Human genetic variation can influence treatment prognosis for hepatitis C virus (HCV). A single nucleotide polymorphism near the IFNL3 gene indicates natural resistance to type 1 HCV, with the T variant associated with poorer treatment outcomes. Additionally, a polymorphism in the interleukin-23 receptor gene correlates with reduced risk of HCV-related liver cancer. HCV appears to have evolved to benefit from allelic variations between geographic regions. Future treatment may focus on precise virus-genome interactions. Mapping the entire human genome could increase understanding of connections between HCV and its human host.

1. Human genetic variation in the context of
hepatitis C virus treatment prognosis
Barker J., Chambers S., Dada O., Islam R., Sergejeva K., Steijl B., Vandra P.1
1 Work carried out: Barker, Background research, image adaptation, evolutionary significance text, abstract; Chambers, background research, abstract; Dada, background research, abstract; Islam, background research, types of variation text, abstract; Sergejeva, background research,
conclusion; Steijl, background research, image adaptation, case study text, editing, poster layout, abstract; Vandra, background research.
Case study: hepatocellular carcinoma in hepatitis C patients
Recent research has identified a number of human genetic variants that appear to affect people’s chances of being able to fight off Hepatitis C Virus
(HCV), with or even without treatment. The chronic inflammation and cell death/regeneration cycle caused by HCV make the disease a major risk factor
for the development of hepatocellular carcinoma (Oliveria Andrade et al 2009). The interleukin 3 receptor (IL-23R) gene has been reported to affect
prognosis: Labib et al (2015) found that the polymorphism GG at position rs11209026 (R381Q, changing arginine 381 into a glutamine) correlated with a
statistically significant reduction in risk of HCV-related hepatocellular carcinoma in patients with HCC compared to both HCV patients without HCC (p =
0.003) and a healthy control group (p <0.001) (Table 1). Interleukin 23 (IL-23) is thought to contribute to autoimmune and inflammatory disease. A study
(Safrany et al) has found that the glutamine variant at rs11209026 affects the functioning of the IL-23R transducing pathway, reducing its response to IL-
23 and preventing the proliferation of T-helper 17 cells, which play a key role in inflammatory response. This in turn is thought to prevent the
development of tumours.
References
Frazer K.A. et al (2009) Human genetic variation and its contribution to complex traits, Nature Reviews Genetics, Volume
10, pp241-251.
Labib H.A. et al (2015) Genetic polymorphism of IL-23R influences susceptibility to HCV-related hepatocellular carcinoma,
Cellular Immunology, Volume 294(1), pp 21-24.
Oliveria Andrade L.J. et al (2009) Association between hepatitis C and hepatocellular carcinoma, Journal of Global
Infectious Diseases, Volume 1(1), pp 33-37.
Safrany E. et al (2009) Variants of the IL23R gene are associated with ankylosing spondylitis but not with Sjögren
syndrome in Hungarian population samples, Scandinavian Journal of Immunology, Volume 70(1), pp 68-74.
Rose R. et al (2013) Viral evolution explains the associations among hepatitis C virus genotype, clinical outcomes, and
human genetic variation, Infection, Genetics and Evolution, Volume 20, pp 418-421.
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https://www.genome.gov/Pages/Education/Modules/GeneticVariation.pdf [Accessed: 17th May 2015].
Wikipedia (2015) Single Nucleotide Polymorphism. [Online] May 2015. Available from: http://en.wikipedia.org/wiki/Single-
nucleotide_polymorphism. [Accessed 26 May 2015].
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http://en.wikipedia.org/wiki/Human_genetic_variation. [Accessed 16th May 2015].
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http://www.yourgenome.org/facts/what-is-genetic-variation. [Accessed 25 May 2015].
Human genetic variation and HCV
Six different strains of hepatitis C virus (HCV) have been
identified in humans; these are generally described as
genotypes 1-6. The strain infecting a patient can affect
treatment prognosis, with types 1 and 4 typically having a
poorer prognosis than types 2 and 3. Furthermore, a single
nucleotide polymorphism (SNP) at position rs12979860,
located near the IFNL3 gene, appears to be a strong indicator
of natural resistance to type 1 HCV, with a T at this position
indicative of a poorer treatment outcome than a C at this
position. Rose et al (2013) posited that this particular variant is
most common in central and east Africa, and least common in
south east Asia (Figure 1), with prevalence closely linked to the
geographical region in which types 1 and 4 HCV evolved. By
comparison, types 2 and 3 HCV, which do not appear to be
affected by this polymorphism, evolved in west Africa and
south Asia respectively, where incidence of the T variant is
much lower. It is therefore argued that the evolution of the HCV
virus has been driven by this genetic variability in regions
where the adaptation resulted in improved viral survival.
Figure 24. Global occurrence of T vs C allele at position
rs12979860 against origins of the six main types of hepatitis
C virus. Incidence of the T allele is highest in geographic
regions where this results in poor treatment prognosis for the
most prevalent strain of HCV.
4 Adapted from Rose et al (2013).
Types of genetic variation
There are several forms of human genetic variation. The most common type are single nucleotide
polymorphisms (SNPs), with an estimated occurrence of ~11 million in the genome (Frazer et al 2009)
(Figure 1), of which ~7 million occur with a minor allele frequency (MAF) of more than 5%; the remainder
has a MAF of 1-5%. These are considered ‘common’, whereas a MAF of <1% indicates a ‘rare’ variant.
Additionally, SNPs located in the same region of a chromosome are often correlated in linkage
disequilibrium (LD), caused by infrequent genetic recombination. ‘LD bins’ are groups of SNPs that are
often inherited together; many of these have been identified by the International HapMap Project, which
has been able to group most of the very common (>5% MAF) SNPs into just ~550,000 bins for people of
European and Asian ancestry, and ~1.1 million for those of African ancestry.
All other variation falls under ‘structural variation’: this includes insertions and deletions (indels), and
block substitions, which consist of variation in a string of adjacent nucleotides. Copy number variation
(CNV), in which one or more nucleotides appear repeatedly in part of the population, is another type of
structural variation. The latter accounts for ~13% of the human genome, with individual CNVs spanning
up to 1kb. Finally, inversions, whereby a string of nucleotides appears in reverse order in some
individuals, are perhaps the least common type of structural variation, but such sections can be as long
as 900kb. Knowledge of the locations and frequencies of structural variation in the genome remains
limited, and cataloguing these variations is a key priority. Furthermore, identifying the role of many genetic
variants is exceedingly difficult as most variations are not thought to contribute to phenotypic diversity.
Abstract
 Genetic variation among individual humans is estimated between 0.1-0.5%, although this includes
only coding DNA, which constitutes only 2% of the human genome. The remainder consists of non-
coding genes, which were once believed to be ‘junk’ DNA. However, recent research suggests that
variation in non-coding regions is as relevant to complex diseases as that in coding sequences.
 Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation. However,
structural variation, which includes all variation incorporating more than a single nucleotide, accounts
for a far greater proportion of genomic variation in terms of the number of nucleotides involved.
 Here we present a case study in which human genetic variation has been found to influence the
treatment prognosis in patients affected by hepatitis C virus. It is speculated that HCV has evolved to
benefit from allelic variation across geographic regions; additionally, risk factors for the development
of hepatocellular carcinoma are found to be linked to genetic variation in the interleukin-23 receptor
gene.
Conclusions
 HCV has accumulated changes over time as a result of selection
pressures including human genetic variation across geographic
regions.
 Future treatment design is likely to focus on the precise interactions
between the virus and the human genome.
 The complete mapping of the human genome will increase
possibilities for the analysis of connections between HCV and its
human host.
Evolutionary significance
Human genetics is the study of inherited genetic variation. Any two humans are genetically 99.5% similar,
however it’s the 0.5% of variation between humans which is of increasing scientific interest today.
Over time genetic variation within and between human populations has produced a vast range of
observable human phenotypes, each influenced by genes, gene-expression, and the environment. Under
different selective pressures, genotypes conferring adaptive advantage result in higher frequencies of
advantageous alleles in different populations over time, while genotypes predisposing weakness, disease
vulnerability and death reduce. Variation of alleles within populations typically arises from random changes
in the gene pool, while variation between populations is commonly observed in geographically distant
and/or ancestrally removed groups (Wikipedia, 2015).
Understanding human genetic variation is significant for both evolutionary studies and future medical
advancements. Sequencing of ancient and modern human DNA helps explain genetic changes in humans
over time as well as the relationships between ancient and geographically separate populations, each
possessing different disease-susceptibility profiles. Understanding these relationships aids medical
progression by identifying linkages between genetic sequences and disease so that therapies can be
identified. Such medical developments are key to improving the health and well-being of the human species
in the future (National Human Genome Research, 2015).
Table 13. Genotype and allelic frequencies of rs11209026 G>A
polymorphism in HCV patients with and without hepatocellular
carcinoma against control group.
3 Adapted from Labib et al (2015)
Control
(n = 100)
HCV, no HCC
(n = 92)
HCV, with HCC
(n = 100)
Allele
frequency
n (%) n (%) n (%)
G
A
167 (83.5)
33 (16.5)
163 (88.6)
21 (11.4)
195 (97.5)
5 (2.5)
Genotypes
GG
GA
AA
73 (73)
21 (21)
6 (6)
75 (81.5)
13 (14.1)
4 (4.4)
95 (95)
5 (5)
0 (0)
Recessive
model
GG
GA + AA
73 (73)
27 (27)
75 (81.5)
17 (18.5)
95 (95)
5 (5)
Figure 12. Using the identification of single nucleotide polymorphisms to determine treatment prognosis.
2 Adapted from Medscape (2015)