ClinVar Genomic variation as it relates to human health

A (GT)n dinucleotide repeat in the 5-prime promoter region of the human HMOX1 gene shows a length polymorphism. In cultured cell lines, Yamada et al. (2000) demonstrated that a low number of (GT)n repeats was related to both increased HMOX1 basal promoter activity and transcriptional upregulation in response to oxidants. Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE), which is a sign of chronic obstructive pulmonary disease (COPD; 606963). HMOX1 plays a protective role as an antioxidant in the lung. Among 201 smokers, Yamada et al. (2000) found an association between CPE and the longer promoter polymorphism. The polymorphisms were grouped into 3 classes: class S alleles (less than 25 repeats), class M alleles (25 to 29 repeats), and class L alleles (30 or more repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in smokers with CPE than in smokers without CPE. These findings suggested that the large size of a (GT)n repeat in the HMOX1 gene promoter may reduce HMOX1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE. Among 749 French adults, including 40% who never smoked, Guenegou et al. (2006) observed an association between carriers of the long (L) allele of the (GT)n polymorphism and decreased lung function, as assessed by forced expiratory volume in 1 second (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio, over an 8-year period (1992 to 2000). At the 8-year follow-up, the mean annual FEV1 and FEV1/FVC declines in patients with 1 or 2 L alleles were -30.9 ml/year and -1.8 U/year. FEV1/FVC decline was steeper in L allele carriers than in noncarriers (-2.6 versus -1.5, p = 0.07). There was a strong interaction between the L allele and smoking. At the 8-year follow-up, the L allele was associated with lower FEV1 and FEV1/FVC in heavy smokers only. Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (-62.0 ml/year) and the steepest FEV1/FVC decline (-8.8 U/year) (p for interaction = 0.009 and 0.0006, respectively). Guenegou et al. (2006) suggested that a long HMOX1 gene promoter in heavy smokers is associated with susceptibility to developing airway obstruction. Siedlinski et al. (2008) followed 1,390 Dutch individuals, including 67.9% who never smoked, with FEV1 measurements every 3 years for 25 years (1965 to 1990). They found that the M/L and L/L genotype constituted a risk factor for accelerated FEV1 decline in the total population compared with any other genotype. The mean adjusted change in FEV1 for the M/L and L/L genotype pool was -24.2 ml/year. S/L, S/S, S/M and M/M genotypes provided, respectively, 6.3 (p = 0.025), 3.6 (p = 0.120), 5.7 (p = 0.005), and 4.9 (p = 0.017) ml/year less decline compared to the M/L and L/L pool. The associations remained significant in smokers. Siedlinski et al. (2008) concluded that their findings replicated those of Guenegou et al. (2006). (less)