Cover Page The handle

Cover Page

The handle

http://hdl.handle.net/1887/138637

holds various files of this Leiden

University dissertation.

Author: Man, P.W.

Title: Vitamin D relationships and genes of a Chinese population in the Netherlands

Issue Date: 2020-12-08

Chapter 7

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phosphate from the gut, both necessary for bone mineralization, and has a significant role in calcium homeostasis. The indicator of vitamin D status is the main circulating metabolite of vitamin D, 25-hydroxyvitamin D [25(OH)D]. Inadequate levels of 25(OH)D and/or calcium may increase the risk of falling in elderly persons and of osteoporosis which in turn, among other factors, is an important predictor of fractures [1]. In children, a low vitamin D status may increase the risk of rickets. Based on reducing detrimental effects on bone health, the Health Council of the Netherlands (Gezondheidsraad) has set the required 25(OH)D level at 30 nmol/L for persons aged 0-70 years and at 50 nmol/L for persons aged ≥70 years [2]. Studies performed in the Netherlands have shown very low serum 25(OH)D levels among non-Western immigrant populations, with median serum 25(OH)D concentrations between 24-38 nmol/L and a prevalence of (severe) vitamin D deficiency [25(OH)D <25 nmol/L] be-tween 19-51% compared to indigenous Dutch who had a median serum 25(OH)D concen-tration of 67 nmol/L and a prevalence of (severe) vitamin D deficiency of 6% [3]. In pregnant Turkish and Moroccan women, mean serum 25(OH)D level was even lower, 15 nmol/L and 20 nmol/L, respectively, compared to 53 nmol/L in the pregnant Dutch women. Overall more than 80% of the Turkish and Moroccan pregnant women were vitamin D deficient compared to 6% of the Dutch [4]. Comparable results of serum 25(OH)D concentrations of 35 nmol/L were found in the SUNSET study among Surinamese people, while the ethnic Dutch in that study had serum 25(OH)D concentrations of 60 nmol/L [5]. Chinese people liv-ing in the Netherlands were, however, not included in these studies, although it is plausible to assume that also they may suffer from low vitamin D status.

Studies of vitamin D among Chinese people performed in Beijing and Hong Kong also showed a high prevalence of vitamin D deficiency in young non-pregnant women; 40% of Beijing women and 18% of Hong Kong women were (severely) vitamin D deficient [25(OH)D ≤25 nmol/L] [6]. Moreover, another study found an increased rate of hip fractures particu-larly among people aged 70 years and older in Beijing, possibly because of a high rate of vitamin D deficiency [7].

In contrast to the other non-Western immigrant groups (Turks, Moroccans, Surinamese, and Antillean) little is known about the general health of Chinese people living in the Netherlands. According to the Social and Cultural Planning Office of the Netherlands (SCP) report of 2011, the physical and psychological health status of Chinese in the Netherlands appeared to be comparable with that of the native Dutch [8]. Because the serum 25(OH)D concentration of the Chinese population in the Netherlands may be too low, with possible health consequences, more research into the vitamin D status and the relationship with different health outcomes in this population is needed.

The main objectives of this thesis were therefore 1) to estimate the vitamin D status of a Chinese population living in the Netherlands and 2) to assess the most important determi-nants of low vitamin D status, 3) to investigate associations between serum 25(OH)D and various health outcomes and, 4) to measure 25(OH)D obtained by dried blood spot, as an alternative for venipuncture, and to compare it with serum and finally, 5) to examine the role of genetic influences on circulating 25(OH)D concentration.

Main findings of the studies presented in this thesis

1. A clear association between serum 25(OH)D and bone mineral density (BMD) was not

found in a literature review among the middle-aged and older Chinese population living in Asia (Chapter 2). Five out of the eleven included studies found a positive relationship. Although it is likely that a positive relationship between serum 25(OH)D and BMD exists in Chinese populations, the evidence is, however, limited and inconclusive.

2. The median serum 25(OH)D concentration of our study population (104 men and 314

women) was significantly lower in men than in women (42.0 nmol/L and 47.0 nmol/L, respectively; p = 0.046) (Chapter 3). It seems that the serum 25(OH)D level of our study population was lower than that of ethnic Dutch (60-67 nmol/L), but better as compared to other non-Western immigrant populations in the Netherlands. Almost one-quarter of our study population did not meet the recommendations of the Dutch Health Council regarding an adequate vitamin D status. Moreover, according to a general international cut-off value of 50 nmol/L even more than half of our Chinese study population had insufficient levels of 25(OH)D [9].

3. Determinants associated with low serum 25(OH)D concentrations (<50 nmol/L) were

non-use of vitamin D supplements and physical activities <3 days/week, defined as a moderate strenuous effort for at least 30 min/day, e.g., walking, cycling, or gardening (Chapter 3).

4. At the population level, a good agreement was found between the measurement

of 25(OH)D3 obtained with dried blood spot (DBS) compared to serum (Chapter 4).

Although DBS is less suitable for individualized assessment of vitamin D status it may adequately rule out vitamin D deficiency in community-dwelling adults and non-institutionalized elderly persons.

5. Serum 25(OH)D levels <30 nmol/L (for persons <70 years) or <50 nmol/L (for persons

≥70 years) tended to be associated with higher fasting blood glucose concentrations (Chapter 5). Associations with other health outcomes (bone health, physical perfor-mance, and other cardio metabolic-related outcomes) were not found.

6. Associations between genetic variants involved in the vitamin D transport and

metabo-lism and vitamin D deficiency, defined at the general cut-off of 50 nmol/L, were not found (Chapter 6). However, after extending the data in a meta-analysis a significant association between the C allele of rs2282679 in group-specific component (GC) gene,

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metabolites, and vitamin D deficiency was observed.

Methodological considerations

In the 2011 SCP report “The Chinese in the Netherlands” [8], and also in the 2011 report of Statistics Netherlands (Centraal Bureau voor de Statistiek, CBS) “Chinezen in Nederland in het

eerste decennium van de 21ste eeuw” [10], Chinese people from Indonesia and Suriname were

indistinguishable as Chinese. In addition, Chinese from Hong Kong, mainland China, and Taiwan, differed culturally with those from Indonesia and Suriname who also often already spoke Dutch and quickly adapted to the Dutch lifestyle. Moreover, Chinese from Indonesia were generally highly educated. By contrast, the first-generation Chinese from Hong Kong, mainland China, and Taiwan was known as a closed, inwardly focused community. Their level of social integration in the Dutch community was low, partly because of a language barrier, and partly because they mainly worked in the restaurant business [8]. The long working days and little leisure time with low exposure to sunlight made them very much different in lifestyle compared to the Chinese from Indonesia and Suriname. In this thesis, only Chinese from Hong Kong, mainland China, and Taiwan have been included.

To recruit potential participants for our study, recommendations of a successful public cam-paign among Chinese against hepatitis B in The Hague in 2010 were used [11]. As advised, we sought for the recruitment of study participants the cooperation and commitment of Chinese welfare, elderly and women organizations, key persons within the Chinese com-munity and Chinese speaking volunteers. To recruit younger participants social media was used. Moreover, our research aim was communicated in a simple way, written information was bilingual available in Dutch and Chinese, and prior to the assessments, bilingual infor-mation meetings were organized.

On the basis of a previous study among non-Western immigrants [3], we aimed at a total of 500 persons to participate in our research; eventually, 418 persons participated. Three-quar-ters of our study population consisted of women. This overrepresentation of women may be due to the fact that Chinese women in the Netherlands are possibly more health-conscious than Chinese men are and, therefore, more willing to participate in health projects. It could also be that men because of the late working hours in the restaurant business were less willing to get up early as the time of fasting blood sampling for our study was between 9:00 and 11:00 a.m.

Participation of people <40 years, was low (12%) despite several efforts, which may be partly due to the lack of having enough key persons in this age category. It might also have been inconvenient for this age category to join our study because three out of the five research

days were held mid-week Tuesday till Friday. As a consequence, our findings in this thesis may not be generalizable to people <40 years.

Because our study was exploratory in nature we included all participants in our analyses, i.e. also participants who suffered from, for example, diabetes or high blood pressure or those who used vitamin D supplements. Rather than to exclude users of glucose-, cholesterol-, and blood pressure-lowering drugs and users of vitamin D supplements, these medications were considered as effect modifiers, and interaction terms were tested to explore possible differential effects between users and non-users of drugs and vitamin D supplements.

Vitamin D status

Vitamin D status is commonly assessed by serum 25-hydroxyvitamin D [25(OH)D] concen-tration. Worldwide there is, however, no consensus regarding the cut-off value for optimal 25(OH)D level. Most government guidelines recommend 50 nmol/L as the threshold in relation to bone health. The Health Council of the Netherlands has set target values for serum 25(OH)D levels at 30 nmol/L for men and women <70 years and 50 nmol/L for men and women ≥70 years based on reducing the risk of rickets in children and fractures in older persons [2]. The U.S. Institute of Medicine (IOM) defines serum 25(OH)D levels of below 30 nmol/L as vitamin D deficient, serum 25(OH)D concentration of 40 nmol/L being sufficient for half of the population, and 25(OH)D levels ≥50 nmol/L being sufficient for practically all persons [9]. The Endocrine Society has advocated even higher thresholds of 75 nmol/L for bone health [12].

The median serum 25(OH)D concentration of our study population was significantly lower in men than in women (42.0 nmol/L and 47.0 nmol/L, respectively; p = 0.046). This may not be surprising considering the possibility that many Chinese men work in the restaurant business with long working days, little leisure time and low exposure to sunlight. Further-more, serum 25(OH)D concentration below 30 nmol/L was observed in 17.5% of the men and in 18.8% of the women (p = 0.755), and below 50 nmol/L in 67.9% of the men and 53.1% of the women (p = 0.008).

Compared to other non-Western immigrant populations in the Netherlands [3, 5], the Chinese population in our study had higher median serum 25(OH)D concentrations (24-38 nmol/L and 46 nmol/L, respectively) and a lower prevalence of severe vitamin D deficiency [25(OH)D <25 nmol/L], 19-51% and 10%, respectively. The assay methods for the measure-ment of serum 25(OH)D concentrations were different between the studies. Therefore, inter-preting results should take this into consideration as different 25(OH)D assays from different laboratories may not be assumed to be comparable [13, 14]. 23.3% of the men and 22.4% of the women (p = 0.880) of our study population did not meet the recommendations of the

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were no convincing indications to show that persons in age category 4-70 years require additional vitamin D for health reasons, the Health Council of the Netherlands nevertheless recommends a target value of 25(OH)D of at least 30 nmol/L [2]. Of the participants in our study who did not meet the recommendations of the Dutch Health Council (n=104), 25 (24%) persons (10 men and 15 women) were ≥70 years, of which only one person was born in the Netherlands. It is, therefore, necessary that awareness for adequate levels of 25(OH)D is maintained, especially among the older population who was born outside of the Netherlands as low levels of 25(OH)D may have detrimental effects on bone health. Moreover, the Health Council of the Netherlands recommends, out of precaution, slightly pigmented people the use of vitamin D supplements.

Target organs and target cells of vitamin D and vitamin D receptor

Vitamin D synthesized in the skin is transported in the bloodstream by vitamin D binding protein (DBP). In the liver, vitamin D is hydroxylated by the enzyme 25-hydroxylase into 25(OH)D. Although 25(OH)D is the major circulating metabolite and indicator for vitamin D status, it has, however, low biological activity. In the kidney 25(OH)D is hydroxylated into active vitamin D, 1,25(OH)2D, through the enzyme 25(OH)D-1α-hydroxylase. This active form

of vitamin D binds to the vitamin D receptor (VDR), resulting in gene expression of the target cell. VDR expression has been identified in virtually every human tissue: in classical target tissues and cells (e.g., bone, kidney, intestine) and non-classical (e.g., immune cells, muscle cells, heart, pancreas, brain). There are strong arguments for the intestine as the primary target organ for vitamin D action [15]. The regulation of extracellular calcium and phosphate homeostasis through increased intestinal absorption of calcium and phosphate, both necessary for bone mineralization, is indeed the best-known action of vitamin D, in contrast to all other functions to which vitamin D is associated.

Vitamin D and bone health

In the last two decades, numerous papers have reported associations between vitamin D and bone health, or more directly between serum 25(OH)D levels and bone mass (bone mineral density, BMD) or fracture outcomes. Most experts agree that there is fair evidence to support the association between serum 25(OH)D and BMD [16, 17], or risk of fracture [1], and that vitamin D in combination with sufficient calcium intake can modestly reduce the risk of femur or other non-vertebral fractures [18, 19]. Higher 25(OH)D concentrations may also improve muscle strength in men and women (≥60 years) [20] and reduce the odds of falling in women ≥65 years [21].

The effect of vitamin D with or without calcium on bone health is, however, not indisput-able. A recent systematic review and meta-analysis concluded that vitamin D or calcium

supplementation did not have an effect on reducing the risk of fractures in community-dwelling older persons [22]. Another systematic review, meta-analysis, and trial sequential analysis also concluded that vitamin D supplementation had no effect on fractures, falls, or bone mineral density [23]. However, these studies were criticized by others because of, e.g., selection bias, too short follow-up in selected studies to demonstrate a benefit on fracture risk, not including trials that combined vitamin D with calcium and compared with placebo, not addressing adherence problems to supplements, including trials which gave vitamin D in bolus doses of which it is known in the literature to increase falls and fractures, and differences in baseline and achieved 25(OH)D concentration between trials [24-28]. Inadequate levels of 25(OH)D are associated with low BMD and may increase the risk of fractures [1]. Osteoporosis is defined by the World Health Organization (WHO) as a BMD less or equal to 2.5 standard deviations below that of a 20-29 years old healthy U.S. white women (i.e. a T-score of ≤-2.5 SD), measured by dual-energy X-ray absorptiometry (DXA) of the lum-bar spine, femoral neck or total hip [29]. Osteoporosis strongly increases with age. As a result of world population ageing [30], the incidence of osteoporosis is increasing worldwide [31]. In the Netherlands, the number of individuals aged 55 years and older with osteoporosis in 2005 was 214,100 for men and 638,600 for women. It is estimated that the prevalence of osteoporosis in the Netherlands will increase with more than 40% (in men 52% and women 37%) from 2005 to 2025 to more than 326,000 for men and almost 880,000 for women [32]. Although the main consequence of osteoporosis is a fracture, it is, however, unclear how many fractures are attributed to osteoporosis, as most fractures are multifactorial. Lötters et al. concluded that in the Netherlands in 2010 32% of all registered fractures were related to osteoporosis (21% in men and 36% in women). The costs of osteoporosis-related fractures were almost € 200 million a year, and it was estimated to increase with 50% from 2010 to 2030 [33]. Apart from healthcare and work-loss costs, fractures cause impaired health-related quality of life and increased mortality [34, 35]. About one-quarter of all persons in the Netherlands age 55 years and older with a hip fracture die in the following year, and about 50% will experience significant functional loss [36].

In Beijing, China, rapidly increasing rates of hip fractures have been reported among Chi-nese people between 2002 to 2006 as compared to 1990 to 1992, particularly in persons over age 70 years [7]. It was suggested that the increase of hip fractures is probably because of a higher rate of vitamin D deficiency due to urbanization with reduced sunlight exposure. Lower exposure to sunlight affects vitamin D status more in older than in younger adults, because of a decreased capacity of cutaneous synthesis of vitamin D in older persons [37]. Moreover, as a consequence of ageing, bones in older persons are more fragile, and older persons are also more likely to fall, which could be prevented by treatment with vitamin D [38, 39]. In addition, an urban lifestyle with decreased weight-bearing activities may result in

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the authors have adjusted for age by using age-stratified data, higher rates of falls may have been the major reason for the increased rates of hip fractures in persons over age 70 years as compared to persons of younger age. On the other hand, these findings do not suggest that vitamin D plays a major role in bone health in persons under age 70 years as no substantial difference in rates of hip fractures could be observed between the two time periods. In our study, an association between serum 25(OH)D concentrations and bone health, mea-sured by quantitative ultrasound of the heel, was not found. A reason for the lack of finding an association might be that, at least a part of, our study population (men and women) work in restaurant business. Frequent mechanical loading, especially of the heel, through occu-pational standing, might have compensated deleterious effects of lower serum 25(OH)D levels on bone.

extra-skeletal consequences of low vitamin D levels

Many papers have been published concerning the possible role of vitamin D in the preven-tion of non-skeletal diseases. These include diabetes, metabolic syndrome, autoimmune diseases (e.g., multiple sclerosis), infectious diseases (e.g., tuberculosis), cardiovascular diseases, breast cancer, prostate cancer, colorectal cancer, depression, and schizophrenia [9, 17, 20, 41-52]. In addition, vitamin D may also decrease total mortality rates [53]. Despite all these associations, an indisputable role for the causality of vitamin D is, however, still not clear [54-56]. Moreover, different experts may interpret the enormous amount of studies on the possibly extra-skeletal health effects of vitamin D in different ways [57]. A comprehen-sive umbrella review of systematic reviews and meta-analyses reported that a clear role of vitamin D could not be identified in multiple health outcomes, although some associations were considered probable [58].

Also, to date, there is no consensus below which level of serum 25(OH)D these extra-skeletal outcomes occur, or on the other side, above which daily intake of vitamin D or above which level of 25(OH)D beneficial effects can be expected [56]. In contrast to the majority of guidelines who consider 50 nmol/L as the threshold for bone health [9, 56, 59], others have recommended higher levels of serum 25(OH)D needed for beneficial extra-skeletal health effects [55, 60].

Our study, examining associations between serum 25(OH)D and various extra-skeletal health outcomes (cardio metabolic risk factors and physical performance) did not show positive effects of vitamin D. However, it appeared that lower serum 25(OH)D levels were associated with higher fasting blood glucose concentrations.

There may be some general explanations for not finding other associations. First, our study population was possibly less dependent on vitamin D due to other health-protective fac-tors, e.g., physical activity. Moreover, the function of vitamin D is regarded as permissive (up to a level where vitamin D status is sufficient, i.e. 25(OH)D ≥50 nmol/L), and necessary for cell function. However, in the absence of a physiological need, vitamin D has no role [61]. Also, the lack of knowledge of the period of time that a vitamin D deficient or replete state has existed could have biased our findings. For example, patients who have started taking vitamin D supplements on their doctor’s advice might therefore not suffer low 25(OH)D levels anymore. However, unfavorable health conditions may still exist, as it may take longer before the onset of beneficial effects of vitamin D on extra-skeletal health outcomes occur. In conclusion, based on our study, the evidence for recommendation of vitamin D supple-mentation to prevent non-skeletal diseases as examined in our study is marginal. On the basis of randomized controlled trials, a comprehensive review also concluded mixed results and some rather modest beneficial effects of vitamin D supplementation on extra-skeletal outcomes [56]. In terms of public health, the 2012 report of the Health Council of the Neth-erlands stated that there was insufficient evidence of whether supplementation of vitamin D can prevent non-skeletal diseases [2]. To date, there is still limited evidence for a causal relationship between vitamin D and extra-skeletal health outcomes.

Total serum 25(oH)D vs bioavailable or free 25(oH)D as a measure for vitamin D status

Because of conflicting findings in observational studies and in search of more convincing clinical benefits of vitamin D supplementation, it was questioned whether serum bioavail-able 25(OH)D [not bound to vitamin D binding protein (DBP)] or free 25(OH)D (not bound to DBP or albumin) might be better markers of vitamin D status than serum total 25(OH)D. DBP binds and transports vitamin D and its metabolites in the bloodstream to target organs. Some studies have reported that serum bioavailable 25(OH)D or free 25(OH)D levels are stronger associated with health outcomes than serum total 25(OH)D levels [62-64], while other publications found opposite findings [65-67]. One study by Powe et al. reported that DBP concentration (measured by a monoclonal ELISA assay) was lower in African Americans than in white Americans, and as a result calculated serum bioavailable 25(OH)D was similar in both populations despite lower serum total 25(OH)D levels in African Americans [62]. Bioavailable 25(OH)D is calculated as the sum of free 25(OH)D and 25(OH)D bound to al-bumin. Free 25(OH)D concentrations could, until recently, only be calculated from the con-centrations of total 25(OH)D, DBP, albumin, and affinity constants for albumin and DBP [68, 69]. As a result, Powe et al. concluded that low serum total 25(OH)D concentrations might not necessarily indicate low levels of serum free or bioavailable 25(OH)D concentrations [62], which may have substantial consequences for recommendations regarding vitamin D

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used (instead of a nowadays more common polyclonal assay), which was refuted by others as wrong because this assay is biased by DBP genotype and consequently by race [65]. It is generally accepted that in healthy black and white people mean DBP concentrations are only minimally different when polyclonal assays are used instead of monoclonal assays, and that levels of calculated and directly measured free 25(OH)D highly correlate with total 25(OH)D concentrations [70-72]. This implies that free 25(OH)D concentrations strongly depend on total 25(OH)D concentrations and that both free 25(OH)D and total 25(OH)D can be used, irrespectively of race and geographical region [71]. However, to date, direct mea-surement of free 25(OH)D is still not well validated and standardized [71]. Nevertheless, as free 25(OH)D is highly important for the local production and action of 1,25(OH)2D in renal

and extra-renal tissues, more studies are needed to determine the clinical benefits of the free 25(OH)D assay in both healthy and disease states. Moreover, a patient was described in a recent case report who suffered a complete deficiency of vitamin D binding protein due to a mutation, resulting in an absence of transport carrier of vitamin D metabolites to the liver and kidney for metabolization into 25(OH)D and 1,25(OH)2D, respectively. Nevertheless,

despite very low serum 25(OH)D concentration, only mild bone disease (osteopenia) and fragility fractures were observed in this patient. The authors suggested that a normal free fraction of 25(OH)D might have been responsible for the relatively normal bone health [73].

Genetic variants influencing serum 25(oH)D concentration

In search of finding explanations for differences in levels of serum 25(OH)D in different populations, apart from exposure to sunlight and dietary intake of vitamin D or vitamin D supplements, genetic influences may play a role in circulating 25(OH)D concentrations. Genome-wide association studies and replication studies have shown that several genetic variants [single nucleotide polymorphisms (SNPs)] involved in vitamin D transport and me-tabolism, affect serum 25(OH)D concentration. The estimates of heritability in different stud-ies vary, however, between 20-85%. This may be explained by differences in environmental and lifestyle factors (e.g., latitude of the country, intake of vitamin D supplements, exposure to sunlight, clothing), season of assessment, age, and sex. A Dutch study found that genes explained 28% of the variation in serum 25(OH)D levels [74]. Our study showed that a common variant in the vitamin D binding protein gene (group-specific component, GC), rs2282679, involved in the transport of vitamin D and its metabolites, was associated with vitamin D deficiency as defined by the Health Council of the Netherlands (<30 nmol/L for persons <70 years or <50 nmol/L for persons ≥70 years), and also (after extending the data in a meta-analysis) at the general cut-off value of 50 nmol/L.

The determination of genetic variants may potentially be interesting as aid in personal-ized health management to identify individuals or groups who would benefit most from

supplementation. Moreover, results of observational studies may be used to study causal associations of 25(OH)D with health outcomes. For this purpose, Mendelian randomization analyses are increasingly used. Despite positive associations in numerous observational studies, Mendelian randomization studies, with exception of multiple sclerosis [75], did not support a causal association between genetically low serum 25(OH)D concentrations and low bone mineral density [76, 77], nor that low levels of 25(OH)D were associated with increased fracture risk [78], or that the association between 25(OH)D concentration and type 2 diabetes or glycemic traits (e.g., fasting blood glucose, fasting insulin, and HbA1c) was likely to be causal [79].

Conclusions

1. About one-quarter of our research population did not meet the Dutch requirement for

an adequate vitamin D status. Moreover, in our study the most important determinants of serum 25(OH)D concentrations <50 nmol/L were non-use of vitamin D supplements and physical activities <3 days/week.

2. The effects of vitamin D described in this thesis on various health outcomes are limited.

Fasting blood glucose tended to be higher at lower serum 25(OH)D concentration. Furthermore, it could be that the relevance of vitamin D in bone health is limited in the adult Chinese population <70 years. It could also well be that in our study population the role of vitamin D was of less importance because of possibly other compensatory and protective mechanisms, e.g., physical activity. However, our analyses were not con-clusive regarding physical activity.

3. Dried blood spot is a convenient and less invasive alternative for venipuncture to

sample blood and measure serum 25(OH)D concentration. At the population level, a good agreement was found between the measurement of 25(OH)D obtained with dried blood spot compared to serum. However, it is less suitable for individual vitamin D status assessment because of the wide range of DBS values relative to serum concentrations.

4. The C-allele of rs2282679 in GC gene was associated with lower levels of serum 25(OH)D.

For the other alleles, possibly influencing serum 25(OH)D concentration, no relationship could be demonstrated in our Chinese population.

Recommendations

1. There seems no reason to deviate from the recommendations for adequate 25(OH)D

levels of the Health Council of the Netherlands, although this thesis did not aim in par-ticular to examine this. Additional analysis showed that of those not meeting the recom-mended Dutch levels of 25(OH)D, 95% were born outside of the Netherlands, thereby possibly lacking information about the role of vitamin D on bone health. Recommenda-tions regarding lifestyle should, therefore, focus on this group of immigrants.

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of the Dutch Innovation Center for Lifestyle Medicine [80], may play an important role. Besides vitamin D supplementation, dietary intake of vitamin D rich food (e.g., fatty fish such as herring, mackerel, salmon, and sardines) and sufficient exposure to sunlight (maximum 15-30 min with bare head and arms between 11:00 a.m. and 3:00 p.m.) while performing outdoor activities are possible suggestions to enhance vitamin D status. Moreover, physical activities, preferably superior to common daily activities, may also maintain or even improve bone mineral density levels through mechanical loading, thereby reducing the risk of osteoporosis. Consequently, the risk of fractures may also decrease as Mendelian randomization analyses have shown a clear association between low bone mineral density and increased risk of fracture [78].

3. Further research should fine-tune the dried blood spot method to make it suitable for

individual 25(OH)D assessment. Moreover, the logistics for a single test requested by, e.g., general practitioners should be examined at competitive costs, as this can obstruct the implementation of DBS.

4. Elderly immigrant populations may be at higher risk for vitamin D deficiency. Future

re-search should be conducted in this group to examine the relationship between vitamin D deficiency and, e.g., fracture.

5. Future studies on genes concerning relationships between vitamin D and health

out-comes may help in explaining discrepancies in findings. Novel genes involved in vitamin D metabolism may provide new insights.

6. SNPs may in future be an aid in personalized health management to identify individuals

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