Genetic Factors Associated with Tuberculosis-Related Clinical Outcomes in HIV-Infected Black African Patients: a Systematic Review and Meta-Analysis

Figures & data

Figure 1. PRISMA flow diagram of systematic literature search and study selection.

TB: Tuberculosis.

Table 1. Characteristics of included studies.

No.	First author	Year	Country	Sites/study	Patient population	Design^† (follow-up time if prospective)	Sample size (n)	Age, years (mean ± SD or median, IQR)	Male (%)	Genetic factors with results, gene (variant)	Outcomes (definitions)	Key results^‡/comments	Ref.
1	Fitness	2004	Malawi	Karonga Prevention Study	HIV patients	Case-control	328	NI	NI	CR1 (A >G at 4795 K1590E)	TB infectivity (TB cases identified mainly through passive self-reporting and confirmation by culture, smear, or histology)	AG vs AA OR = 1.06 (95% CI: 0.59–1.92), P (adjusted for age, sex, zone, ethnic group) = 0.837, count data in Supplementary Table 3	[21]
							193			TNF (-238 G >A)		GA vs GG OR = 2.01 (95% CI: 0.65–6.28), p = 0.228; AA vs GG OR = 0.11 (95% CI: 0.005–2.58), p = 0.171, count data in Supplementary Table 3
							258			VDR (C >T, Bsm I)		CT vs CC OR = 1.65 (95% CI: 0.78–3.52), p = 0.194; TT vs CC OR = 0.12 (95% CI: 0.04–0.40), p = 0.001, count data in Supplementary Table 3
2	Søborg	2007	Tanzania	Mwanza district (from the multi-micronutrient trial	HIV patients	Case-control	274	NI	NI	SLC11A1 (INT4, 3′UTR, D543A, 5′ (CA)n)	TB infectivity (based on culture)	The presence of the 5′(CA)n variant allele was not associated with TB (OR 0.92, 95% CI: 0.53–1.6, p = 0.77), count data in Supplementary Table 3	[22,23]
3	Yimer	2011	Ethiopia	Tikur Anbessa hospital and 6 other health centers (Arada, Beletshachew, Bole, Lideta, Kazan’chiz and Meshua’lekia) in Addis Ababa – part of EDCTP-funded project below	HIV/TB patients	Prospective cohort (56 weeks)	201	NI	NI	CYP2B6 (516G >T, rs3745274, *6)	Drug-induced liver injury (based on the Council for International Organizations of Medical Science criteria)	GT vs GG p = 0.07, TT vs GG p = 0.04, count data in Supplementary Table 3	[24,25]
										ABCB1 (3435C >T, rs1045642)		CT vs CC p = 0.38, TT vs CC p = 0.02, count data in Supplementary Table 3
										CYP3A5 (*1) [vs *3/rs776746, *6, *7/rs241303343]		One *1 allele vs two *1 alleles p = 0.67, zero *1 alleles vs two *1 alleles p = 0.93
										NAT2 acetylators		Rapid acetylators (*4*4, *4*12, *4*13, *12*12, *13*13, *4*5, *4*6, *5*12, *5*13, *6*12, *6*13) vs slow acetylators (*5*5, *5*6, *5*7, *6*6, *6*7) p = 0.039
										UGT2B7 (-372G >A, rs7662029)		GA vs GG p = 0.26, AA vs GG p = 0.08, count data in Supplementary Table 3
										SLCO1B1 (388A >G, rs2306283, *1b)		AG vs GG p = 0.74, AA vs GG p = 0.38, count data in Supplementary Table 3
										SLCO1B1 (521T >C, rs4149056, *5)		TC vs TT p = 0.67, CC vs TT p = 0.92, count data in Supplementary Table 3
4	Hardwick	2012	Ethiopia	EDCTP-funded project on optimization of HIV/TB co-treatment in Africa	HIV patients	Case-control	616	NI	NI	β-Defensin copy number	TB infectivity (defined as definitive [based on sputum-smear or histology] or presumed clinical illness consistent with TB symptoms and signs)	Frequencies of copy numbers 1–9 reported in the Hardwick article	[26,27]
			Tanzania				325
5	Machado	2013	Ethiopia	EDCTP-funded project on optimization of HIV/TB co-treatment in Africa	HIV patients	Cross-sectional	720	NI	NI	FCGR (3A, 3B, 3C/rs10917661)	TB infectivity (defined as definitive [based on sputum-smear or histology] or presumed clinical illness consistent with TB symptoms and signs)	Frequencies of copy numbers reported in the Machado article. In Ethiopians, and for the FCGR3B copy number, there was a slightly higher number of deletions in patients with TB	[28,27]
			Tanzania				347
6	Dhoro	2013	Zimbabwe	Chitungwiza and Wilkins Hospitals in Harare	HIV/TB patients on INH	‘Prospective’ cohort (NI)	142	39 ± 11 (for 189)	48% (for 189)	NAT2*5 (341T >C, rs1801280)	Peripheral neuropathy (numbness, tinginess, pain at ends e.g. fingers) Graded 0–IV)	Count data in Supplementary Table 3	[29,30]
							160			NAT2*14 (191G >A, rs1801279)
7	Samie	2014	South Africa	Donald Frazer, Elim, and Tshilidzini hospitals and the University of Venda	HIV patients	Cross-sectional	170	Categorized (mode 25–45 years) (of 185)	32% (of 185)	CXCR2 (+1208 T >C)	TB infectivity (self-reporting/ structured questionnaire and patient files)	No association was observed Count data in Supplementary Table 3	[31]
8	Samie	2014	South Africa	Donald Frazer, Elim, and Tshilidzini hospitals and the University of Venda	HIV patients	Cross-sectional	113	Categorized (mode 25–45 years) (of 119)	29% (of 119)	IL-7Rα (+1237 G >A)	TB infectivity (self-reporting/ structured questionnaire)	No association was observed Count data in Supplementary Table 3	[32]
9	Dzhivhuho	2016	South Africa	Donald Frazer, Elim, and Tshilidzini hospitals and the University of Venda	HIV patients	Cross-sectional	165	Range 13–73 years (of 188)	31% (of 188)	IL-8 (-251 A >T)	TB infectivity (self-reporting/ structured questionnaire and patient files)	No association was observed Count data in Supplementary Table 3	[33]
10	Sobota	2016	Tanzania and Uganda	DarDar vaccine trial in Tanzania and the Household Contact study in Uganda	HIV patients	Prospective cohort (>8-year follow-up)	581	34 ± 8	27%	GWAS – top hits: rs4921437, rs8028149, rs1616723, rs955263, rs12636260, rs4768760, rs844669, rs4236914, rs4860106, rs1482868 and rs2346943	Active TB (for DarDar trial defined by physical examination, chest radiography, culture, acid-fast bacilli stain, and phlebotomy)	One hit (rs4921437) passed genome-wide significance (5E-08). It lies in the 5q33.3 region near IL12B and is embedded in an H3K27Ac histone mark. OR (adjusted for principal components, sex and country of origin, additive mode) = 0.374 (95% CI: 0.266–0.528), p = 2.11E-08	[34]
11	Sobota	2017	Tanzania and Uganda	DarDar vaccine trial in Tanzania and the Household Contact study in Uganda	HIV patients	Cross-sectional	469	33 ± 8	30%	GWAS – top hits: rs877356, rs7808481 and rs1880386 (dominant mode); rs877356, rs7808481, rs10804666, rs8179938, rs4705073 and rs964739 (additive mode); and, rs1293940, rs2285513, rs2434785, rs10804666, rs4705073, rs2489772 (recessive mode)	TB infectivity (tuberculin skin test) – induration ≥5 mm measured between 48 and 72 h post-injection indicative of infection	One hit (rs877356) passed genome-wide significance. It lies in the region 5q31.1, 57 kb downstream from IL9. OR (adjusted for principal components, sex and country of origin, dominant mode) = 0.267 (95% CI: 0.170–0.422), p = 1.22E-08	[35]
12	Petros	2017	Ethiopia	Kazanchis and Beletshachew health centers and Black Lion university hospital in Addis Ababa	HIV/TB patients	Prospective cohort (6 months)	186 (GWAS)	36 ± 10	47%	GWAS – top hits (combined cohort): rs4842407; rs11012476; rs251891	Drug-induced hepatotoxicity (DIH-based on criteria set by the International DIH Expert Working)	None passed genome-wide significance (5E-08). In the combined cohort, the top hit was rs4842407 (a long intergenic noncoding RNAs variant on chromosome 12) – adjusted (sex, body mass index, baseline CD4 count, and HIV viral load) OR = 5.4 (95% CI 2.8–10.3), p = 5.3E-07	[36,37]
							144 (replication)	37 ± 10	51%
13	Ravimohan	2018	Botswana	Primary care outpatient clinics and at the Princess Marina Hospital in Gaborone	HIV/TB patients	Secondary analysis of a prospective cohort (6 months)	94	mean 37 (range 22–59)	55%	CARD8 (rs2043211), CARD8 (rs6509365), NLRP3 (rs10925026), NLRP3 (rs10754558), IL18 (rs1946518), IL18 (rs549908), IL1B (rs1143627), P2RX7 (rs2230911)	Early mortality (death within 6 months)	In a logistic regression model, NLRP3 rs10754558 was independently associated with death (OR = 4.1, 95% CI 1.04–16.5, p = 0.043). Adjusting for confounding factors (baseline HIV viral load, NVP-based ART, and non-TB opportunistic infections) improved model fit. Other SNPs not associated with mortality (only p-values shown)	[38,39]
14	Calcagno	2019	Uganda	SOUTH Study	HIV/TB patients	Prospective cohort (6 months after the completion of TB treatment)	221	34 (29–40)	59%	SLCO1B1 (032 T >C, rs4149032)	Liver toxicity (any ALT elevation)	Any ALT elevation was more commonly observed in patients with the CC genotype (OR = 2.306, 95% CI 1.075–4.948, p = 0.029) Count data in Supplementary Table 3	[40,41]
										PXR (63396 C >T, rs2472677)	Liver toxicity (ALT elevations at week 8)	ALT elevations higher in patients with the TT genotype (with 4.17%/4.17% vs 0%/0.59% grades 2/3 elevations, p = 0.021) Genotype counts in Supplementary Table 3
											Worsening peripheral neurotoxicity (graded according to division of AIDS toxicity tables)	It was observed more frequently in patients with the TT genotype (OR = 2.944, 95% CI 1.164–7.443, p = 0.018) Count data in Supplementary Table 3
											TB cure (according to the WHO treat-ment guidelines)	TT genotype non-significantly associated with a lower chance of achieving TB cure (66.7% vs 74.9%, p = 0.342)
14	Calcagno	2019	Uganda	SOUTH study	HIV/TB patients	Prospective cohort (6 months after TB treatment completion)	221	34 (29–40)	59%	PXR (63396 C >T, rs2472677)	Mortality (death within the 6 months)	TT genotype associated with higher probability of death (OR = 4.575, 95% CI 1.388–15.083, p = 0.007) Count data in Supplementary Table 3	[40,41]
15	Reid	2019	South Africa	Durban (iThimba and String Study) cohort	HIV patients	Case-control	192	34 (29–39) (of 196)	32% (of 196)	MIF (−794 CATT5-8 microsatellite and an associated −173 G >C SNP, rs755622)	Active TB (based on clinical symptoms and positive culture or GeneXpert test)	The low expression MIF −794 CATT5,6 (5/5 + 5/6 + 6/6) genotypes were significantly higher in cases (82.7%) when compared with controls (68.1%) (OR = 2.23, 95% CI = 1.08–4.71, p = 0.019)	[42]
				Tugela Ferry and Greytown cohorts			164	36 (30–46) (of 165)	52% (of 165)			The low expression MIF (5/5 + 5/6 + 6/6) genotypes were similar in cases (73.0%) and controls (78.1%) (OR = 0.76, 95% CI = 0.36–1.59, p = 0.46)
16	Mthiyane	2020	South Africa	Durban (2 pharmacokinetic studies)	HIV/TB patients	Prospective cohort (29+ days)	120	33 (18–53)	50%	NAT2 acetylators (rapid *4*11, *12*12, *11*12; intermediate *5*12; slow *5*5)	Hepatic adverse events (elevated ALT, AST, alkaline phosphatase, and total bilirubin levels – graded per the Division of AIDS, NIAID, NIH, toxicity tables)	There was no statistically significant difference in adverse effects between genotypes	[43,44,45]
17	Ravimohan	2020	South Africa	Lung function after TB-IRIS study	HIV/TB patients	Prospective cohort (48 weeks post ART initiation)	102	37 (20–58)	57%	NLRC4 (rs385076)	Lung function (forced expiratory volume in 1 second, forced vital capacity)	Patients with the CT/TT genotypes (n = 51) had improved lung function compared with CC patients (n = 51) (forced vital capacity, 206 ml higher; 95% CI, 67–345 ml; p = .004 and forced expiratory volume in 1 s, 143 ml higher; 95% CI, 11–274 ml; p = 0.034)	[46]
18	Seedat	2021	South Africa	Soweto	HIV patients	Prospective cohort (at least 22 months)	727	37 ± 7	15%	HLA alleles (A*24:02, A*29:02, A*29:11, B*15:16, B*45:01/07, B*13:02, C*03:02)	TB infection/immune conversion (a positive tuberculin skin test result (≥5 mm) transverse diameter read approximately 72 h after placement)	In univariate analyses, HLA-A*29:11 (p = 0.030) and B*45:01/07 (p = 0.015) were associated with having a positive test while HLA-A*24:02 (p = 0.014), A*29:02 (p = 0.043) and B*15:16 (p = 0.042) with a negative test These results remained significant for B*45:01/07 (p = 0.029, adj. OR 2.7), A*24:02 (p = 0.021, adj. OR 0.22) and B*15:16 (p = 0.0098, adj. OR 0.22) in multivariable analysis	[47]
18	Seedat	2021	South Africa	Soweto	HIV patients	Prospective cohort (at least 22 months)	727	37 ± 7	15%	HLA alleles (B*07:02, B*41:01, C*06:02; DRB1*04:01, DRB1*11:01, DRB1*15:01)	TB disease (defined as ever being diagnosed with active TB)	In univariate analyses, B*41:01 (p = 0.005), C*06:02 (p = 0.042), DRB1*04:01 (p = 0.003) and DRB1*15:01 (p = 0.029) were associated with TB disease, while HLA-B*07:02 (p = 0.033) and DRB1*11:01 (p = 0.043) were protective. These results remained significant for B*41:01 (p = 0.008, adj. OR 7.2), C*06:02 (p = 0.034, adj. OR 1.8), and DRB1*04:01 (p = 0.009, adj. OR 2.9) in the joint analysis	[47]

† Study design is based on considered review outcome and may defer from that reported in the primary papers, for example, if TB status was measured during recruitment, then a study was cross-sectional despite being reported as prospective in the primary paper.

‡ Based on the Venice interim criteria [20], all presented evidence considered weak.

AIDS: Acquired immunodeficiency syndrome; ART: Antiretroviral therapy; EDCTP: European and Developing Countries Clinical Trial Partnership; GWAS: Genome-wide association study; HIV: Human immunodeficiency virus; NI: No information; OR: Odds ratio; SNP: Single nucleotide polymorphism; TB: Tuberculosis.

Figure 2. Forest plot for association between MIF CATT-794 genotypes and active-tuberculosis disease in the Reid [42] cohorts.

X represents any allele, so 7/X is equivalent to ‘7-containing’.

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