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Variation in optineurin (OPTN) allele frequencies between and within populations.

Ayala-Lugo RM, Pawar H, Reed DM, Lichter PR, Moroi SE, Page M, Eadie J, Azocar V, Maul E, Ntim-Amponsah C, Bromley W, Obeng-Nyarkoh E, Johnson AT, Kijek TG, Downs CA, Johnson JM, Perez-Grossmann RA, Guevara-Fujita ML, Fujita R, Wallace MR, Richards JE - Mol. Vis. (2007)

Bottom Line: The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry.After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare.Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, MI, uSA. rositaya@yahoo.com <rositaya@yahoo.com>

ABSTRACT

Purpose: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations.

Methods: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry.

Results: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries.

Conclusions: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

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Related in: MedlinePlus

Lack of complete cosegregation of E50K with glaucoma in the pedigree of a Chilean family. The arrow indicates the proband (Case 1). Filled symbols are affected individuals with NTG, open symbols are individuals who are unaffected or reported to be unaffected. Symbols with a cross indicate individuals who are glaucoma-suspect, symbols with a center dot indicate glaucoma-affected individuals according to family report, and partially filled symbols denote individuals affected with POAG. Diagonal lines mark deceased individuals. Individuals denoted with ++ have E50 alleles on both chromosomes and ones with M+ carry the E50K heterozygous change. Members of generation four are young enough that they are not expected to be affected yet.
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f1: Lack of complete cosegregation of E50K with glaucoma in the pedigree of a Chilean family. The arrow indicates the proband (Case 1). Filled symbols are affected individuals with NTG, open symbols are individuals who are unaffected or reported to be unaffected. Symbols with a cross indicate individuals who are glaucoma-suspect, symbols with a center dot indicate glaucoma-affected individuals according to family report, and partially filled symbols denote individuals affected with POAG. Diagonal lines mark deceased individuals. Individuals denoted with ++ have E50 alleles on both chromosomes and ones with M+ carry the E50K heterozygous change. Members of generation four are young enough that they are not expected to be affected yet.

Mentions: Case 1, a 52 year old Chilean female (III:1; Figure 1), was diagnosed with NTG at age 42 years and her highest pretreatment IOP was 18 mmHg in both eyes. After bilateral trabeculectomies and betaxolol treatment, her IOPs were 6 mmHg in the right eye and 10 mmHg in the left eye. Gonioscopic exam revealed open angles in both eyes, with iris processes noted circumferentially in both eyes. A dilated funduscopic exam demonstrated advanced glaucomatous cupping with cup-to-disc ratios of 1.0 in both eyes and absence of hemorrhage. Sequence changes were absent in the MYOC gene coding sequence and splice sites. Her family history showed evidence of autosomal dominant inheritance (Figure 1). The E50K mutation was found in three of the proband's four affected relatives that were in the study (II:1, III:2, and III:7; Figure 1). The E50K mutation was absent in the proband's affected aunt (II:3; Figure 1) as well as five unaffected relatives that were screened (Figure 1).


Variation in optineurin (OPTN) allele frequencies between and within populations.

Ayala-Lugo RM, Pawar H, Reed DM, Lichter PR, Moroi SE, Page M, Eadie J, Azocar V, Maul E, Ntim-Amponsah C, Bromley W, Obeng-Nyarkoh E, Johnson AT, Kijek TG, Downs CA, Johnson JM, Perez-Grossmann RA, Guevara-Fujita ML, Fujita R, Wallace MR, Richards JE - Mol. Vis. (2007)

Lack of complete cosegregation of E50K with glaucoma in the pedigree of a Chilean family. The arrow indicates the proband (Case 1). Filled symbols are affected individuals with NTG, open symbols are individuals who are unaffected or reported to be unaffected. Symbols with a cross indicate individuals who are glaucoma-suspect, symbols with a center dot indicate glaucoma-affected individuals according to family report, and partially filled symbols denote individuals affected with POAG. Diagonal lines mark deceased individuals. Individuals denoted with ++ have E50 alleles on both chromosomes and ones with M+ carry the E50K heterozygous change. Members of generation four are young enough that they are not expected to be affected yet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2533035&req=5

f1: Lack of complete cosegregation of E50K with glaucoma in the pedigree of a Chilean family. The arrow indicates the proband (Case 1). Filled symbols are affected individuals with NTG, open symbols are individuals who are unaffected or reported to be unaffected. Symbols with a cross indicate individuals who are glaucoma-suspect, symbols with a center dot indicate glaucoma-affected individuals according to family report, and partially filled symbols denote individuals affected with POAG. Diagonal lines mark deceased individuals. Individuals denoted with ++ have E50 alleles on both chromosomes and ones with M+ carry the E50K heterozygous change. Members of generation four are young enough that they are not expected to be affected yet.
Mentions: Case 1, a 52 year old Chilean female (III:1; Figure 1), was diagnosed with NTG at age 42 years and her highest pretreatment IOP was 18 mmHg in both eyes. After bilateral trabeculectomies and betaxolol treatment, her IOPs were 6 mmHg in the right eye and 10 mmHg in the left eye. Gonioscopic exam revealed open angles in both eyes, with iris processes noted circumferentially in both eyes. A dilated funduscopic exam demonstrated advanced glaucomatous cupping with cup-to-disc ratios of 1.0 in both eyes and absence of hemorrhage. Sequence changes were absent in the MYOC gene coding sequence and splice sites. Her family history showed evidence of autosomal dominant inheritance (Figure 1). The E50K mutation was found in three of the proband's four affected relatives that were in the study (II:1, III:2, and III:7; Figure 1). The E50K mutation was absent in the proband's affected aunt (II:3; Figure 1) as well as five unaffected relatives that were screened (Figure 1).

Bottom Line: The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry.After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare.Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, MI, uSA. rositaya@yahoo.com <rositaya@yahoo.com>

ABSTRACT

Purpose: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations.

Methods: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry.

Results: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries.

Conclusions: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

Show MeSH
Related in: MedlinePlus