cause and cause-specific mortality: Golestan cohort study

Flavonoids, an important subgroup of polyphenols, have a substantial impact on different aspects of health. They have attracted considerable attention during recent decades due to their abundance in the diet and potential health effects [1]. Over the past two decades, a large number of studies have investigated the effects of various flavonoids, (e.g. flavonols, flavones and isoflavones) or their rich sources (e.g. green tea, dark chocolate, and red wine) on degenerative diseases such as cardiovascular disease and cancer, with results favoring protection against these diseases [2‐5].

Dietary flavonoids are chemically diverse and are divided into 6 main subclasses, i.e. flavanols or flavan-3-ols (e.g. catechin, epicatechin, epigallocatechin), anthocyanins (e.g. cyanidin, pelargonidin, delphinidin, peonidin), flavanones (e.g. hesperetin, naringenin), flavonols (e.g. quercetin, kaempferol, myricetin), flavones (e.g. apigenin, luteolin), isoflavones (e.g. daidzein, genistein) and some subsidiary classes such as dihydrochalcones and chalcones (e.g. phloridzin, arbutin, phloretin, and chalconaringenin) [6]. These subclasses vary in their biological efficacy and bioavailability.

Most of the beneficial effects of flavonoids intake are attributed to their antioxidant and anti-inflammatory characteristics; however, some recent studies have suggested several mechanisms for their anti-mutagenic and anti-carcinogenic properties [7]. Some phenolic compounds such as catechins [8], hesperetin [9], and genistein [10] are among the most well-known compounds in this regard.

Although numerous studies have tried to substantiate if there is a viable relationship between consumption of some flavonoids or their food sources and a specific disease or health condition, there are relatively few studies concerning the correlation between total flavonoid or flavonoid subclasses intake and all-cause or cause-specific mortality. The results of a recent Australian cohort study showed that individuals in the highest tertile of intake of total flavonoid and its subclasses had a significantly lower all-cause mortality compared with those in the lowest tertile [11]. However, in another large scale recent cohort study (Nurses’ Health Study II), no significant association was shown between total flavonoid or flavonoid subclasses and all-cause mortality [12]. There are also conflicting results on the associations between the different subclasses of flavonoids intake and all-cause mortality, as well as the association between mortality from specific causes (eg, mortality from CVD or cancer) and total flavonoid or flavonoid subclasses. Just as an example, in a meta-analysis of 14 cohort study, Wang et al. have concluded that dietary intakes of all six flavonoid subclasses are associated with lower risks of CVD [13]; however, in a more recent large scale cohort of Framingham Offspring, the authors have reported only a significant inverse association between higher intake of flavonols and CVD incidence, but not for the other flavonoid subclasses [14].

Because of these inconsistent results, there is a need for several large-scale and well-designed studies to expand our knowledge concerning the role of flavonoids in reducing all-cause and cause-specific mortality risks. Golestan cohort study (GCS), a large-scale prospective study in the northeast of Iran, used a comprehensive and validated food frequency questionnaire and an accurate cause of mortality ascertainment, thus providing an excellent opportunity to assess the relationship between dietary total flavonoid and flavonoid subclasses intake and total and cause-specific mortality.

A total of 42,605 participants were entered into the analysis. The characteristics of the participants based on quintile of total flavonoid intake are shown in Table 1. The participants with higher flavonoid intake had higher calorie intake but lower BMI compared with those with lower polyphenol intakes. They also had a lower smoking rate but higher alcohol consumption.

During 10.63 years of the follow-up period, 5104 deaths cases were reported. There were no marked differences in rates of all-cause mortality, cardiovascular mortality, or cancer mortality by quantiles of total flavonoid intake.

Table 2 shows Cox proportional hazard ratio (HR) and 95% CI for total mortality according to quintiles of total flavonoid and their subclasses. After adjusting for potential confounders such as gender, age, ethnicity, education, marital status, smoking, opium use, alcohol consumption, BMI, hypertension, occupational physical activity and energy intake, participants with higher quantiles of flavanones, flavones, isoflavonoids, and dihydrochalcones had significantly lower all-cause mortality risk compared with those at the lowest group of the consumption (HR: 0.81; CI:0.73–0.89, HR: 0.83; CI:0.76–0.92, HR: 0.88; CI: 0.80–0.96, and HR:0.83; CI:0.77–0.90, respectively).

Regarding CVD mortality, after adjusting for confounding variables, only the consumption of flavanones and flavones (HR: 0.86; CI: 0.73–1, and HR:0.85; CI:0.72–1, respectively) had a significant protective effect and there was no association between the intake of other flavonoids and CVD mortality risk (Table 3). Also regarding stroke mortality, after adjusting for confounding variables, flavones, and dihydrochalcones were the only subclasses of flavonoids which showed a beneficial effect (HR: 0.74; CI: 0.56–0.98 and HR: 0.71; CI: 0.56–0.91).

As shown in Table 4, after adjusting for confounding variables, participants with higher isoflavonoids and dihydrochalcones intakes had a lower risk of cancer mortality (HR: 0.82; CI:0.68–0.98 and HR: 0.84; CI: 0.71–0.99). Isoflavonoids intake had also a protective role regarding GI cancers mortality (HR: 0.80; CI: 0.61–1.04) especially in young and obese participants (p for trends = 0.003 and 0.01, respectively).