Association of Dietary Vitamin K and Risk of Coronary Heart Disease in Middle- Age Adults: the Hordaland Health Study Cohort
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Open access Original research BMJ Open: first published as 10.1136/bmjopen-2019-035953 on 21 May 2020. Downloaded from Association of dietary vitamin K and risk of coronary heart disease in middle- age adults: the Hordaland Health Study Cohort Teresa R Haugsgjerd ,1 Grace M Egeland,1,2 Ottar K Nygård,3,4 Kathrine J Vinknes,5 Gerhard Sulo,6,7 Vegard Lysne,4 Jannicke Igland,1 Grethe S Tell1,8 To cite: Haugsgjerd TR, ABSTRACT Strengths and limitations of this study Egeland GM, Nygård OK, Objective The role of vitamin K in the regulation of et al. Association of dietary vascular calcification is established. However, the ► The study had a long follow-up time with minimal vitamin K and risk of coronary association of dietary vitamins K1 and K2 with risk of heart disease in middle- age competing risk from other causes of death. coronary heart disease (CHD) is inconclusive. adults: the Hordaland Health ► Linkage to a nationwide database assured complete Design Prospective cohort study. Study Cohort. BMJ Open cohort follow- up. Setting We followed participants in the community- based 2020;10:e035953. doi:10.1136/ ► We had information on history of coronary heart dis- Hordaland Health Study from 1997 - 1999 through 2009 bmjopen-2019-035953 ease (CHD) at baseline which enabled us to evaluate to evaluate associations between intake of vitamin K and incident (new onset) CHD. ► Prepublication history and incident (new onset) CHD. Baseline diet was assessed by additional material for this ► The Food Frequency Questionnaire was not validat- a past- year food frequency questionnaire. Energy- adjusted paper are available online. To ed for intake of vitamin K. residuals of vitamin K1 and vitamin K2 intakes were view these files, please visit ► It was not possible to differentiate the various sub- categorised into quartiles. the journal online (http:// dx. doi. types of vitamin K2. org/ 10. 1136/ bmjopen- 2019- Participants 2987 Norwegian men and women, age 035953). 46–49 years. Methods Information on incident CHD events was Received 23 November 2019 obtained from the nationwide Cardiovascular Disease in main dietary sources, and vitamin K2 (K2; Revised 21 February 2020 Norway (CVDNOR) Project. Multivariable Cox regression menaquinones) from dairy products, meat http://bmjopen.bmj.com/ Accepted 17 April 2020 estimated HRs and 95% CIs with test for linear trends and egg yolk as the main dietary sources in across quartiles. Analyses were adjusted for age, sex, total Europe.1–3 K2 has a longer half-life in the energy intake, physical activity, smoking and education. A circulation than K1.4 Both are absorbed third model further adjusted K1 intake for energy- adjusted from the small ileum and jejunum. K1 and fibre and folate, while K2 intake was adjusted for energy- K2 are incorporated into chylomicrons and adjusted saturated fatty acids and calcium. delivered to the liver. K2 is also transported Results During a median follow- up time of 11 years, via low- density lipoprotein and high-density we documented 112 incident CHD cases. In the adjusted analyses, there was no association between intake of lipoprotein (HDL) particles to extrahepatic on October 5, 2021 by guest. Protected copyright. tissue.4 5 vitamin K1 and CHD (HRQ4vsQ1 = 0.92 (95% CI 0.54 to 1.57), p for trend 0.64), while there was a lower risk of Vitamin K functions as a cofactor for the CHD associated with higher intake of energy- adjusted enzyme gamma- glutamyl carboxylase which vitamin K2 (HRQ4vsQ1 = 0.52 (0.29 to 0.94), p for trend converts protein- bound glutamate residues 0.03). Further adjustment for potential dietary confounders into gammacarboxyglutamate (Gla).6 7 Gla- did not materially change the association for K1, while the containing proteins are involved in, for association for K2 was slightly attenuated (HR = 0.58 8 Q4vsQ1 example, the coagulation of blood, inhi- © Author(s) (or their (0.28 to 1.19)). bition of arterial calcification (Matrix Gla employer(s)) 2020. Re- use Conclusions A higher intake of vitamin K2 was Protein) and vascular smooth muscle cell permitted under CC BY-NC. No associated with lower risk of CHD, while there was no commercial re- use. See rights apoptosis and movement that is considered association between intake of vitamin K1 and CHD. 9 and permissions. Published by Trial registration number NCT03013725 protective against vascular injury (Gas-6). BMJ. Matrix Gla Protein is involved in both medial For numbered affiliations see and intimal calcification, and low vitamin K end of article. INTRODUCTION status has been associated with both types 10–14 Correspondence to Vitamin K is a fat- soluble vitamin including of calcification. In addition, a study that Teresa R Haugsgjerd; vitamin K1 (K1; phylloquinone) from green examined the effect of warfarin (a vitamin Teresa. Haugsgjerd@ uib. no leafy vegetables and vegetable oils as the K antagonist) on medial and intimal plaque Haugsgjerd TR, et al. BMJ Open 2020;10:e035953. doi:10.1136/bmjopen-2019-035953 1 Open access calcification in apoE−/− mice concluded that warfarin 27 participants (22 men and 5 women) who had prior BMJ Open: first published as 10.1136/bmjopen-2019-035953 on 21 May 2020. Downloaded from accelerates both medial and intimal calcification of CHD based on self- reported information and/or prior atherosclerotic plaque.15 Patients with both medial and CHD hospitalisations during 1994–1999. Additionally, intimal calcification have a higher cardiovascular risk those with missing information on self- reported myocar- when compared with similar patients without calcifi- dial infarction from the Homocysteine Study (1992– cation.16 17 Therefore, an inverse association between 1993; 4 men and 19 women) were excluded. Further, we vitamin K intake and coronary heart disease (CHD) excluded two participants (one man and one woman) could be expected. Results from observational studies who reported use of warfarin and six participants (two on the association between intake of vitamin K and CHD men and four women) with missing measurement on are inconsistent.18–24 Among the identified studies, three dietary vitamin K intake. The final study population thus found reduced risk of CHD in multivariable adjusted included 1279 men and 1708 women. analyses at higher dietary K219 20 or K1.24 Nordic Nutrition Recommendations include a provi- Patient and public involvement sional recommended intake of vitamin K of 1 µg/kg body Participants were not involved in designing the research weight per day,3 while adequate intake is 90 µg/day for question, conducting the study, or in the interpretation, women and 120 µg/day for men.25 However, these recom- or writing of the results. There are no plans to involve mendations may not be sufficient to attain complete participants or relevant patient communities in dissemi- carboxylation of extrahepatic vitamin K- dependent nation of results. Results are disseminated to study partic- proteins.26 27 ipants via website (https:// husk. w. uib. no). Given the limited number of epidemiological studies,18–24 and the fact that dietary vitamin K sources and Dietary assessment content differ between countries,28–31 further research is Information on food intake was obtained at baseline warranted. The purpose of the current study was to eval- (1997–1999) using a slightly modified version of a previ- uate the association between intake of both K1 and K2 ously described34 past- year 169- item semiquantitative and subsequent CHD events among community-living FFQ. The FFQ was handed out on the health examination middle- age adults in Norway. day, filled out at home and returned by mail to the HUSK project centre. The questionnaire included frequency alternatives (from once a month to several times per day), SUBJECTS AND METHODS the number of units consumed and portion sizes (eg, Study population slices, glasses, spoons) to capture the habitual diet during The current study is a prospective, community-based the past year. The dietary information presented includes cohort study of participants living in Hordaland County, individual food or beverage items, food groups and Norway (known as The Hordaland Health Study (HUSK); nutrient intakes. Daily nutrient intakes were computed http://bmjopen.bmj.com/ https:// husk. w. uib. no/). The recruitment was based on a from a database and software system developed at the cohort from 1992 - 1993 (The Hordaland Homocysteine Department of Nutrition, University of Oslo (KBS, V.3.2). Study), where eligible subjects (Hordaland County resi- The nutrient database is primarily based on the offi- dents born 1950–1951) were identified from the National cial Norwegian food composition table35 and available Population Register on 31 December 1992.32 33 In 1997– literature.28 Data for K1 are mostly developed by public 1999, all living Homocysteine Study cohort members authorities in Finland,36 Sweden37 and USA.38 For some born 1950–1951 and residing in the city of Bergen or Norwegian food products, analyses were performed using the neighbouring suburban municipalities were invited high performance liquid chromatography of fermented on October 5, 2021 by guest. Protected copyright. to participate in HUSK. The baseline examinations were foods.39 K2 was evaluated as one entity with no distinction conducted during 1997–1999 as a collaboration between between the different menaquinones. At time of study, the National Health Screening Service (now The Norwe- the most commonly used dietary supplements in Norway gian Institute of Public Health), The University of Bergen did not contain vitamin K. Thus, vitamin K intake reflects and local health services. Participation rate was 77%. only dietary sources. Measurements used as independent Participants underwent a brief health examination and variables in this study are the total dietary amount of K1 provided a non- fasting blood sample. Information on life- and K2, expressed as energy- adjusted residuals.40 style was collected via self- administered questionnaires.