Two-Stage Genome-Wide Linkage Scan in Keratoconus Sib Pair Families

Li, Xiaohui; Rabinowitz, Yaron S.; Tang, Yun; Picornell, Yoana; Taylor, Kent D.; Hu, Mingshu; Yang, Huiying

doi:10.1167/iovs.06-0214

Cited by 99 publications

(88 citation statements)

References 23 publications

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“…16 Interestingly, other suggestive loci on 5q have been identified also for KTCN. 13,[25][26][27] Our 5q31.1-q35.3 linkage region overlapped two of them, 5q31 and 5q32-q33 in the Caucasian/Hispanic and the Southern Italian populations, respectively 13,26 (Figure 1c). These findings further indicate that the 5q31.1-q35.3 locus might be truly linked with KTCN.…”

Section: Discussionmentioning

confidence: 91%

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Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

et al. 2016

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Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1-q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency o0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T4G in SKP1, c.671G4A in PROB1, and c.527G4A in IL17B in the 5q31.1-q35.3 linkage region, and c.850G4A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1-q35.3 locus might be linked with KTCN.

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Section: Discussionmentioning

confidence: 91%

“…[12][13][14][15] Whole-exome sequencing (WES), which allows determination of the rare and unique coding sequence variants in an individual personal genome, can be also utilized in familial studies. However, due to a number of candidate genes generated by linkage analysis or WES, the evaluation of each individual variant is challenging.…”

Section: Introductionmentioning

confidence: 99%

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

et al. 2016

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“…55,56 LOX (locus 5q23.2), the gene encoding lysyl oxidase (LOX) enzyme, which is involved in collagen and elastin cross-linking, have also been related to keratoconus. 57 Association between single-nucleotide polymorphisms in the hepatocyte growth factor (HGF) gene and keratoconus has been found. 58,59 Multiple studies have reported a statistically significant risk of developing keratoconus in patients with polymorphism of the gene in charge of the IL-1β coding (IL-1B-31 T4C and IL-1B-511 C4T); 60,61 nevertheless, a recent study in a different population found no clear relation between the IL-1B gene polymorphism and the receptor antagonist IL-1 (ILRN VNTR) with the possibility of keratoconus development.…”

Section: Geneticsmentioning

confidence: 99%

Keratoconus: an inflammatory disorder?

Galvis

Sherwin

Tello

et al. 2015

Eye

293

199

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Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.

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“…Genetic studies have led to the identification of several loci on many chromosomes, linked to KTCN, including 1p36.23-36.21, 2p24, 2q13, 3p14-q13, 5q14.3-q21.1, 5q21.2, 5q32-q33, 9q34, 13q32, 14q11.2, 14q24.3, 15q15.1, 15q22. 33-24.2, 16q22.3-q23.1, 17p13, 20q12 [13][14][15][16][17][18][19][20][21][22][23][24][25]. To date, most of the identified loci have not been replicated in other populations.…”

Section: Keratoconusmentioning

confidence: 99%

Linkage Analysis as an Approach for Disease-related Loci Identification

Nowak¹,

Pitarque²,

Molinari³

et al. 2012

CMST

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Extensive progress in human genetics and clinical diagnostics allowed identification of the majority of genetically-related diseases. Still, the genes responsible for numerous diseases have not been recognized and frequently the disease etiology remains unknown. This is true for keratoconus, the study subject of this article. Therefore, before mutation analysis or other sequence variant assessment, it is essential to identify the chromosomal region, where a gene or genes causing the disease phenotype are located. To achieve that, advanced bioinformatics methods are applied to data obtained from molecular research to narrow the chromosomal region containing the disease locus.

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Two-Stage Genome-Wide Linkage Scan in Keratoconus Sib Pair Families

Abstract: These results indicate that one or more loci may contribute to keratoconus susceptibility.

Cited by 99 publications

References 23 publications

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

Keratoconus: an inflammatory disorder?

Linkage Analysis as an Approach for Disease-related Loci Identification

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