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Study of polymorphisms in CFH, ARMS2 and HTRA1 genes as potential risk factors for age related macular degeneration in Indian patients

Divya Gupta, Vani Gupta, Vinita Singh, Shobhit Chawla, Prajnya Ranganath, Shubha R. Phadke*

Abstract


Background: Age-related macular degeneration (AMD) is a common disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been found to be associated with AMD.

Aim: To study the association of polymorphisms in CFH, ARMS2 and HTRA1 genes with AMD in Indian patients.

Settings and Design: Case-control study

Methods and Material: Genotyping for CFH (Y402H), ARMS2 (A69S), HTRA1 (promoter region G/A) were performed in 121 AMD patients and 100 controls by PCR-RFLP.

Statistical Analysis Used: Hardy-Weinberg estimates (HWE) were calculated. Analysis for genotypes was done under additive, recessive as well as dominant models of inheritance showing odds of occurrence using Fisher’s exact test. Pairwise linkage disequilibrium (LD) was measured using SNPStats to predict Lewontin’s LD (D’) and correlation coefficient (r).

Results: Genotype analysis of all three polymorphisms (Y402H in CFH, A69S in ARMS2 and G/A in HTRA1 promoter region) showed the strongest association of AMD with Y402H polymorphism in CFH gene. Odds ratio for Y402H allele in CFH gene was 2.66 under recessive model. Odds ratio for polymorphisms in ARMS2 and HTRA1 genes were 2.41 and 1.97 respectively. Significant LD (D’=0.87, r=0.81) was observed in the presence of variant alleles HTRA1A and ARMS2T for AMD.

Conclusions: Present study suggests that all the three polymorphisms CFH Y402H (T/C), ARMS2 A69S (G/T) and HTRA1 promoter region (G/A) alleles are potential risk factors and are independently associated with AMD in Indian population. Detection of individuals at risk could lead to strategies for prevention, early diagnosis and management of AMD.

Keywords


AMD; ARMS2; CFH; HTRA1; Indian; Polymorphism; PCR-RFLP

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References


Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, et al., The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–10.

Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997;123:199–6.

Meyers SM, Greene T, Gutman FA. A twin study of age-related macular degeneration. Am J Ophthalmol. 1995;120:757–66.

Klein ML, Francis PJ. Genetics of age-related macular degeneration. Ophthalmol Clin North Am. 2003;16:567–74.

Schmidt S, Scott WK, Postel EA, Agarwal A, Hauser ER, De La Paz MA, et al., Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12. BMC Genet. 2004;5:18.

Weeks DE, Conley YP, Tsai HJ, Mah TS, Schmidt S, Postel EA, et al., Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am J Hum Genet. 2004;75:174–89.

Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement Factor H polymorphism and age-related macular degeneration. Science 2005;308:421–24.

Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al., Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–21.

Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al., Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–89.

Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, et al., Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age related macular degeneration. Nat Genet. 2006;38:1055–59.

Ault BH Factor H and the pathogenesis of renal diseases. Pediatr Nephrol 2000;14:1045-53.

Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, et al., Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet. 2001;68:478-84.

Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al., A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Nat Acad Sci. 2005;102:7227-32.

Wang G. Chromosome 10q26 locus and age-related macular degeneration: a progress update. Exp Eye Res. 2014;119:1-7

Yu W1, Dong S, Zhao C, Wang H, Dai F, Yang J. Cumulative association between age-related macular degeneration and less studied genetic variants in PLEKHA1/ARMS2/HTRA1: a meta and gene-cluster analysis. Mol Biol Rep. 2013;10:5551-61

Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, et al., Cigarette smoking strongly modifies the association of LOC387715 and age related macular degeneration. Am J Hum Genet. 2006;78:852–64.

Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77: 389–407.

Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, et al., Hypothetical LOC387715 is a second major susceptibility gene for age related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–36.

Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al., Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nature Genet. 2008;40: 892-96.

Wang G, Spencer KL, Court BL, Olson LM, Scott WK, Haines JL, et al., Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci. 2009;50:3084–90.

Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, et al., A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992-93.

Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, et al., HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989-92.

Kaur I, Katta S, Hussain A, Hussain N, Mathai A, Narayanan R, et al., Variants in the 10q26 gene cluster (LOC387715 and HTRA1) exhibit enhanced risk of age related macular degeneration along with CFH in Indian patients. Invest Ophthalmol Vis Sci. 2008;49:1771- 76.

Kaur I, Hussain A, Hussain N, Das T, Pathanqay, Mathai A, et al., Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration. Invest Ophthalmol. 2006;47:3729-35.

Brantley Jr. MA, Edelstein SL, King JM, Apte RS, Kymes SM, Shiels A. Clinical phenotypes associated with the Complement Factor H Y402H variant in age-related macular degeneration. Am J Ophthalmol. 2007;144:404-08.

Souied EH, Leveziel N, Richard F, Dragon-Durey MA, Coscas G, Soubrane G, et al., Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis. 2005;11:1135-40.

Chu J, Zhou CC, Lu N, Zhang X, Dong FT. Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population. Chin Med J. 2008;121:2525-33.

Xu N, Guan N, Xu J, Yang X, Ma K, Zhou H, et al., Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population. Mol Vis. 2008;14:1373-81.

Teper SJ1, Nowińska A, Wylęgała E. A69S and R38X ARMS2 and Y402H CFH gene polymorphisms as risk factors for neovascular age-related macular degeneration in Poland - a brief report. Med Sci Monit. 2012;2:1-3.

Leveziel N, Souied EH, Richard F, Barbu V, Zourdani A, Morineau G, et al., PLEKHA1-LOC387715-HTRA1 polymorphisms and exudative age-related macular degeneration in the French population. Mol Vis. 2007;13:2153-9

Ross RJ, Bojanowski CM, Wang JJ, Chew EY, Rochtchina E, Ferris FL 3rd, et al., The LOC387715 polymorphism and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci. 2007;48:1128-32.




DOI: http://dx.doi.org/10.21746/ijbio.2015.03.0015

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