EPIDEMIOLOGY
Searching for a needle
in a haystack
Because Alpha 1 Antitrypsin Deficiency (AATD) is still largely underdiagnosed (<10% of what would
be expected from epidemiological data), early detection of AATD subjects remains a primary concern
and must be conducted in reference centres that can provide the best diagnostic tools
Stefania Ottaviani PhD
Angelo Guido Corsico
MD PhD
Ilaria Ferrarotti PhD
Center for Diagnosis
of Inherited Alpha1-
antitrypsin Deficiency
Dept of Internal Medicine
and Therapeutics,
Pneumology Unit
IRCCS San Matteo
Hospital Foundation
University of Pavia, Italy
Alpha 1 Antitrypsin Deficiency (AATD) is
a relatively common genetic condition, which
is often undiagnosed or misdiagnosed. Severe
deficiency is usually associated with the
homozygous PI*ZZ allele combination, but the
clinical expression of other deficient allele
combinations is less well characterised, with PI*SZ
being the most frequent among these combinations. 1
In an attempt to estimate the number of AATD
patients worldwide, Blanco and colleagues studied
cohorts selected from 65 of the 193 countries
globally. 2 They estimated a total of 253,404 Pi*ZZ
worldwide, in the following distribution: Europe,
47.2%; USA, 36.1%; Asia,12.7%; Africa, 1.5%; Australia
1.6%; and, New Zealand 0.9%. Of the almost 120,000
subjects identified as carrying the Pi*ZZ genotype
in Europe, most were found in Germany (20,611),
France (17,191), the Iberian Peninsula (14,522 in
Spain and 4944 in Portugal), the UK (13,044), Italy
(10,652), Poland (6791), The Netherlands (5353),
Denmark (4090), Latvia (4005), Belgium (3193),
and lower numbers were observed in other
European countries. 2
Prevalence of S and Z mutations
Europe
A total of 262 cohorts from 71 countries were
included in the analysis to estimate the prevalence
and the number of SZ subjects worldwide. With the
data provided by these cohorts, a total of 1,490,816
Pi*SZ were estimated: 47.5% in Europe, 39.1% in
America and the Caribbean, 5.8% in Africa, 5.2%
in Asia, and 2.4% in Australia and New Zealand.
By individual countries, the highest numbers
were found in Spain (174,822), followed by France
(161,680), UK (73,973), Italy (64,137), Germany
(60,396), and Portugal (52,836). SZ numbers in the
other countries were very variable, but always much
lower than those mentioned above. 3
Throughout Europe, the frequency of the
Z and S mutations varies widely between countries,
geographic regions, and ethnic groups. The
frequency of the Z variant is highest in Northern
and Western European countries, with a mean gene
frequency of 0.014, peaking in southern Scandinavia
with a gene frequency of >0.02. The prevalence
of PI*Z gradually decreases throughout European
countries in a north–west to south–east direction,
the lowest figures being recorded in eastern Europe
(0.0092). The highest frequency of the S allele is
found in the Iberian Peninsula, with a mean gene
frequency of 0.0564, suggesting the mutation is
likely to have arisen in that region. The prevalence
of PI*S gradually decreases along a south–west to
north–east gradient (0.0176). 4 It has been calculated
that the frequency of the PI*S gene in Spain is
104/1000 inhabitants and that of the PI*Z gene
is 17/1000 inhabitants, with a total of 145,000
PI*SZ and 12,000 PI*ZZ individuals having been
estimated. 5
Based on the number of patients with AATD
(repeatedly coded in 2012 and 2013) and on
the German population data from the Federal
Statistical Office (80,767,500 inhabitants in 2013),
the estimated number of individuals with AATD in
Germany, independent of genotype or health status,
TABLE 1
Allele frequencies in different populations of Exome aggregation Consortium (ExAC) for the major
Population
Sample size
Z
c.1096 G>A
S
c.860 A>T
I
c.187 C>T
Europe
73,284 0.0183 0.0284 0.0004
Asian
25,142
0.00 0.00 0.00
American
11,578 0.0031 0.0219 0.0002
African
10,406 0.0034 0.0078 0.00
Other
978 0.001
0.002 0.00
Global 121,316 0.01170 0.02007 0.00027
Z: name of the allele based on the position in the IEF gel; c.1096: site of the mutation in the cDNA; G>A: base change from guanine to adenine at position; A>T: base change from adenine to thymine;
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