COMPARING VITAMIN D STATUS IN CENTRAL ASIA AND NORTHERN EUROPE

Over the past two decades, the understanding of the roles of vitamin D has expanded to include many nonskeletal effects such as reduced risk of acute respiratory tract infections, autoimmune diseases, cancer, cardiovascular disease, diabetes mellitus, neurological diseases, and adverse pregnancy and birth outcomes. The role of vitamin D for optimal health is well known in Western developed countries but less so in Central Asian countries. This narrative review compares the status of vitamin D between Central Asian countries and Northern European countries. The analysis also summarizes the evidence for the beneficial effects of vitamin D and recommendations for Central Asian countries.


INTRODUCTION
In the past two decades, the understanding of the roles of vitamin D has expanded beyond the classical role of regulating calcium-phosphorus homeostasis and controlling bone metabolism. Evidence continues to mount that vitamin D has many other functions. It reduces risk of musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several cancers, neurocognitive dysfunction and mental illness, as well as infertility and adverse pregnancy and birth outcomes [1,2]. The benefits of vitamin D are generally appreciated in Europe and the United States but relatively unappreciated in Central Asia (CA). This paper strives to determine the health outcomes in CA that would benefit from increasing vitamin D status, present the evidence regarding vitamin D for those outcomes, and recommend action for future research. Data on vitamin D status and health outcomes for three northern European (NE) countries are included for comparison. In this work, health outcomes considered are largely related to mortality rates. Mortality rate data were obtained from the World Health Organization.
To gain an understanding of the interest in vitamin D in CA and NE countries, pubmed.gov and Scopus for CA were searched, using the terms "vitamin D" and "25-hydroxyvitamin D" and the name of each country. To find evidence that better vitamin D status improves various health outcomes, both pubmed.gov and scholar.google.com were searched, using "vitamin D" and "25-hydroxyvitamin D" and the name of the health outcome. Table 1 gives the latitude and longitude of the capital cities of each country, along with the population, life expectancy and healthy life expectancy at birth, infant mortality rate, and chronic disease mortality rate for people aged 30-70 years [3]. Life expectancy and healthy life expectancy at birth is about 10 years shorter in CA than in NE, infant mortality rates are much higher, and chronic disease mortality rates are about three times those in NE.  Table 2 gives age-adjusted mortality rates for males and females for the chronic diseases with the highest mortality rates for CA and NE countries [4].

DATA FOR COUNTRIES IN CENTRAL ASIA AND NORTHERN EUROPE
Although cancer mortality rates are similar between CA and NE, diabetes mellitus mortality rates are much higher in several CA countries.
Cardiovascular disease rates, including both ischemic heart disease (IHD) and stroke, are about five times higher. Chronic obstructive pulmonary disease rates are about twice as high; cirrhosis of the liver rates are more than 10 times higher than in Norway and Sweden; and kidney disease rates are about six times higher. Age-standardized rate per 100,000 population by cause and WHO member state (2015) (1812-GHE2016_Death-rates-country *Liver cancer rate, 92.5; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; IHD, ischemic heart disease; quality of data: G, high; P, death registration data unavailable; T, severe quality issues; Y, moderate. One reason that 25(OH)D concentrations are higher in NE than in CA is that more fatty ocean fish is consumed in NE [5]. Another reason is that summer temperatures in CA are so hot that people probably do not spend much time in the sun.  Table 3 shows [6][7][8][9][10][11][12][13][14][15][16][17][18][19], mean serum 25(OH)D concentrations range from 4 to 23 ng/ml in CA and from 19 to 32 ng/ml in NE. (To convert ng/ml to nmol/L, divide by 2.5.) Few papers were found regarding serum 25(OH)D concentrations in CA, offering further evidence that little concern has been given to vitamin D in that region.

Cancer
Geographical ecological studies report inverse relationships between solar ultraviolet-B (UVB) doses and incidence/mortality rates for about 20 cancers [20]. In Nordic countries, outdoor occupation with UVB exposure is significantly inversely correlated with incidence of 14 cancers [21]. Observational studies show inverse correlations between serum 25(OH)D concentrations and colorectal cancer [22]. Pooled studies involving women, many of whom were taking high doses of vitamin D, indicate inverse correlations between serum 25(OH)D concentration and both all-cancer incidence [23] and breast cancer incidence [24]. Recently the results of a large randomized controlled trial (RCT), VITamin D and OmegA-3 TriaL (VITAL), were released regarding supplementation with 2000 IU/d of vitamin D3 and all-cancer incidence. Although the results for the entire 25,000 participants were not significant, they were for some subgroups. For participants with body mass index <25 kg/m 2 of body surface area, the hazard ratio (HR) was 0.76 (95% Confidence Interval [CI], 0.76 to 0.90); for blacks, HR = 0.77 (95% CI, 0.59 to 1.01); and when results during the first year were omitted, the HR for all-cancer death was 0.79 (95% CI, 0.63 to 0.99). A recent letter to the editor made the case for accepting secondary analyses such as these [5].  [26]. A recent commentary in Nature argued that p = 0.05 is an arbitrary cutoff between significant and not significant [27]. Thus, the 95% CI values slightly larger than 1.00 should be considered to demonstrate significance even though the p-value is slightly larger than 0.05.

Ischemic heart disease
Good observational evidence indicates that serum 25(OH)D concentration is inversely correlated with IHD incidence, but no evidence has come from vitamin D supplementation studies. A 2012 metaanalysis reported that the relative risk of IHD doubled when baseline 25(OH)D concentration decreased from 20 to 6 ng/ml [28]. The most recent vitamin D RCT, the VITAL study, showed no significant benefit for IHD with 2000 IU/d of vitamin D3 supplementation [29]. However, the mean baseline 25(OH)D concentration for participants who provided data was near 31 ng/ml, with few having 25(OH)D concentration below 15 ng/ml. In addition, participants in the control arm were permitted to take up to 600 IU/d (800 IU/d if older than 70 yrs) of vitamin D3.

Stroke
In a meta-analysis of 19 studies, a significantly increased risk of stroke for low 25(OH)D concentration was evident. The risk ratio for stroke incidence for low versus high 25(OH)D from 16 prospective studies was 1.32 (95% CI, 1.19 to 1.46), whereas that from three case-control studies was 6.6 (95% CI, 1.2 to 37.0) [30]. The total risk ratio was 1.60 (95% CI, 1.33 to 1.92). However, vitamin D supplementation has not been shown to reduce risk of stroke [31]. But stroke often occurs for people with very low 25(OH)D concentration, and such people are generally not included in vitamin D RCTs. In addition, hypertension is an important risk factor for stroke [32], and an open-label study reported that participants with hypertension who took 4000 IU/d of vitamin D reduced systolic and diastolic blood pressure by 10-15 mmHg, to below the threshold for hypertension [33].

Chronic obstructive pulmonary disease
A meta-analysis reported that vitamin D supplementation can substantially reduce the rate of moderate/severe chronic obstructive pulmonary disease exacerbations for people with baseline 25(OH)D concentration <10 ng/ml (adjusted incidence rate ratio = 0.55 [95% CI, 0.36 to 0.84]) but not for those with higher baseline concentrations [34].
Cirrhosis of the liver "Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology, with lower levels of vitamin D in alcoholic cirrhosis than in primary biliary cirrhosis" [35]. However, vitamin D supplementation improves the probability of achieving a sustained immune response after antiviral treatment for people with 25(OH)D concentration <20 ng/ml [36]. A review of vitamin D's antimicrobial properties appears in a review by Youssef and colleagues [37].

Chronic kidney disease
A meta-analysis of 16 studies involving 17,053 chronic kidney disease (CKD) patients with 7517 incident deaths indicated that a 10-ng/ml increment in 25(OH)D was associated with a 21% reduction in overall mortality (RR = 0.79 [95% CI, 0.70 to 0.87]) for people with baseline 25(OH)D concentration below about 35 ng/ml [38]. Another meta-analysis showed that the reduction in all-cause mortality rate was higher for CKD patients not receiving dialysis (four studies; risk ratio = 0.53 [95% CI, 0.32 to 0.87]) than those receiving dialysis (16 studies) (risk ratio = 0.66 [95% CI, 0.57 to 0.75]) [39]. However, that paper also reported that vitamin D RCTs have not shown a significant benefit in reducing all-cause or cardiovascular disease mortality rates for CKD patients.

Acute respiratory tract infections
Acute respiratory tract infections (ARIs) are most common in winter, when UVB doses-and thus vitamin D status-are low [40]. A meta-analysis of vitamin D RCTs for ARIs showed that supplementing with vitamin D reduced the risk of ARIs, with greatest impact on people with 25(OH)D concentrations <10 ng/ml (Adjusted Odds Ratio = 0.30 [95% CI, 0.17 to 0.53]) [41].

Pregnancy
Vitamin D status during pregnancy and lactation is an important consideration. The developing fetus relies on genes to guide somatic development. The hormonal metabolite of vitamin D, 1,25(OH)2D, affects the expression of many genes through vitamin D receptors coupled to chromosomes [42]. One important effect of vitamin D during pregnancy is to reduce the risk of preterm delivery. In an openlabel study in South Carolina, women had their 25(OH)D concentration measured near the 12th week of pregnancy and were then given bottles of 5000-IU vitamin D and counseled on how to achieve concentrations of >40 ng/ml [43]. Those women who achieved >40 ng/ml had 61% reduced risk of preterm delivery in comparison with those with 25(OH)D <20 ng/ml (relative risk = 0.41 [95% CI, 0.24 to 0.72]). Higher vitamin D status has also been associated with reduced risk of preeclampsia [44] and gestational diabetes [45] as well as reduced risk of offspring with rickets [46].

All-cause mortality rate
On the basis of the understanding of 25(OH)D concentration-health outcome relations, it was estimated in 2011 that if continental population mean 25(OH)D concentrations were raised from 22 to 44 ng/ml, mortality rates would decrease by 8% (for countries with low life expectancies) to 17% (for countries with high life expectancies). That decrease translates to about 2 years of increased life expectancy [47]. A meta-analysis of 32 observational studies reported that all-cause mortality rates were reduced by about 30±20% when 25(OH)D was increased from 20 to 40 ng/ml [48].

CONCLUSION
Several steps can be taken to improve the vitamin D status in CA. One is to consider fortifying commonly consumed foods such as dairy, flour, and oil foodstuffs [49]. The goal of food fortification should be to have most people achieve a 25(OH)D concentration of at least 20 ng/ml. The second step would be to consider making vitamin D supplements more readily available and to publicize the need for vitamin D, especially for various subgroups of the population. The goal should be to have supplement takers achieve concentrations of at least 30 ng/ml, if not 40 ng/ml [50]. The third step would be to conduct observational studies and clinical trials regarding the health benefits of vitamin D in CA, which may differ from what has been found in other countries.

FUNDING
The author is a recipient of research funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA).

AUTHOR CONTRIBUTIONS
Substantial contributions to the conception or design of the work, acquisition, analysis, and interpretation of data -WBG. Drafting and revising the manuscript -WBG. Final approval of the version to be published -WBG. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved -WBG.

DISCLAIMER
No part of the manuscript has been submitted simultaneously or published elsewhere.