Vitamin D, Genetic Polymorphism and Bone Health in African Americans

Review Article

Austin J Nutr Metab. 2016; 3(1): 1035.

Vitamin D, Genetic Polymorphism and Bone Health in African Americans

Iranikhah M*, Freeman MK and Gunter SG

Department of Pharmacy Practice, Samford University, USA

*Corresponding author: Maryam Iranikhah, Department of Pharmacy Practice, Samford University, McWhorter School of Pharmacy, 800 Lakeshore drive, Birmingham, Alabama, 35229, USA

Received: June 30, 2016; Accepted: August 02, 2016; Published: August 04, 2016

Abstract

Vitamin D deficiency has been associated with many skeletal and extra skeletal diseases such as bone disease, several types of cancers, cardiovascular disease, diabetes and autoimmune disorders. Many of these chronic diseases are disproportionately distributed in our population, with African Americans being more affected than other races/ethnicities. Differences in 25-hydroxyvitamin D concentration among racial/ethnic groups have been suspected to be one of the sources of these health disparities. Darker skin pigmentation has been identified as interfering with UVB radiation of the sun resulting in lower vitamin D synthesis in the skin. In addition, presence of genetic polymorphism in vitamin D-binding proteins and vitamin D receptors that have different affinities for vitamin D may explain differences seen in vitamin D levels between ethnicities. Circulating levels of vitamin D are also predicted by season of blood draw, smoking, sex, age and body mass index which is independent of ethnicity. Regardless of vitamin D levels, African Americans have higher bone mineral density and lower fracture risks than other ethnicities/races. In this review, several clinical trials have been analyzed in order to explain vitamin D deficiency, genetic polymorphism and bone health in African Americans compared to other races.

Keywords: Vitamin D; Genetic polymorphism; Vitamin D binding protein; Bone mineral density; African Americans

Abbreviations

BMD: Bone Mineral Density; VDR: Vitamin D Receptor; SNP: Single Nucleotide Polymorphism; SCP: Start Codon Polymorphism; BMI: Body Mass Index; BMC: Bone Mineral Composition; PCR: Polymerase Chain Reaction; IRAS: Insulin Resistance Atherosclerosis Study; DBP: Vitamin D Binding Protein; (25[OH] D): 25-hydroxyvitamin D; (1,25[OH]2 D): 1,25-dihydroxyvitamin D; SCCS: Southern Community Cohort Study; SD: Standard Deviation; DEXA: Dual Energy X-ray Absorptiometry; HANDLS: Healthy Aging in Neighborhoods of Diversity across the Life Span; PTH: Parathyroid Hormone; GWAS: Genome Wide Association Studies; WAA: West African Ancestry

Introduction

Vitamin D refers to a group of fat soluble structures that are responsible for enhancing the absorption of calcium, magnesium, iron, phosphate and zinc from the intestines. The two important compounds in humans are Vitamin D2 also referred to as ergocalciferol and vitamin D3 also known as cholecalciferol. Both compounds can be obtained from diet and supplements. However, diet and supplements are not considered a major source of vitamin D. Synthesis of vitamin D in the skin which is dependent on exposure to the UVB radiation of the sun is the major source of this vitamin. Regardless of the source, vitamin D is biologically inactive when it enters the body and requires enzymatic hydroxylation in the liver and kidney to become active [1,2]. The first hydroxylation will yield 25-hydroxyvitamin D which is the major circulating metabolite and is a marker of the vitamin D status in the body. The final hydroxylation will yield 1,25-dihydroxyvitamin D, which is the more biologically active metabolite [3].

Other than playing an important role in absorption of calcium, vitamin D regulates over 900 genes that are responsible in various physiologic functions in the body. Vitamin D deficiency has been recognized as a major public health issue that has been linked to many skeletal related diseases such as osteomalacia and osteoporosis and extra skeletal disorders such as cancer, diabetes and cardiovascular disease [4,5].

African Americans have higher bone mineral density and are therefore at lower risk for fractures than Caucasians [6]. However, they have been identified as having a higher deficiency in Vitamin D levels than Caucasians even when they live in sunlight intense southern and southwestern states or who are taking higher dietary vitamin D intake than the recommended daily allowance or greater [7]. While, higher amount of melanin in skin which corresponds to darker skin pigmentation can effect vitamin D synthesis, circulating levels of 25-hydroxyvitamin D are predicted by season of blood draw, smoking, sex, age and body mass index that are independent of race/ ethnicity [7,8].

Elevated levels of parathyroid hormone, is considered a sensitive marker of vitamin D deficiency which is more common in African Americans than Caucasians. African Americans have lower levels of total 25-hydroxyvitamin D and vitamin D binding protein than their Caucasian counterparts. Genetic polymorphism in the vitamin D-binding protein gene produces variant proteins that have different affinity for vitamin D. The prevalence of this polymorphism differs between racial groups [9]. In this review several clinical trials have been analyzed in order to better explain the connection between vitamin D deficiency, genetic polymorphism and the bone health in African Americans.

Methods

A Pub Med search (1966-May 2016) was conducted using the following MeSH terms: African Americans; Vitamin D; Vitamin D Binding protein; and Polymorphism, genetic. A free-text search was conducted using the same search terms. An International Pharmaceutical Abstracts (IPA) search was conducted using the terms vitamin D, vitamin D receptor, polymorphism and African American (1970-May 2016). A Cochrane Central database search was conducted with the following terms: African Americans, Vitamin D, Vitamin D-Binding Protein and Polymorphism, Genetic. A total of 46 articles were identified. Articles were included if the patients were African American, were clinical studies and included information related to genetic polymorphism associated with vitamin D or vitamin D binding protein. A bibliographic search was conducted as well. A total of 12 articles were identified for further analysis. Study quality was assessed by National Institutes of Health Quality Assessment of Controlled Intervention Studies was ranked by good, fair or poor [10,11].

Clinical trial analysis

A cross-sectional study was conducted by Harris, et al. to compare FokI genotype distribution to race, bone mineral density (BMD) and another vitamin D receptor (VDR) polymorphism, BsmI. The FokI single nucleotide polymorphism (SNP) is defined by the presence or absence of a second start codon for translation of the vitamin D receptor (VDR) and genotypes are denoted as follows: homozygous subjects with both start codons are ff, homozygous subjects with only the second start codons are FF and heterozygous subjects are Ff. Inclusion in this study required that subjects be black or white American women, premenopausal, between 20 and 40 years old and in good general health. BMD of the total body, femoral neck and lumbar spine (L2-L4) was assessed. There were 154 women included in this analysis: 72 black women and 82 white women. The FF genotype was most common among black women (n=47; 65%), followed by Ff (n=22; 31%) and ff (n=3; 4%). However, the Ff genotype was most common for white women (n=37; 45%), followed by FF (n=30; 37%) and ff (n=15; 18%). The mean age was 30.5±5.9 years for the FF genotype group, 28.9±5.5 years for Ff and 30.7±5.6 years for ff (P=0.231). Total body BMD was significantly lower for white patients compared to black patients (1.230±0.076 g/cm2 compared to 1.161±0.075, difference = 0.068, 95% CI; 0.042-0.095). BsmI genotypes were found to be similarly distributed between the 2 original groups. Women with the BB genotype had lower BMD of the femoral neck and total body than those with the bb genotype. In the final sample population of this study, there was no statistical significance between the mean age, height, weight and calcium intake across the different genotypes. The one exception was an increased weight in the ff group of white women. Average dietary calcium intake was 701±365 mg/ day, 700±306 mg/day and 802±327 mg/day, respectively (P=0.510). A much higher percentage of white women than black women were homozygous ff (18% compared to 4%), while more black patients had the FF genotype (65% vs 50%) (P< 0.001). Black patients had higher femoral neck BMD scores across the various genotypes (p=0.001). When both black and white women were pooled and adjustments were made for race, weight and age, a statistical difference was detected in the BMD of the femoral neck. Patients with FF genotype had higher BMD at the femoral neck (1.08±0.01) compared to Ff (1.03±0.02) and ff (1.00±0.03; P=0.015). Those who were homozygous ff had 2.9% lower BMD scores than heterozygous Ff and 7.4% less than homozygous FF. The same patterns were evident for the lumbar spine and total body, but no statistical significance was detected. No differences in plasma 1,25(OH)2D, serum parathyroid hormone (PTH) and serum osteocalcin were observed between the genotypes. When genotype, age and weight were adjusted for, the difference in BMD at the femoral neck between black and white women decreased considerably (0.069±0.023 to 0.045±0.024; P=0.015). Relationships between start codon polymorphism (SCP) and BsmI were analyzed for the entire sample as well black and white women separately. SCP and BsmI were not found to be independent for the group as a whole or for white women considered separately. African American patients have higher BMD levels at the femoral neck region. The author’s concluded that SCP polymorphism appears to have an effect on peak bone density, specifically at the femoral neck [12].

A cross-sectional cohort analysis by Zmuda, et al. examined the effect that polymorphisms in the VDR gene have on bone mass and rate of bone loss in African American women over 2 years. The cohort of African American women (n=101) were at least 65 years old, able to ambulate independently and had no history of bilateral hip replacement. One hundred and sixty-five women completed the initial evaluation and 113 returned for the second examination. Associations between the BsmI, ApaI and TaqI VDR gene polymorphisms, bone mass and the rate of bone loss were evaluated. Genotypes are identified as follows: lowercase letters denote the presence of the restriction enzyme site; conversely, absence of the restriction enzyme site is denoted by an uppercase letter. The frequency distribution of the various genes was reported as follows: B=0.36, b=0.64; A=0.67, a=0.33; T=0.58, t=0.42. As observed in previous studies involving Caucasian and Japanese women, a significant association between b and T alleles was found (n=76 and n=86, respectively; P< 0.001). Further analyses were adjusted for age and body weight due to differences noted between genotypes. No association was found between BMD or broadband ultrasound attenuation (BUA) for any site or any polymorphism. For the oldest group of women (≥ 70 years old), there was a significant correlation between genotype and bone mass. Patients with the tt genotype had five times more bone loss than those with the (TaqI) Tt genotype at the hip (P=0.04). Heterozygous women experienced intermediate bone loss; less than tt, but more than TT. At the BsmI site, women who were heterozygous (BsmI) Bb experienced the most bone loss (P=0.004). The change in BMD per year was not found to be significantly different for any of the genotypes. No statistical significance was found when calculations were further adjusted for baseline BMD, baseline body weight or weight change. A 14% difference was noted in calcium absorption between the BB and bb genotypes; BB subjects had less absorption than those who were bb (P=0.08). No associations of this kind were found with the ApaI polymorphism. In this study, polymorphisms at the VDR gene (e.g., BsmI, ApaI and TaqI) were not associated with BMD or bone turnover in this population of African American women [13].

A cross-sectional cohort study to analyze how this polymorphism affects risk factors associated with osteoporosis, biochemical markers of bone health and calcium absorption was also done by Zmuda, et al. The study population was drawn from a cohort of 156 African American women who were at least 65 years old, communitydwelling, able to ambulate independently and who had no history of a bilateral hip replacement. Of these women, 104 were genotyped for the FokI SCP. Genotypes were defined as FF, Ff and ff; homozygous FF denotes absence of the restriction site and homozygous ff represents presence of the restriction site. The frequencies of the F allele and f allele were 78.4% and 21.6%, respectively. FF was the most frequent genotype (n=65; 62.5%), followed by Ff (n=33; 31.7%) and ff (n=6; 5.8%). Low prevalence of the ff genotype is consistent with previous findings in African Americans. No significant differences in genotypes were observed for age, weight, height, body mass index (BMI), dietary calcium intake, calcium supplementation, alcohol use, exercise (walking), smoking status, receipt of thiazide diuretics oral estrogen replacement therapy, history of fracture since age 50 or poor health status. There was no significant difference found between genotypes for hip or calcaneal BMD, calcaneal ultrasound or pelvic radiograph. Total hip BMD was 0.87 g/cm2 (SD=0.13) for patients with the FF genotype, 0.86 g/cm2 (SD=0.17) for Ff patients and 0.83 g/cm2 (SD=0.08) for the ff group (P=0.69). Calcaneal BMD for all groups was 0.46 g/cm2 (SD=0.10; P=0.99). Hip axis length was 128.6 mm (SD=9.1), 125.6 mm (SD=9.3) and 127.0 (SD=3.5; P=0.35). The other markers of bone health and turn over (serum osteocalcin, cross-linked NTx) as well as fractional absorption of calcium were also found to be similar across the genotype groups. After adjustment for factors such as age, weight, dietary calcium intake, health status, estrogen replacements therapy, thiazide diuretic use, smoking history and walking for exercise, no statistical difference was identified between the genotypes. Analyses were conducted with and without the rare f allele with similar and non-significant differences. Results of this study reveal that the ff allele is rare in the African-American community compared to others and the significance of differences in this allele has yet to be elucidated. However, it appears that the VDR start codon polymorphism is not associated with several markers of osteoporotic risk [14].

Citation: Iranikhah M, Freeman MK and Gunter SG. Vitamin D, Genetic Polymorphism and Bone Health in African Americans. Austin J Nutr Metab. 2016; 3(1): 1035.