Polymorphism of angiotensin-converting enzyme gene in sarcoidosis.

Abstract

Sarcoidosis is the disease in which increased levels of serum Angiotensin-converting enzyme (sACE) are most often detected. It has recently been shown that the deletion (D) or the insertion (I) of a 250bp-DNA fragment in the ACE gene accounts for three main ACE genotypes (i.e., II, ID, and DD) and for 47% of total phenotypic variance in sACE level. The aim of our work was to investigate whether or not patients with sarcoidosis have an increased incidence of those ACE genotypes coding for highest sACE levels and to investigate whether or not sACE level in sarcoidosis is related to ACE genotypes. We studied 61 unrelated patients with sarcoidosis (test group) and 80 unrelated healthy control subjects (control group). The ACE I and D alleles were detected with polymerase chain reaction on genomic DNA. In the control group we found an ACE genotype distribution that agreed with the Hardy-Weinberg proportion. The ACE genotype distribution was not significantly different in the test group. There was no correlation between ACE genotype and roentgenologic stage of sarcoidosis. Plotting the sACE level in the control group against ACE genotype, we found a trend of increasing mean sACE value according to the order II < ID < DD. The same trend for ACE genotype was found in the test group, in which it also paralleled the trend of sACE values plotted against roentgenologic stage, according to the order Stage I < Stage II < Stage III. We conclude that in sarcoidosis the ACE genotype distribution is not altered. The trends for increasing sACE values in sarcoidosis according to both ACE genotype and roentgenologic stage would suggest that both mechanisms play a role in determining sACE level.

Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

“…The characteristics of 12 analyses (Arbustini et al 1996;Furuya et al 1996;Sharma et al 1997;Tomita et al 1997;Takemoto et al 1998;Garrib et al 1998;Maliarik et al 1998;Pietinalho et al 1999;Papadopoulos et al 2000;Planck et al 2002;Alia et al 2005) on the risk of sarcoidosis in subjects with intron16 ID polymorphism in the ACE gene are summarized in Table 2. These studies involved 1,392 patients and 2,147 controls.…”

“…2 The results of individual and summary OR estimates with 95% CI, fixed-effect model: (a) ID/ACE polymorphism-dominant genetic model; (b) ID/ACE polymorphism-recessive genetic model. The size of the square is proportional to the percent weight of each study; horizontal lines represent the 95% CI higher production of sACE in both the general population and sarcoidosis patients (Rigat et al 1990;Tiret et al 1992;Arbustini et al 1996;Furuya et al 1996;Sharma et al 1997;Tomita et al 1997;Csaszar et al 1997). All these findings have contributed to the idea of the ID/ACE polymorphism's involvement in sarcoidosis etiology and/or pathogenesis, but neither the individual studies (except for African Americans) nor our meta-analysis confirmed this idea.…”

“…The final review was performed on 17 studies analyzing polymorphisms in the ACE gene, 12 of them being case control studies on insertion/deletion (ID) polymorphisms in intron 16, and these were submitted for meta-analysis (Arbustini et al 1996;Furuya et al 1996;Sharma et al 1997;Tomita et al 1997;Takemoto et al 1998;Garrib et al 1998;Maliarik et al 1998;Pietinalho et al 1999;Papadopoulos et al 2000;Planck et al 2002;Alia et al 2005). The remaining five studies not included were family-based studies, studies evaluating serum ACE levels or studies evaluating sarcoidosis symptoms (Csaszar et al 1997;Niimi et al1998;Kawakami et al 1998;Schurmann et al 2001;Rybicki et al 2004).…”

“…(Arbustini et al 1996;Furuya et al 1996;Sharma et al 1997;Tomita et al 1997;Takemoto et al1998;Garrib et al 1998;Maliarik et al 1998;Pietinalho et al 1999;Papadopoulos et al 2000;Planck et al 2002;Alia et al 2005;Csaszar et al1997;Niimi et al1998;Kawakami et al1998;Schurmann et al2001;Rybicki et al2004) 12 (Arbustini et al 1996;Furuya et al 1996;Sharma et al1997;Tomita et al 1997;Takemoto et al 1998;Garrib et al 1998;Maliarik et al 1998;Pietinalho et al 1999;Papadopoulos et al 2000;Planck et al 2002;Alia et al 2005) A-5466C (Rybicki et al2004;Seitzer et al1997;Takashige et al1999;Somskövi et al1999;Yamaguchi et al2001;Labunski et al2001;Grutters et al2002;Pandey et al2002;Mrazek et al2005) 7 (Seitzer et al 1997;Takashige et al 1999;Somskövi et al 1999;Yamaguchi et al 2001;Labunski et al 2001;Pandey et al2002;Mrazek et al2005) -238 3 …”

Genetic aspects in sarcoidosis

“…Probably this polymorphism is the best characterized in sarcoidosis (table 2). 1) Genotype distribution is not different between patients with sarcoidosis and controls in the Caucasians groups studied: Italians [95], Americans [96], and Finnish [97]; 2) Contrasting results were achieved in the Japanese: no association was found in a large series of subjects from central Japan [98], whereas an early report found an excess of ID or DD genotypes among females patients (OR 2.18) [99]: 3) In marked contrast, the DD genotype was a significant risk factor for African-American sarcoid patients (OR 3.17), especially in those with a family history of the disorder [96]. 4) No correlation was found between ACE genotype and sarcoidosis parameters, such as chest radiograph stage, extrapulmonary involvement, and progression in Italian and Japanese patients, whereas a modest correlation was found between the II genotype and radiographic progression among the African-American patients [96].…”