Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa

<div><p>Background</p><p>Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.</p><p>Methods</p><p>We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.</p><p>Results</p><p>Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29–42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17–114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14–0.67).</p><p>Conclusions</p><p>Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.</p></div

Hazard of sputum culture conversion by vitamin D receptor gene single nucleotide polymorphism.

<p>Hazard of sputum culture conversion by vitamin D receptor gene single nucleotide polymorphism.</p

Poor tuberculosis treatment outcome by vitamin D receptor gene single nucleotide polymorphism, N = 88.

<p>Poor tuberculosis treatment outcome by vitamin D receptor gene single nucleotide polymorphism, N = 88.</p

Actual distance travelled by participants (n = 404) to the health facility at which XDR TB was diagnosed, KwaZulu-Natal, 2011–2014.

<p>Actual distance travelled by participants (n = 404) to the health facility at which XDR TB was diagnosed, KwaZulu-Natal, 2011–2014.</p

Distribution of all XDR TB cases diagnosed per health facility (left panel) and enrolled XDR TB cases per health facility and residential location (right panel), KwaZulu-Natal, 2011–2014.

<p>Distribution of all XDR TB cases diagnosed per health facility (left panel) and enrolled XDR TB cases per health facility and residential location (right panel), KwaZulu-Natal, 2011–2014.</p

Road classes and road speeds in KwaZulu-Natal province, as defined by the KwaZulu-Natal Department of Transport.

<p>Road classes and road speeds in KwaZulu-Natal province, as defined by the KwaZulu-Natal Department of Transport.</p

Mean travel distance and time to the nearest clinic, nearest hospital and the facility that diagnosed XDR TB, by district.

<p>Mean travel distance and time to the nearest clinic, nearest hospital and the facility that diagnosed XDR TB, by district.</p

Spider plot showing straight line distance from participants’ residence to the health facility at which they presented that diagnosed XDR TB, KwaZulu-Natal, 2011–2014.

<p>Spider plot showing straight line distance from participants’ residence to the health facility at which they presented that diagnosed XDR TB, KwaZulu-Natal, 2011–2014.</p

Baseline participant characteristics and 2-month sputum culture status.

<p>Baseline participant characteristics and 2-month sputum culture status.</p

Principal component analysis of study participants compared to HapMap ethnic groups.

<p>Principal component analysis of study participants compared to HapMap ethnic groups.</p