Alpha1-Antitrypsin Polymorphism in Fibromyalgia Syndrome Patients from the Asturias Province in Northern Spain: A Significantly Higher Prevalence of the PI*Z Deficiency Allele in Patients Than in the General Population

Abstract

Background: Recent evidence suggests that the alpha1-antitrypsin [AT] gene may play a role in the pathogenesis of the fibromyalgia syndrome [FMS]. The objective of the present study is to compare the AT gene frequency between FMS patients and the general population [GP] from the central region of the Asturias Province in Northern Spain.Method: The AT proteinase inhibitor phenotypes were characterized by isoelectric focusing on serum from a cohort of 250 individual FMS subjects, who fulfilled the American College of Rheumatology criteria for FMS, and on serum from a control cohort of 1,111 GP subjects. The FMS subjects [238 females and 12 males] were enlisted from an outpatient hospital clinic setting. The mean age of the FMS cohort was of 49.02 years. The GP control cohort [45 percent males and 55 percent females] was enrolled using an epidemiological technique of simple random sampling in the general population from the same region of Asturias. The GP sample size was 1,111, the mean age was of 46.2 years. Mean outcome measures were AT-PI phenotyping characterization [performed by isoelectric focusing] and AT serum concentration [measured by nephelometry]. Results: Calculated mean allele frequencies for PI*S and PI*Z [the two most frequent AT deficiency alleles] were 64 [95 percent confidence interval [CI]: 45-90] and 40 [CI: 25-62] per 1,000, respectively, for the FMS cohort, as compared with 100 [CI: 88-113] and 19.7 [CI: 14.5-26.6] per 1,000 for the GP cohort. Calculated prevalences [Hardy-Weinberg statistics formula] were 1/14 in FMS versus 1/29 in GP for MZ; 1/195 in FMS versus 1/254 in GP for SZ; and 1/625 in FMS versus 1/2,573 in GP for ZZ. For PI*Z, the calculated odd ratio among FMS versus GP was 2.06 [CI: 1.16-3.63]. A binomial proof [contrast hypothesis] stated that FMS AT-Z gene frequency differed significantly from the GP Z gene frequency [P = 0.007].Conclusion: The most common AT severe-deficient allele [i.e., PI*Z] has been found with a two-fold higher frequency in the FMS cohort than in the GP cohort. The high odds ratio found for PI*Z indicates a significant difference for PI*Z frequency in the FMS cohort as compared with the GP cohort. Our findings suggest that AT deficiency might play an important role in FMS development and clinical expression in, at least, a subset of FMS subjects.

The phenotypic and genetic signatures of common musculoskeletal pain conditions

“…Several MHC class I and II antigens, including HLA-B58, HLA-DR4, HLA-DR5 and HLA-DR8 , have been associated with chronic pain, 103,104 although these findings have not been consistently replicated. 105 Inflammatory mechanisms have also been investigated, with notable findings for the α 1 -antitrypsin gene, SERPINA1 ; in Spanish 106 and US 107 cohorts, the Z allele of SERPINA1 , which enables production of only limited amounts of α 1 -antitrypsin, was more frequent in patients with fibromyalgia than in the general population.…”

Estimates of the Prevalence and Number of Fibromyalgia Syndrome Patients and Their Alpha-1 Antitrypsin Phenotypic Distribution in Ten Countries

“…Combined PFS of these cohorts was 5. (18), evidencing that PI*Z allele had a twice higher frequency in FMS patients than in the general population [ Table 1], was rejected for the present analysis because these FMS patients suffered severe FMS, and supposing that AAT deficiency could be related to severe FMS, this fact could result in the aggregation of Z genes.…”

“…The calculated statistical value of mean PFS for the study on Swedish Caucasians was 8.8. Gene frequency for PI*S allele was 24 [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and 23 [17][18][19][20][21][22][23][24][25][26][27][28][29][30] for PI*Z per 1,000.…”

“…So far, the risk for the development of FMS in AAT deficiency patients has not yet been studied. The only existing study in Asturian patients with moderate-severe FMS has shown an intracellular accumulation of AAT, whereas no significant differences were found among the four subgroups [ Recently, evidence from several clinical, epidemiological, and muscle biopsy studies have been found in favor of a relationship between AAT and FMS (16)(17)(18). Taken together, these findings would suggest that AAT deficiency might play an important role in at least a subset of FMS patients, most likely because of the loss of AAT anti-inflammatory efficacy.…”

“…A possible relationship between Z-AAT deficiency and FMS has been recently reported (16)(17)(18)(19), on the basis of: 1. a clinical alert, consisting in the repetitive positive response of FMS symptoms to AAT replacementtherapy in two ZZ FMS patients (16), 2. the finding of abnormal muscle and endothelium deposits of AAT in the muscle biopsy of an FMS patient with AAT-MZ deficiency (17) (17) showing AAT deposits in both the lumen and the endothelium of muscle small vessels and myofibrils, as well as different degrees of muscle atrophy in FMS patients with AAT deficiency [ Table 2]. These abnormal findings were much more remarkable in FMS patients with Z alleles [according to gradient ZZ>SZ>MZ>MS].…”