ABSTRACT
Apoptosis may perpetuate some forms of inflammation. Of the apoptotic pathway proteins, Fas is particularly overexpressed in sarcoidosis. We hypothesized that Fas promoter single nucleotide polymorphisms (SNPs) contribute to the development and severity of sarcoidosis. Associations of known Fas promoter SNPs (-670, -690 and -1377) and deduced haplotypes with sarcoidosis and sarcoidosis severity were evaluated using matched case-control (n = 656 pairs) and case-comparison (n = 656) studies, respectively, using conditional logistic regression. Hardy-Weinberg equilibrium was confirmed for all three polymorphisms in African-Americans (AA), and for the -670 and -1377 in whites. Genotype and allele frequencies were significantly different between whites and AA. Race-stratified analysis revealed that a common haplotype, -1377G/-690T/-670G, was associated with sarcoidosis [odds ratio (OR) = 1.78, P = 0.05] only in AA. The haplotype -1377G/-690C/-670A was negatively associated with sarcoidosis (OR = 0.39, P = 0.03) only in AA. In conclusion, the consistency of these findings suggests that Fas promoter genetic variants may be related to sarcoidosis disease risk in AA.
Subject(s)
Black or African American/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Sarcoidosis/genetics , fas Receptor/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Incidence , Male , Middle Aged , Sarcoidosis/epidemiology , Severity of Illness Index , White People/geneticsABSTRACT
Tumour necrosis factor (TNF)-alpha has been shown to be an important factor in animal models of chronic obstructive pulmonary disease (COPD). However, human studies of TNF polymorphisms in COPD have been equivocal. Six TNF single nucleotide polymorphisms (-1031C/T, -863C/A, -857C/T, -237G/A, -308G/A and +487G/A) and their haplotypes were investigated in 423 Caucasian smokers (298 patients with spirometric evidence of COPD and 125 without airflow obstruction). The -308 minor allele (A) had a higher odds ratio (OR) of being associated with COPD in multivariate analysis (controlling for age, sex, pack-yrs; OR 1.9, 95% confidence interval (CI) 1.1-3.2) and was also associated with worse forced expiratory volume in one second/forced vital capacity. The -237 minor allele (A) had a lower OR of being associated with COPD (OR 0.40, 95% CI 0.19-0.86). In COPD patients, the -857 minor allele (T) had a lower OR of being associated with severe stages of COPD (Global Initiative for Obstructive Lung Disease stage III and IV versus stage I and II, OR 0.46, 95% CI 0.24-0.88). Other TNF single nucleotide polymorphisms were not associated with COPD but the -1031/-863 haplotype CC/TC had a lower OR in COPD patients versus smoking controls (OR 0.22, 95% CI 0.05-0.97). The present study adds further evidence that tumour necrosis factor genotypes play a role in susceptibility to cigarette smoke.