Rs11200638

rs11200638, a SNP in the HTRA1 promoter, is associated with a 10 fold increased risk of wet age related macular degeneration in Japanese and Caucasian  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.

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.

rs10490924 and rs11200638 defined 2 significant haplotypes associated with increased risk of neovascular AMD.

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

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.

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.

An analysis of the joint effects of rs1061170, rs11200638 and rs10490924 on AMD


 * 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.

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.