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From SNPedia

Geno Mag Summary
(A;A) 3.5 ~10x increased risk of wet age related macular degeneration
(A;G) 2 ~2x increased risk of age related macular degeneration
(G;G) 0 normal
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
1000 genomesrs11200638
23andMe allrs11200638
SNP Nexus

GWAS Ctlgrs11200638
Max Magnitude3.5
rs11200638, a SNP in the HTRA1 promoter, is associated with a 10 fold increased risk of wet age related macular degeneration in Japanese [PMID 17053108] and Caucasian [PMID 17053109] populations. Further confirmed [PMID 18207215, PMID 18206206]. The genotype at highest risk is (A;A).

Note, most studies have shown that that this SNP is highly predictive (i.e. is in near perfect (D'>0.98) linkage disequilibrium) with rs10490924, thus the status of one very closely predicts the status of the other. However, one Caucasian AMD study reported the linkage disequilibrium measure for these two SNPs on 10q26, (i.e., rs10490924, which is upstream of HTRA1 in LOC387715/ARMS2, and rs11200638) as D'=0.8, and all four possible haplotypes of the two SNPs were detected in the samples. Further, this same study reported that these two SNPs appear to contribute equally to the risk of AMD (both GA and CNV) and show no evidence of interaction with CFH [PMID 18682806OA-icon.png].

A 2011 meta-analysis concluded that rs11200638(A;G) and (A;A) carriers had 2.243 and 8.669 times the risk of developing AMD, respectively, when compared with those who carry the (G;G) genotype.[PMID 21031019OA-icon.png]

[PMID 18164066OA-icon.png] rs10490924 and rs11200638 defined 2 significant haplotypes associated with increased risk of neovascular AMD.

[PMID 17884985OA-icon.png] show that rs11200638 has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas

[PMID 18301036] A study of 95 Taiwanese Chinese confirms rs11200638(A) allele risk for both wet and dry forms of AMD, with heterozygote odds ratio of 1.97 [CI:0.81-4.81], homozygote OR = 8.59 [CI: 3.28-22.49], p=6.7x10-3 for an additive allele-dosage model.

[PMID 18316707OA-icon.png] A study of Chinese AMD patients reports a 7.6x increased risk for rs11200638(A), and finds that smoking almost doubles the risk, to 15.7x increased risk. Carriers of both rs11200638 and rs800292 risk alleles pushes the odds ratio up to 23x. Overall, an "extremely high" population attributable risk (PAR) of 78% reported for these SNPs.

[PMID 18682806OA-icon.png] An analysis of the joint effects of rs1061170, rs11200638 and rs10490924 on AMD

[PMID 18316707OA-icon.png]
  • rs11200638 1.7x10-14 (-625G>A)is the most significant associated SNP with a high OR of 7.6 (95%CI: 3.94-14.51)
  • rs2672598 3.0x10-10 (-487T>C)
  • rs1049331 3.7x10-12 (102C>T, Ala34Ala)
  • rs2293870 3.7x10-12 (108G>T, Gly36Gly)
  • haplotype ACCTT, significantly predisposes to AMD (p= 6.68x10-14)
  • smoking and rs800292 (184G>A, Val62Ile) of CFH.
  • The combined OR for disease of smoking and rs11200638 (HTRA1) caused a 15.7 fold increased risk
  • The combined OR for rs800292 and rs11200638 showed a 23.3 fold increased risk
  • An extremely high population attributable risk (PAR) of 78% was also found.

[PMID 19026638] A meta-analysis of 14 case-control studies published prior to Sept. 2008 concluded that rs11200638 probably increases the risk of wet AMD in all populations.

SNP rs11200638
PubMedID [PMID 17053108]
Condition Wet age-related macular degeneration
Gene HTRA1
Risk Allele A
pValue 8.00E-012
OR 1.6
95% CI 0.71-3.61

[PMID 19259132OA-icon.png] Multilocus analysis of age-related macular degeneration.

[PMID 19255159OA-icon.png] Age-Related Macular Degeneration Associated ARMS2 is not a Mitochondrial but Cytosolic Protein.

DescLOC387715 GENE

[PMID 19680273] ARMS2/HTRA1 and CFH polymorphisms are not associated with choroidal neovascularization in highly myopic eyes of the elderly Japanese population

[PMID 19798546] Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women

[PMID 19796758OA-icon.png] Comprehensive Analysis of Complement Factor H and LOC387715/ARMS2/HTRA1 Variants with Respect to Phenotype in Advanced Age-related Macular Degeneration

[PMID 19491722] Analyses of single nucleotide polymorphisms and haplotype linkage of LOC387715 and the HTRA1 gene in exudative age-related macular degeneration in a Chinese cohort

[PMID 19933195] Analysis of six genetic risk factors highly associated with AMD in the region surrounding ARMS2 and HTRA1 on chromosome 10q26

[PMID 20132989] Phenotype and Genotype Characteristics of Age-related Macular Degeneration in a Japanese Population

[PMID 20678803] Complement Factor H and High-Temperature Requirement A-1 Genotypes and Treatment Response of Age-related Macular Degeneration

[PMID 21067572OA-icon.png] Association Analysis of Nine Candidate Gene Polymorphisms in Indian Patients with Type 2 Diabetic Retinopathy

[PMID 21191724] Haplotype analysis of the ARMS2/HTRA1 region in Japanese patients with typical neovascular age-related macular degeneration or polypoidal choroidal vasculopathy



[PMID 21913742] Genetic predictors of response to photodynamictherapy

[PMID 22509112OA-icon.png] Genetic associations in polypoidal choroidal vasculopathy: A systematic review and meta-analysis

[PMID 21959923] Association of ARMS2/HTRA1 variants with polypoidal choroidal vasculopathy phenotype in a Korean population

[PMID 22594510] Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population

[PMID 22699975OA-icon.png] Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

[PMID 22259222OA-icon.png] Chlamydia infection status, genotype, and age-related macular degeneration

[PMID 17327825OA-icon.png] An update on the genetics of age-related macular degeneration.

[PMID 17426452] HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.

[PMID 17438519OA-icon.png] HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration.

[PMID 17568988] Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population.

[PMID 17692272] LOC387715/HTRA1 variants in polypoidal choroidal vasculopathy and age-related macular degeneration in a Japanese population.

[PMID 17904186] HTRA1 variant increases risk to neovascular age-related macular degeneration in Chinese population.

[PMID 17917691OA-icon.png] Genetic markers and biomarkers for age-related macular degeneration.

[PMID 18079691] PLEKHA1-LOC387715-HTRA1 polymorphisms and exudative age-related macular degeneration in the French population.

[PMID 18162041OA-icon.png] Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking.

[PMID 18362109] Genotype-phenotype correlations for exudative age-related macular degeneration associated with homozygous HTRA1 and CFH genotypes.

[PMID 18427598OA-icon.png] Human HtrA1 in the archived eyes with age-related macular degeneration.

[PMID 18436811] Variants in the 10q26 gene cluster (LOC387715 and HTRA1) exhibit enhanced risk of age-related macular degeneration along with CFH in Indian patients.

[PMID 18515590] Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy.

[PMID 18535016OA-icon.png] Rhesus monkeys and humans share common susceptibility genes for age-related macular disease.

[PMID 18682812OA-icon.png] Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population.

[PMID 18718667OA-icon.png] The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples.

[PMID 18939352] Correlation between CFH Y402H and HTRA1 rs11200638 genotype to typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy phenotype in the Japanese population.

[PMID 19026761OA-icon.png] Molecular pathology of age-related macular degeneration.

[PMID 19048105OA-icon.png] Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration.

[PMID 19065273OA-icon.png] Sequence variants in HTRA1 and LOC387715/ARMS2 and phenotype and response to photodynamic therapy in neovascular age-related macular degeneration in populations from Israel.

[PMID 19169232] Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study.

[PMID 19187590] Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population.

[PMID 19202148OA-icon.png] Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.

[PMID 19628747OA-icon.png] Toll-like receptor polymorphisms and age-related macular degeneration: replication in three case-control samples.

[PMID 19845562] Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients.

[PMID 19933189] Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa.

[PMID 20140183OA-icon.png] Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration.

[PMID 20157352OA-icon.png] Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population.

[PMID 20161815OA-icon.png] SERPING1 polymorphisms in polypoidal choroidal vasculopathy.

[PMID 20445115] An intergenic region between the tagSNP rs3793917 and rs11200638 in the HTRA1 gene indicates association with age-related macular degeneration.

[PMID 20456446] LOC387715/HTRA1 polymorphisms, smoking and combined effects on exudative age-related macular degeneration in a Korean population.

[PMID 20664794OA-icon.png] Age-related macular degeneration-associated variants at chromosome 10q26 do not significantly alter ARMS2 and HTRA1 transcript levels in the human retina.

[PMID 20689796OA-icon.png] Monozygotic twins with polypoidal choroidal vasuculopathy.

[PMID 20881291OA-icon.png] Persons with age-related maculopathy risk genotypes and clinically normal eyes have reduced mesopic vision.

[PMID 21203342OA-icon.png] Elevated C-reactive protein levels and ARMS2/HTRA1 gene variants in subjects without age-related macular degeneration.

[PMID 21558292] CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration.

[PMID 21609242] Age-related macular degeneration-susceptibility single nucleotide polymorphisms in a han chinese control population.

[PMID 22491416] Differentiation of exudative age-related macular degeneration and polypoidal choroidal vasculopathy in the ARMS2/HTRA1 locus.

[PMID 22618592] Association of genetic polymorphisms and age-related macular degeneration in chinese population.

GET Evidence
impact pathogenic
qualified_impact Insufficiently evaluated pathogenic
overall_frequency 0.195122

[PMID 23337555OA-icon.png] Pharmacogenetics for Genes Associated with Age-Related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT)

[PMID 23582991] Genetic Influences on the Outcome of Anti-Vascular Endothelial Growth Factor Treatment in Neovascular Age-related Macular Degeneration

[PMID 23644223OA-icon.png] Variants at chromosome 10q26 locus and the expression of HTRA1 in the retina

[PMID 24080590] Genetic Association with Response to Intravitreal Ranibizumab for Neovascular Age-Related Macular Degeneration in the Han Chinese Population

[PMID 24393350] Genes in the High-Density Lipoprotein Metabolic Pathway in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

[PMID 22556410OA-icon.png] Detrimental role for human high temperature requirement serine protease A1 (HTRA1) in the pathogenesis of intervertebral disc (IVD) degeneration.

[PMID 23204795OA-icon.png] Pharmacogenetic influence of LOC387715/HTRA1 on the efficacy of bevacizumab treatment for age-related macular degeneration in a Korean population.

[PMID 24865190] Association of Specific Genetic Polymorphisms with Age-related Macular Degeneration in a Northern Chinese Population

Risk rs11200638(A;A)
Alt rs11200638(A;A)
Reference rs11200638(G;G)
Significance Other
Disease Age-related macular degeneration 7 Susceptibility to neovascular type of age-related macular degeneration
Variation info
Gene HTRA1
CLNDBN Age-related macular degeneration 7 Susceptibility to neovascular type of age-related macular degeneration
Reversed 0
HGVS NC_000010.10:g.124220544G>A
CLNSRC OMIM Allelic Variant
CLNACC RCV000007914.2, RCV000007915.2,

[PMID 26217379OA-icon.png] Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world

[PMID 25627090] Age-related macular degeneration phenotypes associated with mutually exclusive homozygous risk variants in CFH and HTRA1 genes

[PMID 26681391] Reticular Pseudodrusen and Their Association with Age-Related Macular Degeneration: The Melbourne Collaborative Cohort Study.