A snapshot of genetic lineages of Mycobacterium
tuberculosis in Ireland over a two-year period, 2010 and
M M Fitzgibbon (MFitzgibbon@STJAMES.IE)1, N Gibbons1, E Roycroft1,2, S Jackson3, J O’Donnell3, D O’Flanagan3, T R Rogers1,2
1. Irish Mycobacteria Reference Laboratory, St. James’ Hospital, Dublin, Ireland
2. Department of Clinical Microbiology, Trinity College, Dublin, Ireland
3. Health Protection Surveillance Centre, Dublin, Ireland
Citation style for this article:
Fitzgibbon MM, Gibbons N, Roycroft E, Jackson S, O’Donnell J, O’Flanagan D, Rogers TR. A snapshot of genetic lineages of Mycobacterium tuberculosis in Ireland
over a two-year period, 2010 and 2011. Euro Surveill. 2013;18(3):pii=20367. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20367
Article submitted on 09 July 2012 / published on 17 January 2013
Mycobacterial interspersed repetitive-unit-variable-
number tandem repeat typing alone was used to inves-
tigate the genetic lineages among 361 Mycobacterium
tuberculosis strains circulating in Ireland over a two-
year period, 2010 and 2011. The majority of isolates,
63% (229/361), belonged to lineage 4 (Euro-American),
while lineages 1 (Indo-Oceanic), 2 (East-Asian) and 3
(East-African–Indian) represented 12% of isolates
each (42/361, 45/361, and 45/361, respectively).
Sub-lineages Beijing (lineage 2), East-African–Indian
(lineage 1) and Delhi/central-Asian (lineage 3) pre-
dominated among foreign-born cases, while a higher
proportion of Euro-American lineages were identi-
fied among cases born in Ireland. Eighteen molecu-
lar clusters involving 63 tuberculosis (TB) cases were
identified across four sub-lineages of lineage 4. While
the mean cluster size was 3.5 TB cases, the largest
cluster (involving 12 Irish-born cases) was identified
in the Latin American–Mediterranean sub-lineage.
Clustering of isolates was higher among Irish-born
TB cases (47 of 63 clustered cases), whereas only one
cluster (3/63) involved solely foreign-born individu-
als. Four multidrug-resistant cases identified during
this period represented lineages 2 and 4. This study
provides the first insight into the structure of the M.
tuberculosis population in Ireland.
Tuberculosis (TB) caused by Mycobacterium tuberculo-
sis remains a serious challenge to public health world-
wide. Despite an overall decline in case notification
rates for TB across Europe, rates vary significantly, with
the highest rates reported from eastern Europe and the
Baltic States . Multidrug-resistant (MDR) TB contin-
ues to be a major problem and an added burden in high-
incidence countries such as Romania (108.2/100,000)
and the Baltic states Lithuania (62.1/100,000), Latvia
(43.2/100,000) and Estonia (30.7/100,000) . Ireland
has a low incidence, with notification rates that ranged
between 9.7 and 11.3 per 100,000 population between
2001 and 2010 although to some extent this may have
been influenced by migrants arriving from high-burden
countries [1-2]. In Ireland, TB is a statutorily notifiable
disease, and in a recent report on the epidemiology of
TB in the country, the proportion of culture-confirmed
TB cases was 71.2% in 2009 and 63.2% in 2010 (data
from 2010 were not finalised at the time of submission)
. These proportions are similar to those reported for
previous years .
Disruption of transmission chains is a key factor in
controlling TB both at a national and international
level . In recent years, there have been significant
advances in developing the molecular tools required
for rapid diagnosis of TB . Analysis of variable-num-
ber tandem repeat (VNTR) sequences at mycobacterial
interspersed repetitive units (MIRU) has emerged as a
valuable marker for genotyping strains of the M. tuber-
culosis complex . In large population-based studies,
MIRU-VNTR typing has been shown to have similar dis-
criminatory power when compared to IS6110 restriction
fragment length polymorphism (RFLP) typing [5-7]. An
optimised set of 24 MIRU-VNTR markers has become the
gold standard for genotyping M. tuberculosis complex
strains worldwide [5,7]. MIRU-VNTR typing is a PCR-
based method that yields rapid, reproducible results
that are expressed as a 24-digit numerical code which
allows for easy exchange of data [5-8]. This method
can be applied to early mycobacterial cultures and
more recently has been successfully applied directly to
smear-positive specimens [5,9]. Previous studies have
shown MIRU-VNTR typing to be useful in comparing
strains (i) at national and international level, (ii) among
household contacts, (iii) associated with drug resist-
ance and (iv) to determine the evolutionary pathway
of TB [5-6,10-16]. At European level, MIRU-VNTR typing
has been adopted for the molecular surveillance of the
international transmission of MDR-TB and extensively
drug-resistant TB .
In November 2009, molecular genotyping in the form
of 24-locus MIRU-VNTR typing was introduced at the
Irish Mycobacteria Reference Laboratory (IMRL) which
both cultures and receives isolates from microbiology
laboratories around the country. To allow for rapid,
high-throughput genotyping of M. tuberculosis, the
commercial MIRU-VNTR typing kit (GenoScreen, Lille,
France) was introduced in 2010 [5,7]. As 24-locus MIRU-
VNTR typing is considered the gold standard genotyp-
ing method, all M. tuberculosis isolates identified at
the IMRL are currently typed prospectively with this
method, and it is envisaged that all M. tuberculosis
isolates recovered since 2000 will be typed on a retro-
Here we report the first analysis of the structure of the
M. tuberculosis population in Ireland for isolates recov-
ered during 2010 and 2011 following the introduction
of 24-locus MIRU-VNTR typing to the diagnostic labo-
ratory. It needs to be noted that at the time there was
an under-representation of isolates from the southern
region of Ireland.
M. tuberculosis isolates (n=361) recovered in or referred
to the IMRL over a two-year period (2010–11) were
typed with the MIRU-VNTR typing kit (GenoScreen) .
Validation of the MIRU-VNTR technique was performed
using the MIRU-VNTR Calibration Kit (GenoScreen).
PCR products were subjected to electrophoresis using
a 3130 genetic analyser (Applied Biosystems). Sizing
of fragments and MIRU-VNTR allele assignation was
performed using GeneMapper software (Applied
Biosystems). Phylogenetic lineages were assigned
to each isolate using the MIRU-VNTRplus online tool
The 24-locus MIRU-VNTR panel comprised the follow-
ing loci: MIRU 02, VNTR 42, VNTR 43, MIRU 04, MIRU
40, MIRU 10, MIRU 16, VNTR 1955, MIRU 20, QUB 11b,
ETR A, VNTR 46, VNTR 47, VNTR 48, MIRU 23, MIRU 24,
MIRU 26, MIRU 27, VNTR 49, MIRU 31, VNTR 52, QUB
26, VNTR 53, and MIRU 39. The MIRU-VNTR profiles are
reported as a series of 24 numbers that correspond
to the number of alleles at each of the loci described
Clusters of isolates were defined as two or more iso-
lates with indistinguishable MIRU-VNTR patterns. The
strain clustering rate was calculated as (nc-c)/n, where
nc was the total number of strain-clustered cases, c
was the number of clusters and n was the total number
of isolates .
Enhanced surveillance of TB was implemented in
Ireland in 1998. Enhanced TB notification forms are
completed by public health doctors, summarising all
available clinical, microbiological, histological and epi-
demiological information. These data are collated in
the regional public health departments. Anonymised
data are then submitted electronically to the Health
Protection Surveillance Centre (HPSC) for the produc-
tion of reports on a weekly, quarterly and annual basis.
Since January 2011, cases of TB have been reported
through the Computerised Infectious Disease Reporting
system (CIDR). CIDR is a web-based system developed
to integrate case-based clinical and laboratory data in
order to manage the surveillance and control of notifi-
able infectious diseases in Ireland. Prior to using CIDR
for TB surveillance, MIRU-VNTR typing results were not
linked to case-based epidemiological data. In addition
to recording sporadic case-based data, CIDR also facil-
itates the reporting of clustered cases, according to
Irish outbreak case definitions . Clustered cases can
be reported via a summary aggregate outbreak data
module to which the relevant disaggregate case-based
surveillance data can also be linked.
The TB enhanced surveillance data for 2011 (epidemio-
logical and linked laboratory data) used in this publica-
tion were extracted from CIDR on 17 April 2012 using
Business Objects XI software and were analysed using
Microsoft Excel. Data for 2011 were provisional at the
time of extraction and subject to ongoing validation
Results are presented in two separate sections. In the
first part, genotyping results for isolates recovered in
2010–11 are presented. As epidemiological data link-
ing was available from 2011 onwards, the second part
of the results section (enhanced surveillance) refers to
genotyping results linked to epidemiological data for
2011 isolates only.
Some 361 M. tuberculosis isolates were recovered
in or referred to the IMRL during 2010–11, represent-
ing 63.6% of culture-positive cases identified through
the national TB surveillance system in that period.
Genotyping of M. tuberculosis isolates recovered dur-
ing the study period yielded four global lineages
(Table 1). The majority (63%) belonged to lineage 4
(Euro-American), while lineages 1 (Indo-Oceanic), 2
(East-Asian) and 3 (East-African–Indian) represented
12% each. Among the 229 Euro-American strains, sub-
lineages Latin American–Mediterranean (LAM) (23%),
Haarlem (21%), H37Rv (19%) and Haarlem/X (13%) were
most prevalent (Table 1).
Within lineage 4, 18 clusters were identified involving
63 TB cases (Table 2). The strain clustering rate varied
between different sub-lineages, but was highest for
the LAM sub-lineage (6.9%). While the mean cluster
size was 3.5 TB cases, the largest cluster (involving 12
Irish-born cases, representing 19% of all clustered iso-
lates) was identified within the LAM sub-lineage (Table
2). Four other clusters within the LAM sub-lineage con-
tained between 4.7% (3/63) and 12.7% (8/63) of clus-
tered cases. Among the clustered cases of Haarlem,
H37Rv and Haarlem/X, cluster sizes ranged from 3.2
to 9.5%, at 3.2% and from 3.2 to 4.7% of isolates,
Only one cluster (3/63) contained exclusively foreign-
born individuals, 12 clusters (47/63) involved Irish-
born cases only, while five clusters (13/63) were mixed.
In addition, one small cluster was observed among the
isolates from lineage 2.
The four MDR-TB cases identified during this period
represented lineages 2 (Beijing) and 4 (Ural, H37Rv and
LAM). None of the MDR-TB cases were clustered.
Tuberculosis enhanced surveillance data for
2011 isolates (epidemiological and laboratory)
In 2011, 432 TB cases were provisionally reported on
CIDR, of which approximately 166 (38%) were typed. At
the time of data extraction, 136 TB cases were updated
to include MIRU typing results (representing 81.9% of
166 typed isolates). Of the 136 TB cases with a MIRU
typing result, 34 were clustered in 11 clusters with dif-
ferent MIRU types. Clusters ranged in size from eight to
two TB cases. Of the 11 MIRU type clusters, five, com-
prising 18 TB cases, were confirmed by public health
departments as outbreaks meeting the Irish case
The Beijing sub-lineage was most prevalent (15.4%)
and associated with a small cluster. Sub-lineages
Haarlem, LAM, and H37Rv were most prevalent among
lineage 4 strains, while lineage 1 and lineage 3 rep-
resented 11.8% and 10.3% of typed isolates, respec-
tively. Interestingly, isolates recovered from pulmonary
specimens were mostly correlated with lineage 4
strains, while the majority of isolates recovered from
extra-pulmonary specimens belonged to lineages 1 and
3 (Figure 1). In lineage 3, nine of 14 isolates were recov-
ered from patients born in Pakistan, while the remain-
ing five isolates were recovered from patients born in
India (n=2), Kenya (n=1), Nepal (n=1) and Nigeria (n=1).
Only one lineage 1 isolate was recovered from an Irish-
born patient, while six were recovered from patients
born in the Philippines. Other countries represented
among lineage 1 isolates were Bangladesh, India,
Mozambique, Pakistan, Somalia and Vietnam.
The distribution of lineages among Irish-born and for-
eign-born TB cases is shown in Figure 2. Of the 127 TB
cases for whom MIRU-VNTR and country of birth were
known, 51.5% were foreign-born and 41% were Irish-
born. Lineages 1, 2 and 3 predominated among foreign-
born TB cases, while a higher proportion of lineage 4
isolates were identified among Irish-born cases.
This study has provided a snapshot of the genetic diver-
sity of M. tuberculosis in Ireland. Due to the small num-
bers of isolates in our study, statistical analysis would
not be significant and was not performed. Although
data on sub-lineages were analysed by age and sex,
the resulting frequencies were too small to draw firm
conclusions from. However, when age and sex analyses
were further stratified by country of birth, these data
were broadly similar to the age and sex profile of the
Irish TB notification data.
A large diverse group of isolates has been identified,
suggesting a low degree of active transmission among
TB patients. The distribution of genetic lineages is sim-
ilar to other recent studies that used different typing
techniques and in which lineage 4 (Euro-American) pre-
dominated among circulating M. tuberculosis strains
[12,19-21]. In previous work conducted in the south-
west region of Ireland, lineage 4 predominated, and
clustering of isolates was associated with Irish nation-
als and lineage 4 isolates only . In our study, the
distribution of genetic lineages among extra-pulmo-
nary specimens (where lineages 1 and 3 predominated)
was similar to a recently published large-scale study
conducted in the United States (US) investigating the
relationship between genetic lineages and clinical
sites of infection . In the US study, the highest per-
centage of isolates recovered from extra-pulmonary
Distribution of lineages among Mycobacterium
tuberculosis isolates, Ireland, 2010–11 (n=361)
3 East–African–Indian Delhi/central-Asian
Lineage 4 total
Uganda I & II
a The category Others includes isolates for which the sub-lineages
were not clearly defined
specimens was from lineages 1 (22.6%) and 3 (34.3%)
. However, due to the small numbers of exclusive
extra-pulmonary specimens (n=30) and limited epide-
miological data, statistical analysis of the relationship
between lineage and clinical site of infection was not
possible in our report.
Molecular clustering of isolates in our study was more
common among Irish-born individuals. These findings
were similar to a previous Irish study conducted by Ojo
et al. in the south-west region of Ireland, but unlike
a recent study conducted in Switzerland [12,22]. We
identified 18 clusters in lineage 4, and the mean clus-
ter size was 3.5 TB cases. The largest cluster, involving
12 TB cases, belonged to the LAM lineage and spanned
a period of 18 months. A second cluster identified in
the LAM lineage differed by a single locus variant (SLV)
at locus 2996. Similarly, in the Haarlem lineage, the
two largest clusters differed by a SLV at locus 2996
also. MIRU 26 (or locus 2996) has yielded stable com-
parable results in a large-scale study investigating
824 M. tuberculosis isolates conducted at the Institut
Pasteur de Lille, France, in 2006 . Molecular typing
played a key role in identifying a dominant M. tubercu-
losis strain (known as the Mercian strain) circulating in
the West Midlands region in the United Kingdom (UK)
over a five-year period, highlighting the importance of
cluster analysis . Prospective molecular typing can
identify rapidly expanding clusters of M. tuberculosis
before they spread further into the community. A sin-
gle dominant MIRU-VNTR type was not observed in this
study, however, this could be due to the study period
being short. In contrast, prospective molecular typing
of M. tuberculosis by RFLP, performed since 1993 in the
Netherlands, has proven to be effective. DNA finger-
printing data has been shown to be a powerful tool in
defining epidemiological links and guiding TB control
programmes in the Netherlands [24-25].
Another limitation of this study is that only one typing
method was used to investigate the M. tuberculosis
population structure in Ireland. Previous studies have
shown that a combination of MIRU-VNTR typing and
spoligotyping can differentiate more readily between
M. tuberculosis strains [26-27]. However, in a previous
Irish study using both spoligotyping and MIRU-VNTR
typing, MIRU-VNTR typing identified clusters among
spoligotype groups, thus providing supporting evi-
dence that MIRU-VNTR typing is a more discriminatory
typing method . The discriminatory power of the
24-locus MIRU-VNTR panel used in this study has shown
to be similar to IS6110 RFLP analysis . However, the
discriminatory power of 24-locus MIRU-VNTR typing
differs among genetic lineages, and the inclusion of
Clusters of Mycobacterium tuberculosis isolates within lineage 4 (Euro-American), Ireland, 2010–11 (n=172 isolates)
No. of isolates/
Latin American–Mediterranean5230 (8.3)56.9
H37Rv 44 8 (2.2)41.1
Haarlem/X 29 7 (1.9)31.1
Total clustered lineage 4 cases172 6318 -
a The numbers in this 24-digit profile correspond to the number of alleles at each of the following loci: MIRU 02, VNTR 42, VNTR 43, MIRU 04,
MIRU 40, MIRU 10, MIRU 16, VNTR 1955, MIRU 20, QUB 11b, ETR A, VNTR 46, VNTR 47, VNTR 48, MIRU 23, MIRU 24, MIRU 26, MIRU 27, VNTR
49, MIRU 31, VNTR 52, QUB 26, VNTR 53, MIRU 39.
Distribution of Mycobacterium tuberculosis lineages by site of infection, Ireland, 2011 (n=136)
CAS: central-Asian; EAI: east-African–Indian; LAM: Latin American–Mediterranean.
Number of cases
Distribution of lineages among Irish and non-Irish typed Mycobacterium tuberculosis cases, Ireland, 2011 (n=127)
CAS: central-Asian; EAI: east-African–Indian; LAM: Latin American–Mediterranean.
7114346 13 14611
Number of cases
additional hypervariable loci may be required to dif-
ferentiate among strains of lineages 2 (Beijing) and 3
(Delhi/central-Asian). For enhanced cluster or outbreak
analysis, whole-genome sequencing has been shown
to differentiate among strains with identical 24-locus
MIRU-VNTR patterns [28-29]. The role of whole-genome
sequencing in investigating community outbreaks in
the UK was reported recently . Walker et al. esti-
mated that the rate of genetic changes was 0.5 single
nucleotide polymorphisms (SNPs) per genome per year.
Furthermore, the maximum number of genetic changes
over three years would be five SNPs and 10 SNPs over
10 years . It has also been proposed that clustering
of isolates increases over longer periods as transmis-
sion chains are more efficiently analysed and reported
. But the M. tuberculosis genotype involved in the
cluster must be considered as for example the Beijing
lineage has increased ability to spread and cause dis-
ease. While clustering was limited in our study, the
study period was too short to draw clear conclusions.
Although the reproducibility of MIRU-VNTR typing has
been well documented, results from the first world-
wide proficiency study on this method were surprising
. Intra- and inter- laboratory reproducibility varied
depending on the typing methods employed in each
laboratory. In our setting, when the commercial MIRU-
VNTR typing kit was used to analyse the quality control
panel, 100% concordance was achieved with the refer-
ence data (30/30 tested strains) and 100% intra-labo-
ratory reproducibility was achieved. These findings are
important to consider when typing data is exchanged
Although six of the 11 MIRU typing clusters identified
during 2011 were not confirmed as outbreaks by pub-
lic health departments, it is possible that the reason
why four of these clusters did not meet the Irish TB out-
break case definitions was the small number (n=2) of
involved cases .
In summary, this study has provided the first insights
into the structure of the M. tuberculosis population in
Ireland. Although the incidence of TB has remained
static in Ireland over the last decade, there has been
mass immigration to this island nation. Not surpris-
ingly, lineage 4 predominated among circulating strains
of M. tuberculosis in the present study. But the degree
of diversity among M. tuberculosis was unexpected.
Future studies in the IMRL involving retrospective gen-
otyping analysis of M. tuberculosis isolates collected
since 2000 may provide an interesting epidemiologi-
cal picture. Continued molecular surveillance is impor-
tant as it has been suggested that the transmissibility
profile of M. tuberculosis strains may be influenced by
their genetic and evolutionary background. This under-
standing of the dynamics of M. tuberculosis strains will
provide novel insights into the M. tuberculosis popula-
tion structure and how it relates to the epidemiology of
TB in Europe and beyond.
The authors would like to thank all the departments of public
health, clinicians and laboratories for providing the surveil-
lance data on these TB cases.
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