ClinVar Genomic variation as it relates to human health

Age-Related Macular Degeneration 4 In a genomewide scan for polymorphisms associated with age-related macular degeneration (ARMD4; 610698), Klein et al. (2005) identified a common intronic variant (rs380390) of the CFH gene. Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-to-histidine change at amino acid 402 (Y402H; rs1061170). Haines et al. (2005) independently determined that the 1277T-C transition in exon 9 of the CFH gene, resulting in the Y402H variant, increased the risk of ARMD with odds ratios between 2.45 and 5.57. They stated that the Y402H variant likely explains approximately 43% of ARMD. Similar results were obtained by Edwards et al. (2005). Zareparsi et al. (2005) found a strong association of the Y402H variant of the CFH gene with susceptibility to ARMD. They found that the frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls. A multiplicative model fitted the data well, and they estimated the population frequency of the high-risk C allele to be 0.39 and the genotype relative risk to be 2.44 for TC heterozygotes and 5.93 for CC homozygotes. Hageman et al. (2005) found significant association between the Y402H variant and ARMD among 954 cases. The authors stated that the Y402H variant is located in exon 9 within a region that binds heparin and C-reactive protein (CRP; 123260). Clark et al. (2006) reported that the Y402H variant (Y384H in the mature protein) is adjacent to a heparin-binding site in complement control protein module-7 (CCP7) of CFH. They found that the variants differentially recognized heparin. Gotoh et al. (2006) found no association between the Y402H polymorphism and exudative ARMD among 146 Japanese patients and 105 Japanese controls. The frequency of the C allele was much lower in Japanese controls (0.04) compared to Caucasians (see Zareparsi et al., 2005). Li et al. (2006) observed strong association between ARMD disease status and the Y402H variant of CFH, although they found 20 other CFH variants showing even stronger association. Among 2 common susceptibility haplotypes, 2 common protective haplotypes, and a set of rare haplotypes which in the aggregate seemed to be associated with increased disease susceptibility, the C allele of Y402H was present in approximately 94% of chromosomes that carried the most common risk haplotype and was absent from the common protective haplotypes. However, the allele was also absent from chromosomes carrying the second most common risk haplotype. Johnson et al. (2006) genotyped 28 postmortem donor eyes for the Y402H variant and found that there was no difference in ocular CFH-labeling patterns between genotypes. However, H/H eyes had significantly higher levels of the CFH-binding CRP in the choroidal stroma, with no differences in CFH transcription levels or evidence for local ocular CRP transcription. Johnson et al. (2006) suggested that increased levels of CRP in the choroid may reflect a state of chronic inflammation resulting from attenuated CFH complement-inhibitory activity in H/H individuals, and the authors also noted that there may be alterations in the CRP-binding site in CFH, which lies within the domain containing the Y402H polymorphism. Seddon et al. (2006) analyzed the 1277T-C variant of CFH, body mass index (BMI), and smoking status in 574 cases of advanced ARMD and 280 controls, and found that the number of risk alleles was associated with advanced ARMD (OR, 2.7 for TC; OR, 7.4 for CC) and that smoking and BMI were independently related to ARMD (OR, 5.1 and 2.1, respectively). The CC genotype plus higher BMI or smoking conferred the greatest risks (OR, 5.9 and 10.2, respectively). Seddon et al. (2006) concluded that genetic and environmental factors are independently associated with ARMD, and that modifiable factors alter genetic susceptibility. Adopting a structural approach, Herbert et al. (2007) characterized interaction of the Y402H site with chemically defined glycosaminoglycans (GAGs). They found that residue 402 occupies a critical position on a face of CCP7 that recognizes GAGs, suggesting that variation at this site would modulate the ability to distinguish between GAGs according to type and density of sulfation. Sjoberg et al. (2007) showed that the H384 variant exhibited relatively poor binding to CRP and FMOD (600245) compared with Y384. In contrast, H384 bound more effectively to DNA and necrotic cells than Y384. In a Central European population of Caucasoid descent, Wegscheider et al. (2007) found that the prevalence of the CFH 402HH genotype was significantly higher in patients with exudative ARMD than in controls (35.2% vs 8.6%, P less than 0.01). Homozygosity for the polymorphism was associated with an odds ratio of 5.78 for exudative ARMD. Subgroup analysis revealed that the CFH 402HH genotype was significantly more prevalent in eyes with predominantly classic with no occult choroidal neovascularization (CNV) than in those with either retinal angiomatous proliferation, occult with no classic CNV, or predominantly classic with occult CNV. Using a population-based study among Latinos, Tedeschi-Blok et al. (2007) found that the CFH Y402H polymorphism was not a major risk factor for overall early ARMD, but may play an important role in susceptibility to bilateral early ARMD. Bilateral early ARMD cases were 1.7 times more likely to carry at least 1 copy of the his402 allele (P = 0.03) compared with controls and unilateral early ARMD cases. Grassi et al. (2007) screened 50 patients with the cuticular drusen phenotype of ARMD, 700 patients with typical ARMD, and 252 controls for the Y402H substitution. The histidine variant was present in 70% of the cuticular cohort, 55% of the typical ARMD cases, and 34% of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = 0.003); genotype distribution between the 3 groups was similarly significant (P less than 0.001). Grassi et al. (2007) suggested that the complement cascade might play a greater role in the pathogenesis of the cuticular drusen subtype than in ARMD as a whole. Grassi et al. (2007) stated the Y402H polymorphism results from a 1204T-C transition. Scott et al. (2007) examined the potential gene-environment interaction between cigarette smoking and the CFH Y402H polymorphism, 2 strong risk factors for ARMD. Effects of both Y402H genotype and cigarette smoking were stronger when comparing neovascular (grade 5) ARMD with grade 1 controls than when comparing all cases (grades 3-5) with grades 1-2 controls. Scott et al. (2007) concluded that cigarette smoking and 1277T-C are independent risk factors for ARMD and that both risk factors are associated more strongly with neovascular (wet) ARMD than with all other forms of ARMD combined. In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and the CC genotype of rs1061170 (OR, 6.2; p = 1.9 x 10(-12)). In a study of 2,167 individuals with the CFH Y402H mutation or the ARMS2 A69S mutation (611313.0001), Ho et al. (2011) found that high dietary intake of nutrients with antioxidant properties reduced the risk of early ARMD. Weismann et al. (2011) demonstrated that the CFH polymorphism H402 markedly reduces the ability of CFH to bind malondialdehyde (MDA), a common lipid peroxidation product that accumulates in many pathophysiologic processes including ARMD. Clark et al. (2010) found that the 402H variant of CFH bound less well than the 402Y form to heparan sulfate and dermatan sulfate within Bruch membrane when added exogenously as probes. Both bound equally well to RPE. The 2 variants also differed in their ability to interact with desulfated heparin. Lauer et al. (2011) showed that the Y402H polymorphism affected surface recruitment of CFH by monomeric CRP (123260) to specific patches on necrotic RPE cells. Reduced monomeric CRP binding of the CFH H402 variant resulted in complement activation, generation of antiinflammatory mediators, inflammation, and pathology. Basal Laminar Drusen Boon et al. (2008) found compound heterozygosity for the Y402H variant of CFH and another mutation in affected members of 5 families with basal laminar drusen maculopathy (126700). The mutations found with Y402H included gln408 to ter (134370.0019), arg1078 to ser (134370.0020) and 350+6T-G (134370.0021). No signs of a renal disorder suggesting atypical hemolytic uremic syndrome or type II membranoproliferative glomerulonephritis were found in these patients. Boon et al. (2008) considered it possible that in these patients the residual CFH activity was sufficient for normal renal function, whereas the ocular environment may be more sensitive to deposition and damage. History Kardys et al. (2006) genotyped 5,520 men and women without a history of coronary heart disease for the Y402H polymorphism and found that after adjustment for age, gender, established cardiovascular risk factors, and CRP (123260) level, H/H homozygotes had a hazard ratio of 1.77 for myocardial infarction. However, in a prospective study of 335 Caucasian men with myocardial infarction and matched controls, Zee et al. (2006) found no association of the Y402H polymorphism with disease or with baseline levels of C-reactive protein. In addition, Stark et al. (2007) found no association of Y402H with MI in a total of 2,161 individuals from the German MI family study. Nicaud et al. (2007) studied 1,303 cases with CAD from the AtheroGene Study and 483 controls from Germany and 1,034 MI patients from the ECTIM Study and 1,039 controls from the United Kingdom and France and found no association between Y402H and heart disease. (less)

Age-Related Macular Degeneration 4 In a genomewide scan for polymorphisms associated with age-related macular degeneration (ARMD4; 610698), Klein et al. (2005) identified a common intronic variant (rs380390) of the CFH gene. Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-to-histidine change at amino acid 402 (Y402H; rs1061170). Haines et al. (2005) independently determined that the 1277T-C transition in exon 9 of the CFH gene, resulting in the Y402H variant, increased the risk of ARMD with odds ratios between 2.45 and 5.57. They stated that the Y402H variant likely explains approximately 43% of ARMD. Similar results were obtained by Edwards et al. (2005). Zareparsi et al. (2005) found a strong association of the Y402H variant of the CFH gene with susceptibility to ARMD. They found that the frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls. A multiplicative model fitted the data well, and they estimated the population frequency of the high-risk C allele to be 0.39 and the genotype relative risk to be 2.44 for TC heterozygotes and 5.93 for CC homozygotes. Hageman et al. (2005) found significant association between the Y402H variant and ARMD among 954 cases. The authors stated that the Y402H variant is located in exon 9 within a region that binds heparin and C-reactive protein (CRP; 123260). Clark et al. (2006) reported that the Y402H variant (Y384H in the mature protein) is adjacent to a heparin-binding site in complement control protein module-7 (CCP7) of CFH. They found that the variants differentially recognized heparin. Gotoh et al. (2006) found no association between the Y402H polymorphism and exudative ARMD among 146 Japanese patients and 105 Japanese controls. The frequency of the C allele was much lower in Japanese controls (0.04) compared to Caucasians (see Zareparsi et al., 2005). Li et al. (2006) observed strong association between ARMD disease status and the Y402H variant of CFH, although they found 20 other CFH variants showing even stronger association. Among 2 common susceptibility haplotypes, 2 common protective haplotypes, and a set of rare haplotypes which in the aggregate seemed to be associated with increased disease susceptibility, the C allele of Y402H was present in approximately 94% of chromosomes that carried the most common risk haplotype and was absent from the common protective haplotypes. However, the allele was also absent from chromosomes carrying the second most common risk haplotype. Johnson et al. (2006) genotyped 28 postmortem donor eyes for the Y402H variant and found that there was no difference in ocular CFH-labeling patterns between genotypes. However, H/H eyes had significantly higher levels of the CFH-binding CRP in the choroidal stroma, with no differences in CFH transcription levels or evidence for local ocular CRP transcription. Johnson et al. (2006) suggested that increased levels of CRP in the choroid may reflect a state of chronic inflammation resulting from attenuated CFH complement-inhibitory activity in H/H individuals, and the authors also noted that there may be alterations in the CRP-binding site in CFH, which lies within the domain containing the Y402H polymorphism. Seddon et al. (2006) analyzed the 1277T-C variant of CFH, body mass index (BMI), and smoking status in 574 cases of advanced ARMD and 280 controls, and found that the number of risk alleles was associated with advanced ARMD (OR, 2.7 for TC; OR, 7.4 for CC) and that smoking and BMI were independently related to ARMD (OR, 5.1 and 2.1, respectively). The CC genotype plus higher BMI or smoking conferred the greatest risks (OR, 5.9 and 10.2, respectively). Seddon et al. (2006) concluded that genetic and environmental factors are independently associated with ARMD, and that modifiable factors alter genetic susceptibility. Adopting a structural approach, Herbert et al. (2007) characterized interaction of the Y402H site with chemically defined glycosaminoglycans (GAGs). They found that residue 402 occupies a critical position on a face of CCP7 that recognizes GAGs, suggesting that variation at this site would modulate the ability to distinguish between GAGs according to type and density of sulfation. Sjoberg et al. (2007) showed that the H384 variant exhibited relatively poor binding to CRP and FMOD (600245) compared with Y384. In contrast, H384 bound more effectively to DNA and necrotic cells than Y384. In a Central European population of Caucasoid descent, Wegscheider et al. (2007) found that the prevalence of the CFH 402HH genotype was significantly higher in patients with exudative ARMD than in controls (35.2% vs 8.6%, P less than 0.01). Homozygosity for the polymorphism was associated with an odds ratio of 5.78 for exudative ARMD. Subgroup analysis revealed that the CFH 402HH genotype was significantly more prevalent in eyes with predominantly classic with no occult choroidal neovascularization (CNV) than in those with either retinal angiomatous proliferation, occult with no classic CNV, or predominantly classic with occult CNV. Using a population-based study among Latinos, Tedeschi-Blok et al. (2007) found that the CFH Y402H polymorphism was not a major risk factor for overall early ARMD, but may play an important role in susceptibility to bilateral early ARMD. Bilateral early ARMD cases were 1.7 times more likely to carry at least 1 copy of the his402 allele (P = 0.03) compared with controls and unilateral early ARMD cases. Grassi et al. (2007) screened 50 patients with the cuticular drusen phenotype of ARMD, 700 patients with typical ARMD, and 252 controls for the Y402H substitution. The histidine variant was present in 70% of the cuticular cohort, 55% of the typical ARMD cases, and 34% of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = 0.003); genotype distribution between the 3 groups was similarly significant (P less than 0.001). Grassi et al. (2007) suggested that the complement cascade might play a greater role in the pathogenesis of the cuticular drusen subtype than in ARMD as a whole. Grassi et al. (2007) stated the Y402H polymorphism results from a 1204T-C transition. Scott et al. (2007) examined the potential gene-environment interaction between cigarette smoking and the CFH Y402H polymorphism, 2 strong risk factors for ARMD. Effects of both Y402H genotype and cigarette smoking were stronger when comparing neovascular (grade 5) ARMD with grade 1 controls than when comparing all cases (grades 3-5) with grades 1-2 controls. Scott et al. (2007) concluded that cigarette smoking and 1277T-C are independent risk factors for ARMD and that both risk factors are associated more strongly with neovascular (wet) ARMD than with all other forms of ARMD combined. In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and the CC genotype of rs1061170 (OR, 6.2; p = 1.9 x 10(-12)). In a study of 2,167 individuals with the CFH Y402H mutation or the ARMS2 A69S mutation (611313.0001), Ho et al. (2011) found that high dietary intake of nutrients with antioxidant properties reduced the risk of early ARMD. Weismann et al. (2011) demonstrated that the CFH polymorphism H402 markedly reduces the ability of CFH to bind malondialdehyde (MDA), a common lipid peroxidation product that accumulates in many pathophysiologic processes including ARMD. Clark et al. (2010) found that the 402H variant of CFH bound less well than the 402Y form to heparan sulfate and dermatan sulfate within Bruch membrane when added exogenously as probes. Both bound equally well to RPE. The 2 variants also differed in their ability to interact with desulfated heparin. Lauer et al. (2011) showed that the Y402H polymorphism affected surface recruitment of CFH by monomeric CRP (123260) to specific patches on necrotic RPE cells. Reduced monomeric CRP binding of the CFH H402 variant resulted in complement activation, generation of antiinflammatory mediators, inflammation, and pathology. Basal Laminar Drusen Boon et al. (2008) found compound heterozygosity for the Y402H variant of CFH and another mutation in affected members of 5 families with basal laminar drusen maculopathy (126700). The mutations found with Y402H included gln408 to ter (134370.0019), arg1078 to ser (134370.0020) and 350+6T-G (134370.0021). No signs of a renal disorder suggesting atypical hemolytic uremic syndrome or type II membranoproliferative glomerulonephritis were found in these patients. Boon et al. (2008) considered it possible that in these patients the residual CFH activity was sufficient for normal renal function, whereas the ocular environment may be more sensitive to deposition and damage. History Kardys et al. (2006) genotyped 5,520 men and women without a history of coronary heart disease for the Y402H polymorphism and found that after adjustment for age, gender, established cardiovascular risk factors, and CRP (123260) level, H/H homozygotes had a hazard ratio of 1.77 for myocardial infarction. However, in a prospective study of 335 Caucasian men with myocardial infarction and matched controls, Zee et al. (2006) found no association of the Y402H polymorphism with disease or with baseline levels of C-reactive protein. In addition, Stark et al. (2007) found no association of Y402H with MI in a total of 2,161 individuals from the German MI family study. Nicaud et al. (2007) studied 1,303 cases with CAD from the AtheroGene Study and 483 controls from Germany and 1,034 MI patients from the ECTIM Study and 1,039 controls from the United Kingdom and France and found no association between Y402H and heart disease. (less)