HPE Alpha 1 Antitrypsin Deficiency | Page 11

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 hospitalpharmacyeurope.com | 2019 | 11