@article {1340, title = {Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Oct 31}, pages = {8514-9}, abstract = {

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 {\texttimes} 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 {\texttimes} 10(-7)) and rs17501108 (P = 9.9 {\texttimes} 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 7, Corneal Topography, Enzyme-Linked Immunosorbent Assay, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hepatocyte Growth Factor, Humans, Keratoconus, Middle Aged, Nucleic Acid Hybridization, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Tagged Sites}, issn = {1552-5783}, doi = {10.1167/iovs.11-8261}, author = {Burdon, Kathryn P and Macgregor, Stuart and Bykhovskaya, Yelena and Javadiyan, Sharhbanou and Li, Xiaohui and Laurie, Kate J and Muszynska, Dorota and Lindsay, Richard and Lechner, Judith and Haritunians, Talin and Henders, Anjali K and Dash, Durga and Siscovick, David and Anand, Seema and Aldave, Anthony and Coster, Douglas J and Szczotka-Flynn, Loretta and Mills, Richard A and Iyengar, Sudha K and Taylor, Kent D and Phillips, Tony and Montgomery, Grant W and Rotter, Jerome I and Hewitt, Alex W and Sharma, Shiwani and Rabinowitz, Yaron S and Willoughby, Colin and Craig, Jamie E} } @article {1555, title = {A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Jan 15}, pages = {421-9}, abstract = {

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 {\texttimes} 10(-8), 2.4 {\texttimes} 10(-7) and 3.1 {\texttimes} 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 {\texttimes} 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 {\texttimes} 10(-5) and 2.6 {\texttimes} 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 {\texttimes} 10(-7) (unadjusted P= 1.2 {\texttimes} 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

}, keywords = {Case-Control Studies, Chromosomes, Human, Pair 2, Cohort Studies, Corneal Transplantation, Developed Countries, Genome-Wide Association Study, Humans, Keratoconus, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddr460}, author = {Li, Xiaohui and Bykhovskaya, Yelena and Haritunians, Talin and Siscovick, David and Aldave, Anthony and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Rotter, Jerome I and Taylor, Kent D and Rabinowitz, Yaron S} } @article {1543, title = {Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.}, journal = {Invest Ophthalmol Vis Sci}, volume = {53}, year = {2012}, month = {2012 Jun 28}, pages = {4152-7}, abstract = {

PURPOSE: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

METHODS: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.

RESULTS: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3{\texttimes}10(-3) and 7{\texttimes}10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7{\texttimes}10(-3) and 7.7{\texttimes}10(-4), respectively. Meta P values of 4.0{\texttimes}10(-5) and 4.0{\texttimes}10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.

CONCLUSIONS: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

}, keywords = {Case-Control Studies, Cornea, Corneal Topography, DNA, Family, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratoconus, Polymorphism, Genetic, Protein-Lysine 6-Oxidase}, issn = {1552-5783}, doi = {10.1167/iovs.11-9268}, author = {Bykhovskaya, Yelena and Li, Xiaohui and Epifantseva, Irina and Haritunians, Talin and Siscovick, David and Aldave, Anthony and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Taylor, Kent D and Rotter, Jerome I and Rabinowitz, Yaron S} }