Association Between Dairy and Ischemic Heart Disease Among Chinese Adult: A Prospective Study in Qingdao

Jiahui Song Qingdao University School of Public Healh https://orcid.org/0000-0002-6875-0516 Chi Pan Qingdao University School of Public Healh Feifei Li Qingdao Municipal Center for Disease Control and Prevention Yu Guo Chinese Academy of Medical Sciences Pei Pei Chinese Academy of Medical Sciences Xiaocao Tian (  txc_2006911@126.com ) Qingdao Municipal Center for Disease Control and Prevention Shaojie Wang Qingdao Municipal Center for Disease Control and Prevention Ruqin Gao Qingdao Municipal Center for Disease Control and Prevention Zengchang Pang Qingdao Municipal Center for Disease Control and Prevention Zhengming Chen University of Oxford Nu eld Department of Population Health Liming Li Peking University Health Science Center


Introduction
IHD is the leading cause of death worldwide [1]. The number of death caused by IHD reached 9.14 million and the number of disability-adjusted life years (DALYs) reached 182.03 million in 2019 [2]. In 2016, the IHD mortality rate ranked rst, accounting for 40% of mortality in Chinese adults [3], which has become a serious public health issue [4]. IHD hospitalization rates annually increased 5.4% among the China Kadoorie Biobank(CKB) cohort study [5].
Most western countries dietary guidelines recommended intake low-fat milk in place of full-fat dairy (i.e. milk fat >3%)[6], while WHO recommended an intake of whole milk or dairy products (e.g. cheese) of 250g/day [7]. Dairy contains more saturated than unsaturated fat. Previous studies linked intake of full-fat dairy with increasing the risk of IHD [8]. It seems that low-fat dairy foods might be bene cial to high-fat dairy foods for health, but almost all the fat in the milk (i.e. butter or cream) remains in the human food supply. It has been reported that saturated fatty acids in dairy will increase the risk of IHD by affecting the content of low-density lipoproteins (LDL) or blood pressure [9][10][11], while saturated fatty acids in dairy do not adversely affect cholesterol levels [12,13], which mainly came from western countries. However, Chinese adults consumed few dairy products (e.g. butter, cheese), the average intake of dairy products was 24.7 g/d in 2012 [14], owing to lactose intolerance. The association between dairy and IHD risk has rarely been investigated among Chinese adults. The present study was to investigate the association between dairy consumption and the risk of IHD.
The ethics board of the University of Oxford, and the National, Shandong Provincial and the Qingdao Centers for Disease Control and Prevention in China all approved this study. All the participants in the survey had signed written informed consent.

Data collection
The laptop-based questionnaire was completed by trained health works, including sociodemographic information (age, education, occupation, household income, marital status), lifestyle (alcohol consumption, smoking status), family history, dairy products, and other diet frequency (rice, wheat, other staple foods, red meat, poultry, sh, eggs, fresh fruit, fresh vegetables, soybean, and preserved vegetables) in last 12 months. The date on the frequency of dairy (e.g. milk, yogurt) consumption included 5 groups (never/rarely, 1-3 d/month, 1-3 d/week, 4-6 d/week, daily).
Physiological measurements include body weight, height, waist circumference (WC), blood pressure, random glucose, etc. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m 2 ). For each individual, blood pressure was measured twice and taken as the average. A third measure was required if the blood pressure difference was more than 10 mm Hg between the rst two measures, and take the average of the last two blood pressure values recorded. Random blood glucose levels were measured immediately following sample collection using the SureStep Plus System (Johnson & Johnson, New Brunswick, NJ, USA).

Follow-up for IHD and MCE
The primary outcome was the IHD (International Classi cation of Diseases-10 I20-I25) and MCE(major coronary event) incident, and IHD mortality. Which was ascertained through the Disease Surveillance Point System(DSPs) and the new national health insurance databases [18]. Participants were followed up from baseline until the date of IHD or MCE incidence, IHD mortality, loss to follow-up, or December 31, 2015, whichever came rst.

Statistical Analysis
The series of characteristics of the participants were described with frequency (N) and percentages (%) according to categories of dairy consumption, using Student t-test for continuous variables and Chi-square test for categorical variables.
Multivariable Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% con dence interval (CI) of dairy consumption and IHD risk, which were adjusted for gender (male or female), age (continuous variable), education (below high school, high school and above), occupation, marital status, household income (<20,000 yuan or ≥20,000 yuan), diet frequency (egg, fresh vegetables, red meat, fresh fruit, poultry, soybean), smoking status (non-current smoking or current smoking), alcohol consumption (non-current drinking or current drinking), metabolic equivalent of task (MET), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and random glucose (continuous variable), family history of myocardial infarction (MI).
All p values were two-sided, p<0.05 was considered to be statistically signi cant. All analyses were performed using SPSS (version 25.0). All graphs were plotted using R 4.0.5 (https://www.R-project.org/).

Characteristics of participants
Among the 33,355 participants, the mean (SD) age at baseline was 50.7 (10.0) years. 32.4% of male and 34.6% of female participants consumed dairy daily ( Table 1). Participants that consumed dairy more frequently were female, more likely with higher education level, higher MET, lower blood pressure and lower BMI (P<0.05) (Additional le 1: Supplementary  Table S1). Multi-factor Cox regression was used to analyze the relationship between dairy consumption and the onset of IHD. After adjusting for major covariates, compared with participants who never or rarely consumed dairy, higher dairy intake had a natural effect on the incidence of IHD, MCE, and IHD mortality ( Table 3, 4, and Additional le 1: Supplementary Table S2). While the inverse association was stronger in males than in females, and no statistically signi cant association was found between dairy consumption and IHD in females.

Subgroup Analyses
Subgroup analysis was done to investigate the relationship between dairy consumption and risk of IHD, according to baseline characteristics ( Figure.1). The association between dairy and IHD was differed by education (p-values for interaction: 0.017 for males, and 0.014 for females), household income (p-values for interaction: 0.048 for males, and 0.032 for females). Stronger inverse associations among males who non-current smoking (p-values for interaction: 0.036), males who non-current drink, although the interaction test was not statistically signi cant for the latter one. No similar associations were observed across subgroups strati ed according to age, occupation, marital status, alcohol consumption, MET, BMI, SBP and family history of MI (all p values for interaction >0.05). For further statistical analysis, individuals of dairy product consumption were combined into three groups (never/rarely, <4 days/week, ≥4 days/week).
Model 1: strati ed by age-at-risk, gender (only in total population) Model 2: as for model 1, additionally adjusted for education, occupation, marital status, household income, and food consumption (eggs, fresh fruit, fresh vegetables, soybean, red meat, poultry), alcohol consumption, smoking status, MET, family history of MI Model 3: as for model 2, additionally adjusted for BMI, SBP, DBP, random glucose In addition, stronger positive associations were also observed among females with age >50y (p-value for interaction: 0.929), although the interaction test was not statistically signi cant.

Discussion
This large prospective study showed that intake of dairy regularly is not related to the onset of IHD, in line with previous studies [19,20]. However, the association between dairy and IHD varies depending on gender. For males, compared with those who never or rarely intake dairy, who intake dairy ≥4 days/week exerted a signi cant protective effect on the IHD onset, while no similar association was observed in females.

Comparison with other studies
Dairy is rich in nutrients (e.g. amino acid, calcium, vitamins), was an ideal food for healthy people of all age groups. The Chinese dietary Guideline (2016) recommended that adults intake dairy 300g/day (e.g. milk, yogurt) [21]. The overall level of dairy intake still did not meet the dietary reference values. The Korean Genome Epidemiology Study (KoGES), consisting of 7354 healthy Korean adults aged 40-69, supported those who intake higher milk, or dairy products had a protective association on the cardiovascular system [22]. The Guangzhou Biobank Cohort Study (GBCS) reported that fullfat dairy has a protective association on cardiovascular [23].
Nutrient content and bioactive ingredients in dairy vary greatly [24]. This indicates that it was whole food rather than single nutrients that should be focused on. Full-fat dairy may be related to lowering levels of homocysteine, hypolipidemic and protecting individuals from hypertension [25,26], thus may reduce the risk for IHD. It has been reported intake of fullfat dairy was in neutral or inverse association with the onset of IHD [27,28].

Association between dairy consumption and IHD
The relationship between dairy consumption and IHD risk was more pronounced in males with higher education, household income 20,000 yuan, and non-current smoking. That is because smoking is an important risk factor for central obesity and is associated with DNA methylation and oxidative stress [29,30], heavy smoking tended to have multiple other health-related risk factors, weakening the protection of dairy products. In addition, higher consumption of dairy was related to a lower risk of metabolic syndrome [31], reducing the risk of IHD, which may be contributed to the large amount of calcium contained in dairy [32][33][34]. The association was more pronounced in males than in females [35,36].
For females, who aged >50 years and with lower education level (below high school), higher dairy consumption would increase the risk of IHD, but the risk was more likely to attribute to physiological effects. This may be because the body hormone levels of females modi ed after menopause, which would increase the risk of IHD [37]. And higher education was associated with a later age at natural menopause through effects on lifestyle behaviors[38].

Strengths and limitations of this study
The present study had several strengths, including large sample size, a relatively long follow-up, and comprehensive evaluation of various factors on the relationship between dairy consumption and IHD onset among Chinese adults. A few limitations need to be considered.  Figure 1 Subgroup analysis of associations between dairy consumption ≥4 days/week and IHD according to baseline characteristics in males. Adjusted HRs (95% CIs) dairy consumption by subgroups, age at baseline (years), gender (male or female), education(below high school, high school and above), household income, occupation, marital status(married, live along), and food consumption(eggs, fresh fruit, fresh vegetables, soybean, red meat, poultry), alcohol consumption,

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.