ClinVar Genomic variation as it relates to human health

Cystic Fibrosis Lung Disease, Modifier of Drumm et al. (2005) found that patients with cystic fibrosis (CF; 219700) and homozygosity for the common phe508del mutation (602421.0001) had an increased risk of severe pulmonary disease (odds ratio = 2.2) if they were also homozygous for C at nucleotide 29 of the TGFB1 gene, corresponding to a change in codon 10. The authors referred to this genotype as codon 10 CC and the SNP as C29T. A change from the more common base at this position, T, to C results in an amino acid change from leucine to proline (L10P) (Knowles, 2005). In a study of 1,019 Canadian pediatric CF patients, Dorfman et al. (2008) found a significant association between earlier age of first P. aeruginosa infection and MBL2 (154545) deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10. MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TFGB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function. In a study of 472 CF patient/parent trios, Bremer et al. (2008) found that a 3-SNP haplotype (CTC) composed of the -509 SNP (rs1800469) C allele, the codon 10 SNP (rs1982073) T allele, and a 3-prime SNP (rs8179181) C allele was highly associated with increased lung function in patients grouped by CFTR genotype. Bremer et al. (2008) concluded that TGFB1 is a modifier of CF lung disease, with a beneficial effect of certain variants on the pulmonary phenotype. Breast Cancer, Invasive, Susceptibility to In studies using data contributed to the Breast Cancer Association Consortium (BCAC), Cox et al. (2007) found evidence for a significant dose-dependent association of the proline-encoding allele of the L10P SNP (rs1982073) with increased risk of invasive breast cancer (see 114480) based on analyses of data from 11 studies comprising 12,946 cases and 15,109 controls. Odds ratios of 1.07 and 1.16 were observed for heterozygotes and rare homozygotes, respectively, compared with common homozygotes. Cox et al. (2007) noted that the proline variant has been associated with higher circulating levels of acid-activatable TGF-beta and increased rates of TGF-beta secretion in in vitro transfection experiments. The significant association of the proline variant was confined to individuals with progesterone receptor (607311)-negative tumors (P = 0.017). (less)

Cystic Fibrosis Lung Disease, Modifier of Drumm et al. (2005) found that patients with cystic fibrosis (CF; 219700) and homozygosity for the common phe508del mutation (602421.0001) had an increased risk of severe pulmonary disease (odds ratio = 2.2) if they were also homozygous for C at nucleotide 29 of the TGFB1 gene, corresponding to a change in codon 10. The authors referred to this genotype as codon 10 CC and the SNP as C29T. A change from the more common base at this position, T, to C results in an amino acid change from leucine to proline (L10P) (Knowles, 2005). In a study of 1,019 Canadian pediatric CF patients, Dorfman et al. (2008) found a significant association between earlier age of first P. aeruginosa infection and MBL2 (154545) deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10. MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TFGB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function. In a study of 472 CF patient/parent trios, Bremer et al. (2008) found that a 3-SNP haplotype (CTC) composed of the -509 SNP (rs1800469) C allele, the codon 10 SNP (rs1982073) T allele, and a 3-prime SNP (rs8179181) C allele was highly associated with increased lung function in patients grouped by CFTR genotype. Bremer et al. (2008) concluded that TGFB1 is a modifier of CF lung disease, with a beneficial effect of certain variants on the pulmonary phenotype. Breast Cancer, Invasive, Susceptibility to In studies using data contributed to the Breast Cancer Association Consortium (BCAC), Cox et al. (2007) found evidence for a significant dose-dependent association of the proline-encoding allele of the L10P SNP (rs1982073) with increased risk of invasive breast cancer (see 114480) based on analyses of data from 11 studies comprising 12,946 cases and 15,109 controls. Odds ratios of 1.07 and 1.16 were observed for heterozygotes and rare homozygotes, respectively, compared with common homozygotes. Cox et al. (2007) noted that the proline variant has been associated with higher circulating levels of acid-activatable TGF-beta and increased rates of TGF-beta secretion in in vitro transfection experiments. The significant association of the proline variant was confined to individuals with progesterone receptor (607311)-negative tumors (P = 0.017). (less)