was 19,162. The prevalence of AATD in the German
population was 23.73 per 100,000 in all age groups
and 29.36 per 100,000 in those individuals aged
≥30 years. 6
Other
In Saudi Arabia, the prevalence of PI*S and PI*Z was
21.8% and 7.7%, respectively, in 1000 COPD patients,
while within 1000 normal samples, these alleles
occurred in 8.9% of patients for PI*S and 1.6% for
PI*Z. The AATD genotype frequencies (PI*ZZ, PI*SS,
and PI*SZ) were 6.5 per 1000 and 87 per 1000 for
normal and COPD-affected Saudi individuals. 7
In North America, Australia and New Zealand,
S and Z allele frequencies are a reflection of the
European Caucasian population frequency, with
intermediate and high values of both genes. High Z
allele frequencies are found in Afghanistan, where
the Pashtuns, an ethnic group that constitutes up
to 42% of the Afghan population, have an Indo-
European ethnic origin. Both S and Z alleles are rare
in Asians and Australian aboriginals. 8
A study conducted in the COPD Kazakh
population demonstrates that AATD is present in
Kazakhistan. Genotyping of 187 samples revealed
3 (1.6%) PI*MZ and 1 (0.53%) PI*MS. Phenotyping
identified also two samples (1.1%) with the rare
deficiency variant I (frequency 1.1%). 9
Seyama and colleagues recently confirmed the
extreme rarity of AATD in Japan, mainly caused by
the Siiyama variant. 10
Rare alleles
Beside the two most common deficient alleles,
S and Z, an ever-increasing number of ‘rare variants’
have been discovered and characterised.
Many rare alleles result from different molecular
mechanisms, including large gene deletions,
intron mutations, nonsense mutations, frameshift
mutations due to small insertions or deletions,
and missense mutations associated with amino
acid substitutions in potentially critical structural
elements. Because these mutations are difficult to
find with the usual genotype/phenotype methods,
rare alleles can only be detected by molecular
biology techniques, such as genome sequencing,
which are not routinely available in all
laboratories. 11
Rare variants are frequent in Central and
Southern Italy, where the Mmalton variant
(particularly in Sardinia) and the Mprocida variant
are more prevalent than PI*Z. 12
The World Health
Organization
guidance for
testing every
patient with
a diagnosis of
COPD or adult-
onset asthma for
AATD should be
standard
The higher number of PI*SZ and rare variants in
the Spanish Registry of Patients with AAT (REDAAT)
is most likely related to a higher prevalence of the
S allele in the Spanish population or even some
of the rare alleles as in other Mediterranean
areas. 13,14 For example, the Alpha One International
Registry (AIR) has 11% of PI*SZ and only 1% of rare
variants and the American Registry of the Alpha
One Foundation (AOF) includes 70% of PI*ZZ, but
heterozygotes MZ are also included. 15,16
The development of national registries of
patients with AATD has increased knowledge of
epidemiology of severe AATD genotypes.
In Italy, a total of 422 adult subjects with severe
AATD were enrolled in the Registry with the
following genotypes: PI*ZZ (61.1%), PI*SZ (17.5%),
PI*SS (0.9%) and other genotypes with one rare
deficient/Null allele (R) in combination with an
S or Z allele, or with two rare deficient/Null alleles
(20,4%). The 20.4% frequency for AATD patients with
at least one deficient rare variant is the highest so
far recorded in National registries of AATD. 17
The high percentage of rare mutations recorded
in the Italian registry is probably due to both the
very different genetic component of the Italian
population and the completeness of the diagnostic
procedure. 12
In the REDAAT, the adult population consisted
of 469 individuals, comprising 74.2% PI*ZZ, 21.3%
PI*SZ and 4.5% of whom were carriers of rare
variants. 18
Fregonese and colleagues genotyped all known
Dutch subjects with absent serum AAT, and
compared their lung function values (FEV1 and KCO)
with those of individuals with ZZ and SZ genotype,
matched for age and smoking history. All subjects
with absent serum AAT presented homozygous Null
mutations. The study showed that serum levels of
AAT are correlated with the severity of emphysema.
Subjects with Null mutations should be considered
a subgroup at particularly high risk of emphysema
within AATD. Early detection of carriers of this
genotype would be important for preventive and
therapeutic interventions. 19
The Irish National Targeted Detection Programe
identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS and
22 subjects carrying at least a rare allele. Moreover,
the analysis of 1100 randomly selected individuals
identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. 20
This data showed how AATD in Ireland is more
prevalent than previously estimated 21 with Z and S
allele frequencies among the highest in the world.
AATD pathological variants (from www.ncbi.nlm.nih.gov/snp)
F
c.739 C>T
Plowell
c.839 A>T
Mwurzburg/Mheerlen Mmalton
c.1177C>T /c.1178C>T
c.227_229 del
Mprocida
c.194 C>T
0.0045 0.0006 0.0015 0.0001 0.0001
0.00 0.00 0.0002
0.0002
0.00
0.0002 0.0004 0.0003 0.0006 0.00
0.0013 0.00
0.0002 0.0001 0.00
0.00 0.00 0.00 0.00 0.00
0.00288 0.00044 0.00097 0.00018 0.00004
C>T: base change from cytosine to thymine
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