Killer Cell Immunoglobulin-Like Receptor Genotypes and Haplotypes Contribute to Susceptibility to Hepatitis B Virus and Hepatitis C Virus Infection in Cameroon

Abstract

Over 325 million people worldwide are living with hepatitis B and C viral infections and are at greater risk of developing hepatocellular carcinoma. The interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate ligands, human leukocyte antigens, modulate both infection processes and disease progression. We report here (1) genotype and haplotype variations in KIR genes in Cameroon and (2) their impact on susceptibility to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In 98 unrelated individuals (33 HCV+, 31 HBV+, and 34 uninfected healthy controls), we determined the presence of 15 KIR genes by polymerase chain reaction–sequence-specific primer techniques. One pseudogene and all 14 KIR genes were present. We identified 36 KIR genotypes, 5 of which have not been previously reported in public databases. Two inhibitory (KIR2DL1 and KIR2DL3) and three activating (KIR2DS4, KIR2DS2, and KIR2DS3) genes were present in all HCV-infected individuals. Similarly, KIR3DL1, KIR2DL1, and KIR2DS4 were present at 100% in the HBV+ group. Compared with uninfected healthy controls, the frequencies of KIR2DL2 and KIR3DS1 were significantly lower in the HBV+ group (p = 0.003 and p < 0.001, respectively). Conversely, KIR3DS1 was significantly overrepresented in the HCV+ group compared with controls (97.0% vs. 64.7%, respectively, p < 0.001). These results may imply that KIR3DS1 carriers were less likely to be HBV infected, but may be predisposed to HCV infection compared with uninfected controls, indicating their important role in transmission of these viruses. However, phenotypic, functional, and genomic studies to elucidate the role of these KIR genotypes and haplotypes in infection with HBV and HCV are important.

Introduction

Hepatitis B virus (HBV) and hepatitis C virus (HCV) account for the majority of cases of hepatocellular carcinoma worldwide. It is estimated that 325 million people are living with hepatitis B and C infections in 2018 (WHO 2019). In highly endemic areas, HBV can be transmitted through different routes, including perinatally from mother to child, sexually, or through contact with contaminated body fluids. HBV and HCV infections are endemic in Cameroon, with about 11% chronically infected with HBV and about 6.5% with HCV (Bigna et al., 2017a, 2017b).

Host genetic factors have been associated with differential outcomes of many infectious diseases (de Wit et al., 2016; Yano et al., 2013; Yindom et al., 2010; Zwolińska, 2009).

Among the immune factors, variants of genes encoding the killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) are strong correlates of susceptibility or resistance to viral infections, including HBV and HCV infections (Araujo et al., 2014; Martin and Carrington, 2013; Shepherd et al., 2015). KIRs are a family of activating and inhibitory type I transmembrane glycoproteins with two to three extracellular domains (Campbell and Purdy, 2011) and are highly polymorphic. They serve as key regulators of natural killer (NK) cell function and are expressed by NK cells and some T cell lymphocytes (Caligiuri, 2008). The KIR locus resides within the leukocyte receptor complex and spans a region of about 150–200 kb on the human chromosome 19q13.4 (Wende et al., 1999).

There are 15 KIR genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, and 3DS1) and 2 pseudogenes (2DP1 and 3DP1). More than 20 KIR haplotypes and at least 40 KIR genotypes have been reported from different geographic populations. Recently, it was demonstrated that KIR genes modulate susceptibility to hepatitis B infection (Yindom et al., 2017).

KIR genes and their cognate HLA ligands have been associated with differential outcomes of hepatitis B and C disease progression, but there is very little data on their mechanism of action. The compound genotype, KIR3DS1/HLA Bw4-80I, is associated with protection from rapid progression to AIDS (Hens et al., 2016; Qi et al., 2006), while KIR2DL3/HLA-C1 directly influences clearance of HCV (Khakoo et al., 2004).

Furthermore, some KIR genes, including KIR2DL3 and KIR3DS1, have a protective role against HBV infection (Di Bona et al., 2017; Kibar et al., 2014). Several studies have reported that the KIR3DS1 gene is less frequent in African populations (<25%) compared with Caucasians (>50%) and Asians (<30%) (Hollenbach et al., 2012). KIR genes have not been fully mapped in Cameroon with over 250 ethnic groups (Louis et al., 1995). In this study, we identified variations of KIR genes in unrelated individuals infected with HBV, HCV, and uninfected (healthy) controls in Cameroon and evaluated their association with susceptibility to infection.

Materials and Methods

Study participants

A total of 98 unrelated individuals were recruited from two main cities (Douala and Yaoundé) in Cameroon between January 2016 and December 2018 and each gave written informed consent to participate in this study. They were all screened for HBV, HCV, and HIV infections using the rapid tests, Determine HIV (Alere), HBsAg (ABON), anti-HCV (ABON), and ELISA (Murex), respectively, following manufacturers' instructions. Thirty-one (31.6%) were HBV infected, 33 (33.7%) HCV infected, and 34 (34.7%) tested negative for all three viruses. Questionnaires were administered to collect demographic characteristics (Table 1).

Table 1.

Demographic Characteristics of the Study Population

	Control,^a n (%)	HBV+, n (%)	HCV+, n (%)	Frequency (%)	p
No. of participants	34 (34.7)	31 (31.6)	33 (33.7)
Sex
Male	16 (28.0)	27 (47.4)	14 (24.6)		<0.001
Female	18 (43.9)	4 (9.8)	19 (46.3)		<0.001
Age, years
Median (IQR)	29 (27–35)	36 (29–43)	62 (57–66)
Mean (SD)	30.6 (5.7)	37.1 (11.0)	59.2 (12.9)	69.8	<0.001
Marital status
Single		16 (51.6)	5 (15.2)		<0.001
Married		15 (48.4)	21 (63.6)
Widowed		0 (0.0)	7 (21.2)

Control individuals tested negative for HBV, HCV, and HIV. p: uncorrected p-value. Between groups, age differences were compared using analysis of variance, the differences remained significant after Bonferroni correction, as shown below: (a) Control versus (HBV+) p1 = 0.039; (b) Control versus (HCV+) p2 = 0.000; (c) (HBV+) versus (HCV+) p3 = 0.000.

HBV, hepatitis B virus; HCV, hepatitis C virus; IQR, interquartile range; SD, standard deviation.

Ten milliliters of blood was collected from each participant and processed within 4 h to obtain plasma and buffy coat, which were stored at −20°C until analyses. Genomic DNA was extracted from the buffy coat using the QIAamp DNA mini extraction kit (Qiagen) following manufacturer's instructions. This study was approved by the Cameroon National Ethics Committee on Human Health Research.

KIR typing

Genomic DNA samples were typed by the polymerase chain reaction–sequence-specific primer (PCR-SSP) techniques as previously described (Martin and Carrington, 2008) to detect the presence of 14 KIR genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, and 3DS1) and 1 pseudogene (2DP1). Two KIR-specific primer pairs were used to amplify segments of different sizes from the same KIR gene. The amplicons were visualized on a 2% agarose gel by electrophoresis under a UV transilluminator. Discordant results (one band present and the other absent for the same gene) were repeated and if one of the bands was consistently positive, it was then considered positive. A pair of internal control primers to check for PCR efficiency was included in each reaction that amplifies the HLA-DRB1 gene.

Data analyses

Statistical analyses were done using IBM SPSS Statistics for Windows, v25 (IBM Corp., Armonk, NY), and Stata, v14.1 (Stata Corp., College Station, TX). The observed frequency for each KIR gene was obtained by direct counting and verified using Microsoft Excel 2013. These frequencies were compared between groups (HBV+ and HCV+ and uninfected controls) using the chi-square, Fisher exact test, and independent samples t-test, as appropriate. p < 0.05 was considered statistically significant after Bonferroni correction for multiplicity testing. We assigned KIR haplotypes and genotypes identification based on reported IDs available in public databases, including the Allele Frequency Net Database (www.allelefrequencies.net).

Results

Demographic and clinical characteristics of the study population

Of the 98 participants recruited, 57 were males (58.2%) and significantly overrepresented in the HBV-infected group (47.4%) compared with the HCV-infected group (24.6%) and uninfected controls (28.0%). Median age was significantly different between groups (Table 1). Participants infected with HCV were significantly older (median 62 years) than their HBV+ counterparts and uninfected control groups (36 and 29 years, respectively, p < 0.001). A significant proportion of those infected with HCV (63.6%) were either married or living with a partner. This is, however, not the case with the HBV+ individuals as similar numbers of married and single participants were affected.

Distribution of KIR genes and association with hepatitis infection

We investigated three framework genes (KIR3DL2, KIR3DL3, and KIR2DL4) and they were present in all samples, with the exception of KIR2DL4 that was absent in one uninfected control participant (Table 2). Most inhibitory KIR genes were present in more than 90% of the study population, with the exception of KIR2DL2 (82.7% overall frequency), and the least common was KIR2DL5 (62.2%). Interestingly, KIR2DL2 was significantly less frequent in the HBV+ group compared with their HCV-infected counterparts and uninfected controls (58.1%, 97.0%, and 91.2%), respectively. Univariate analyses comparing observed KIR frequencies between uninfected controls and HBV-infected (Table 3) or HCV-infected (Table 4) participants revealed that KIR3DS1 is strongly, but differentially, associated with both disease models.

Table 2.

Killer Cell Immunoglobulin-Like Receptor Frequency Distribution by Disease Status

KIR gene	Control, n (%)	HBV+, n (%)	HCV+, n (%)	χ²	p	p_c
2DL1	34 (100.0)	31 (100.0)	33 (100.0)
2DL2	31 (91.2)	18 (58.1)	32 (97.0)	8.31	0.0157	0.1256
2DL3	33 (97.1)	29 (93.6)	33 (100.0)	0.20	0.9058	ns
2DL4	33 (97.1)	31 (100.0)	33 (100.0)	0.06	0.9719	ns
2DL5	20 (58.8)	20 (64.5)	21 (63.6)	0.19	0.9118	ns
2DS1	29 (85.3)	28 (90.3)	30 (90.9)	0.19	0.9098	ns
2DS2	22 (64.7)	19 (61.3)	33 (100.0)	8.92	0.0116	0.0928
2DS3	18 (52.9)	13 (41.9)	33 (100.0)	18.37	<0.0001	8 × 10 ⁻⁴
2DS4	33 (97.1)	31 (100.0)	33 (100.0)	0.06	0.9719	ns
2DS5	17 (50.0)	14 (45.2)	23 (69.7)	3.26	0.1959	ns
3DL1	34 (100.0)	31 (100.0)	32 (97.0)	0.06	0.9706	ns
3DL2	34 (100.0)	31 (100.0)	33 (100.0)
3DL3	34 (100.0)	31 (100.0)	33 (100.0)
3DS1	22 (64.7)	4 (12.9)	32 (97.0)	34.02	<0.0001	8 × 10 ⁻⁴
2DP1	34 (100.0)	30 (97.0)	31 (94.0)	0.18	0.9125	ns

Number of participants per group: 31 HBV+, 33 HCV+, and 34 uninfected controls; χ²: chi-squared with two degrees of freedom from the Kruskal–Wallis test of equality of populations; p: uncorrected p-values; p_c: p-values corrected for multiplicity testing using the Bonferroni method are shown below:

KIR2DL2: (a) Control versus (HBV+) p1 = 0.005; (b) Control versus (HCV+) p2 = 0.62; and (c) (HBV+) versus (HCV+) p3 = 0.0005.

KIR2DS2: (a) Control versus (HBV+) p1 = 0.97; (b) Control versus (HCV+) p2 = 0.0005; and (c) (HBV+) versus (HCV+) p3 = 0.0002.

KIR2DS3:(a) Control versus (HBV+) p1 = 0.52; (b) Control versus (HCV+) p2 = 0.00000; and (c) (HBV+) versus (HCV+) p3 = 0.0000.

KIR3DS1: (a) Control versus (HBV+) p1 = 0.52; (b) Control versus (HCV+) p2 = 0.000; and (c) (HBV+) versus (HCV+) p3 = 0.000.

KIR, killer cell immunoglobulin-like receptor.

Table 3.

Killer Cell Immunoglobulin-Like Receptor Association with Hepatitis B Virus Infection

	Control, n (%)	HBV+, n (%)	OR (95% CI)	p
Number	34	31
KIR 2DL2	31 (91.2)	18 (58.1)	0.13 (0.02–0.61)	0.0021
KIR 2DL3	33 (97.1)	29 (93.6)	0.44 (0.03–5.25)	0.5038
KIR 2DS1	29 (85.3)	28 (90.3)	1.61 (0.35–7.50)	0.5408
KIR 2DS2	22 (64.7)	19 (61.3)	0.86 (0.31–2.39)	0.7773
KIR 2DS3	18 (52.9)	13 (41.9)	0.64 (0.23–1.74)	0.3786
KIR 2DS5	17 (50.0)	14 (45.2)	0.82 (0.30–2.20)	0.6987
KIR 3DS1	22 (64.7)	4 (12.9)	0.08 (0.02–0.36)	2.39 × 10 ⁻⁵

Only KIR genes with apparent variability between groups are shown, p: uncorrected p-values.

Table 4.

Killer Cell Immunoglobulin-Like Receptor Association with Hepatitis C Virus Infection

	Control, n (%)	HCV+, n (%)	OR (95% CI) or Chi-squared	p
Number	34	33
KIR2DL2	31 (91.2)	32 (97.0)	3.09 (0.29–32.52)	0.3207
KIR 2DL5	20 (58.8)	21 (63.6)	1.23 (0.45–3.31)	0.6883
KIR 2DS1	29 (85.3)	30 (90.9)	1.72 (0.37–8.02)	0.4819
KIR 2DS2	22 (64.7)	33 (100.0)	0.667	0.141
KIR 2DS3	18 (52.9)	33 (100.0)	—	—
KIR 2DS5	17 (50.0)	23 (69.7)	2.30 (0.82–6.44)	0.1029
KIR 3DS1	22 (64.7)	32 (97.0)	17.45 (1.70–179.31)	9.21 × 10 ⁻⁴
KIR 2DP1	34 (100.0)	31 (94.0)	2.09	0.148

Only KIR genes with apparent variability between groups are shown, p: uncorrected p-values.

KIR3DS1 carriers were significantly less likely to be HBV infected compared with uninfected controls (12.9%vs. 64.7%, odds ratio [OR] = 0.08, p = 2.4 × 10⁻⁵). Conversely, a significant proportion of HCV-infected participants were KIR3DS1 carriers (97.0% vs. 64.7%, OR = 17.45, p = 9.2 × 10⁻⁴; Table 4), suggesting that this three-domain KIR activating gene may predispose its carriers to HCV infection in the study population in Cameroon. Carriers of two other activating KIR genes (KIR2DS2 and KIR2DS3) were also all infected with HCV (Table 4).

Thirty-six KIR genotypes, 5 of which have not been previously reported, were found in 98 individuals (Table 5; Supplementary Tables S1 and S2). The most frequent genotypes we identified in the study population include genotypes 6 (25.5%), 11 (7.1%), 15 (7.1%), 233 (7.1), and 9 (5.1%). Of note, genotype 6 belongs to the Bx haplogroup with all 15 KIR genes present, as illustrated in Table 5. We found genotype 6 to be overrepresented in the HCV-infected group compared with uninfected controls and HBV-positive participants (51.5%, 17.7%, and 6.5%, respectively, p = 0.005).

Table 5.

Frequencies of Common Killer Cell Immunoglobulin-Like Receptor Genotypes and Profiles Stratified by Disease Groups

In a univariate analysis comparing HCV-positive individuals with uninfected controls, carriers of genotype 6 were five times more likely to be HCV infected than people without this genotype. Similarly, we found genotype 15 to be present only in the HBV-infected group (22.6%), suggesting its role in the susceptibility to HBV. It shares nine genes in common with genotype 6, but lacks KIR2DL2, KIR2DS2, KIR2DS3, KIR2DL5, KIR2DS5, and KIR3DS1 (Table 5).

Effects of centromeric and telomeric motifs and KIR genotype on hepatitis B and C

We identified individual KIR motifs in each study participant based on KIR genes present at their centromeric and telomeric loci, as previously reported (Cooley et al., 2010). Comparisons of the groups of genes present at the telomeric and centromeric loci were performed between the HBV-positive versus uninfected groups and the HCV-positive versus uninfected groups. It was observed that the centromeric A (c-A)/A genotype was significantly more frequent in the HBV-infected group compared with the uninfected group (38.7% vs. 5.9%, p = 0.002, OR = 0.099, 95% confidence interval [CI]: 0.020–0.491), while the c-A/B genotype was more frequent in the uninfected group compared with the HBV-positive group (p = 0.001, OR = 8.51, 95% CI = 2.141–33.83) (Table 6).

Table 6.

Frequencies of Centromeric, Telomeric, and Killer Cell Immunoglobulin-Like Receptor Motifs Stratified by Disease Status

	HBV+, n (%)	HCV+, n (%)	Control, n (%)	OR ^b (95% CI)	p_b	OR ^c (95% CI)	p_c
Centromeric motif
c-A/A	12 (38.7)	0 (0.0)	2 (5.9)	0.1 (0.0-0.5)	0.002^*	1.0 (0.1–7.3)	1.000
c-A/B	17 (54.8)	33 (100.0)	31 (91.2)	8.5 (2.1–33.8)	0.001^*	1.0 (0.2–5.5)	1.000
c-B/B	2 (6.5)	0 (0.0)	1 (2.9)	0.4 (0.3–5.1)	0.602	1.0 (0.6–16.2)	1.000
Telomeric motif
t-A/A	3 (9.7)	0 (0.0)	5 (14.7)	1.6 (0.4–7.4)	0.711	—	—
t-A/B	28 (90.3)	32 (96.9)	28 (82.3)	0.5 (0.1–2.2)	0.480	0.1 (0.0–1.3)	1.020
t-B/B	0 (0.0)	1 (3.0)	1 (2.9)		1.000	1.0 (0.6–16.2)	1.000
KIR haplotype
AA	1 (3.2)	0 (0.0)	1 (2.9)	0.9 (0.5–15.2)	1.000	—	—
Bx	30 (96.7)	33 (100.0)	33 (97.0)	1.1 (0.1–18.4)	1.000	—	—

Thirty-one participants were HBV+, 33 were HCV+, and 34 uninfected controls tested negative for HIV and both hepatitis viruses; p_b: p-value of comparison between HBV+ and uninfected control groups; p_c: p-value of comparison between HCV+ and uninfected controls.

c-A, centromeric A. ^*p-Value is significant.

Discussion

KIRs, alongside their cognate HLA class I ligands, have been associated with several viral infections and autoimmune diseases. In this study, KIR genes and genotypes were characterized in HBV- and HCV-infected and uninfected individuals recruited from two major cities in Cameroon. We investigated the presence of 15 KIR genes using well-defined techniques and observed that all 15 KIR genes were present in our study population.

Reports from sub-Saharan Africa have shown that activating KIR genes are relatively infrequent compared with other populations. In this study, it was observed that the KIR3DS1 gene was least frequent in the hepatitis B-infected group compared with other groups, which is coherent with other reports from sub-Saharan Africa (Norman et al., 2007; Yindom et al., 2010). One plausible interpretation is that KIR3DS1 may offer protection against HBV infection (although in this small sample) of the Cameroonian population. In addition, the inhibitory KIR2DL2 gene may also offer protection against acquisition of HBV, although to a lesser degree than KIR3DS1 in the studied population. This is consistent with data published by Zhi-ming et al. (2008), which showed that KIR3DS1, 2DS2, and 2DL5 are protective genes that facilitate HBV clearance.

Conversely, KIR3DS1 is strongly associated with susceptibility to infection with hepatitis C virus. We found that all but one HCV-positive individual were KIR3DS1 carriers compared with 2/3 of the uninfected group (97.0% vs. 64.7%, respectively, p = 9.21 × 10⁻⁴). Two other activating genes (KIR2DS2 and KIR2DS3) were associated with susceptibility to HCV infection. Both genes were present in all hepatitis C-infected individuals compared with about half (KIR2DS3) or 2/3 (KIR2DS2) of the uninfected group. Other studies with bigger sample sizes are needed to highlight the effects of these genes in HCV and HBV transmission and disease susceptibility.

Thirty-six KIR genotypes were identified with five previously unreported, which might be specific to the Cameroonian population. Haplotype B profiles were the most frequent in our study population. Genotype 6 that possesses all 15 KIR genes was present in a quarter of our sample (25.5%) and appears to significantly predispose its carriers to HCV acquisition.

At the telomeric and centromeric levels, homozygosity for c-A motif (c-A/A) was overrepresented in the hepatitis B individuals, while the heterozygous motif c-A/B was present in all HCV-infected participants. Telomeric motifs, however, were similarly distributed across groups.

Conclusion

Genetic epidemiological studies have shown that host genetic variations significantly modulate viral infections (López-Vázquez et al., 2007; Yindom et al., 2017). However, no study has evaluated the role of KIR genes in viral hepatitis in Cameroon. Although with a small sample size, this study is one of the few to report on the KIR gene frequencies and profiles from Cameroon. We found five potentially novel KIR genotypes, which will be deposited in public databases to contribute to the growing number of KIR haplogroups reported. These data therefore lay the ground for further in vitro studies on the mechanisms of action of host factors against hepatitis B and C infections and could provide useful information for development of better treatments and vaccines.

Footnotes

Author Disclosure Statement

The authors declare they have no conflicting financial interests.

Funding Information

This work was supported by the Chantal Biya International Reference Centre for Research on Prevention and Management of HIV/AIDS (CIRCB).

Supplementary Material

Abbreviations Used

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