Low vitamin D levels have been associated with asthma severity in children. Young, urban African Americans (AAs) have high rates of hypovitaminosis D and asthma. Our objective was to determine associations between variants in vitamin D metabolism genes and asthma characteristics in a pilot study of young urban AAs.
Materials and Methods
Two urban AA cohorts of subjects aged 6 to 20 years (139 subjects with asthma and 74 subjects without asthma) were genotyped for 12 single nucleotide polymorphisms (SNPs) in 3 vitamin D metabolism genes: VDR (vitamin D receptor), CYP24A1 (cytochrome P450 vitamin D 24-hydroxylase), and CYP2R1 (cytochrome P450 vitamin D 25-hydroxylase). In a case-control analysis, SNPs were studied for associations with an asthma diagnosis. Within the asthmatic cohort, SNPs were analyzed for associations with quantitative asthma characteristics. All analyses were adjusted for age, sex, and body mass index percentile.
Results
Only the CYP2R1 SNP rs10766197 homozygous minor genotype was associated with asthma (P = 0.044). CYP24A1 SNP rs2248137 was associated with lower vitamin D levels (P = 0.006). Within the asthma cohort, multiple significant associations between SNPs and asthma characteristics were identified; VDR SNP rs2228570 was associated with the higher nighttime asthma morbidity scores (P = 0.04), lower baseline spirometric measures (P < 0.05), 1 or more positive aeroallergen skin test (P = 0.003), and increased immunoglobulin E levels (P < 0.001).
Discussion
This pilot study demonstrates that variants in vitamin D metabolism genes are associated with quantitative asthma characteristics in young, urban AAs. The collection of these associations provides evidence for the need for a large population-based study of vitamin D-relevant SNPs in this cohort.
CooksonW. The alliance of genes and environment in asthma and allergy. Nature. 1999;402:B5–B11.
2.
BeasleyR. The burden of asthma with specific reference to the United States. J Allergy Clin Immunol. 2002;109:S482–S489.
3.
BurrML, ButlandBK, KingS, . Changes in asthma prevalence: two surveys 15 years apart. Arch Dis Child. 1989;64:1452–1456.
4.
BusseW, EliasJ, SheppardD, . Airway remodeling and repair. Am J Respir Crit Care Med. 1999;160:1035–1042.
5.
FahyJV, CorryDB, BousheyHA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med. 2000;6:15–20.
6.
RogersDF. Airway goblet cell hyperplasia in asthma: hypersecretory and anti-inflammatory?Clin Exp Allergy. 2002;32:1124–1127.
7.
BlythDI. The homeostatic role of bronchoconstriction. Respiration. 2001;68:217–223.
8.
HolickMF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281.
9.
DevereuxG, LitonjuaAA, TurnerSW, . Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr. 2007;85:853–859.
10.
WittkeA, WeaverV, MahonBD, . Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol. 2004;173:3432–3436.
11.
FreishtatRJ, MitchellLW, GhimbovschiSD, . NKG2A and CD56 are coexpressed on activated TH2 but not TH1 lymphocytes. Hum Immunol. 2005;66:1223–1234.
12.
BoonstraA, BarratFJ, CrainC, . 1alpha, 25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974–4980.
13.
LemireJM, ArcherDC, BeckL, . Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr. 1995;125:1704S-1708S.
14.
SimmonsJD, MullighanC, WelshKI, . Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut. 2000;47:211–214.
15.
Ramos-LopezE, BruckP, JansenT, . CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev. 2007;23:631–636.
CamargoCAJr, Rifas-ShimanSL, LitonjuaAA, . Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr. 2007;85:788–795.
18.
LeeJM, SmithJR, PhilippBL, . Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila). 2007;46:42–44.
19.
GordonCM, DePeterKC, FeldmanHA, . Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158:531–537.
20.
MooreCE, MurphyMM, HolickMF. Vitamin D intakes by children and adults in the United States differ among ethnic groups. J Nutr. 2005;135:2478–2485.
21.
PintoJM, SchneiderJ, PerezR, . Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis. J Allergy Clin Immunol. 2008;122:415–417.
22.
Nesby-O'DellS, ScanlonKS, CogswellME, . Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002;76:187–192.
23.
HarrisSS, Dawson-HughesB. Seasonal changes in plasma 25-hydroxyvitamin D concentrations of young American black and white women. Am J Clin Nutr. 1998;67:1232–1236.
24.
WjstM, AltmullerJ, Faus-KesslerT, . Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res. 2006;7:60.
25.
PoonAH, LapriseC, LemireM, . Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med. 2004;170:967–973.
26.
RabyBA, LazarusR, SilvermanEK, . Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004;170:1057–1065.
27.
DruilheA, ZahmJM, BenayounL, . Epithelium expression and function of retinoid receptors in asthma. Am J Respir Cell Mol Biol. 2008;38:276–282.
28.
SzpirerJ, SzpirerC, RiviereM, . The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7. Genomics. 1991; 11:168–173.
SakakiT, KagawaN, YamamotoK, . Metabolism of vitamin D3 by cytochromes P450. Front Biosci. 2005;10:119–134.
31.
ChengJB, MotolaDL, MangelsdorfDJ, . De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem. 2003;278:38084–38093.
32.
BisgaardH, KlugB. Lung function measurement in awake young children. Eur Respir J. 1995;8:2067–2075.
33.
BuksteinDA, McGrathMM, BuchnerDA, . Evaluation of a short form for measuring health-related quality of life among pediatric asthma patients. J Allergy Clin Immunol. 2000;105:245–251.
34.
GorelickMH, BrousseauDC, StevensMW. Validity and responsiveness of a brief, asthma-specific quality-of-life instrument in children with acute asthma. Ann Allergy Asthma Immunol. 2004;92:47–51.
35.
Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120:S94–S138.
36.
MisraM, PacaudD, PetrykA, . Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122:398–417.
37.
CarterGD, CarterR, JonesJ, . How accurate are assays for 25-hydroxyvitamin D? Data from the international vitamin D external quality assessment scheme. Clin Chem. 2004;50:2195–2197.
38.
ErsfeldDL, RaoDS, BodyJ-J, . Analytical and clinical validation of the 25 OH vitamin D assay for the LIAISON® automated analyzer. Clin Biochem. 2004;37:867–874.
39.
VollmertC, IlligT, AltmullerJ, . Single nucleotide polymorphism screening and association analysis-exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma. Clin Exp Allergy. 2004;34:1841–1850.
40.
WittkeA, ChangA, FroicuM, . Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch Biochem Biophys. 2007;460:306–313.
41.
WjstM. Variants in the vitamin D receptor gene and asthma. BMC Genet. 2005;6:2.
42.
KosoyR, NassirR, TianC, . Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum Mutat. 2009;30:69–78.
43.
PritchardJK, StephensM, DonnellyP. Inference of population structure using multilocus genotype data. Genetics. 2000;155:945–959.
44.
FreishtatRJ, IqbalSF, PillaiDK, . High prevalence of vitamin D deficiency among inner-city African American youth with asthma in Washington, DC. J Pediatr. 2010;156:948–952.
MoormanJE, RuddRA, JohnsonCA, . National surveillance for asthma-United States, 1980-2004. MMWR Surveill Summ. 2007;56:1–54.
47.
StrunkRC, FordJG, TaggartV. Reducing disparities in asthma care: priorities for research-National Heart, Lung, and Blood Institute workshop report. J Allergy Clin Immunol. 2002;109:229–237.
48.
HaldarP, PavordID, ShawDE, . Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–224.
49.
JosephCL, OwnbyDR, PetersonEL, . Racial differences in physiologic parameters related to asthma among middle-class children. Chest. 2000;117:1336–1344.
50.
MillerJE. The effects of race/ethnicity and income on early childhood asthma prevalence and health care use. Am J Public Health. 2000;90:428–430.
WortsmanJ, MatsuokaLY, ChenTC, . Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690–693.
53.
BlackPN, ScraggR. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 2005;128:3792–3798.
54.
XystrakisE, KusumakarS, BoswellS, . Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116:146–155.
55.
TamezS, NorizoeC, OchiaiK, . Vitamin D receptor polymorphisms and prognosis of patients with epithelial ovarian cancer. Br J Cancer. 2009;101:1957–1960.
56.
Penna-MartinezM, Ramos-LopezE, SternJ, . Vitamin D receptor polymorphisms in differentiated thyroid carcinoma. Thyroid. 2009;19:623–628.
57.
PanierakisC, GoulielmosG, MamoulakisD, . Vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Crete, Greece. Clin Immunol. 2009;133:276–281.
58.
LaaksonenMM, OutilaTA, KarkkainenMU, . Associations of vitamin D receptor, calcium-sensing receptor and parathyroid hormone gene polymorphisms with calcium homeostasis and peripheral bone density in adult Finns. J Nutrigenet Nutrigenomics. 2009;2:55–63.
59.
LitonjuaAA, WeissST. Is vitamin D deficiency to blame for the asthma epidemic?J Allergy Clin Immunol. 2007;120:1031–1035.
