Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration

Kylee L. Spencer, Michael A. Hauser, Lana M. Olson, Nathalie Schnetz-Boutaud, William K Scott, Silke Schmidt, Paul Gallins, Anita Agarwal, Eric A. Postel, Margaret A Pericak-Vance, Jonathan L. Haines

Research output: Contribution to journalArticle

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Abstract

PURPOSE. Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported. METHODS. The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families. RESULTS. TWO protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases ∼13%, in controls ∼20%, P = 0.001; P2 frequency in cases ∼5%, in controls ∼8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction). CONCLUSIONS. Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.

Original languageEnglish
Pages (from-to)4277-4283
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number9
DOIs
StatePublished - Sep 1 2007

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Complement Factor H
Macular Degeneration
Haplotypes
Genes
Smoking
Chromosomes, Human, Pair 1
Logistic Models
Quality of Life

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration. / Spencer, Kylee L.; Hauser, Michael A.; Olson, Lana M.; Schnetz-Boutaud, Nathalie; Scott, William K; Schmidt, Silke; Gallins, Paul; Agarwal, Anita; Postel, Eric A.; Pericak-Vance, Margaret A; Haines, Jonathan L.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 9, 01.09.2007, p. 4277-4283.

Research output: Contribution to journalArticle

Spencer, KL, Hauser, MA, Olson, LM, Schnetz-Boutaud, N, Scott, WK, Schmidt, S, Gallins, P, Agarwal, A, Postel, EA, Pericak-Vance, MA & Haines, JL 2007, 'Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration', Investigative Ophthalmology and Visual Science, vol. 48, no. 9, pp. 4277-4283. https://doi.org/10.1167/iovs.06-1427
Spencer, Kylee L. ; Hauser, Michael A. ; Olson, Lana M. ; Schnetz-Boutaud, Nathalie ; Scott, William K ; Schmidt, Silke ; Gallins, Paul ; Agarwal, Anita ; Postel, Eric A. ; Pericak-Vance, Margaret A ; Haines, Jonathan L. / Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 9. pp. 4277-4283.
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abstract = "PURPOSE. Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported. METHODS. The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families. RESULTS. TWO protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases ∼13{\%}, in controls ∼20{\%}, P = 0.001; P2 frequency in cases ∼5{\%}, in controls ∼8{\%}, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction). CONCLUSIONS. Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.",
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T1 - Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration

AU - Spencer, Kylee L.

AU - Hauser, Michael A.

AU - Olson, Lana M.

AU - Schnetz-Boutaud, Nathalie

AU - Scott, William K

AU - Schmidt, Silke

AU - Gallins, Paul

AU - Agarwal, Anita

AU - Postel, Eric A.

AU - Pericak-Vance, Margaret A

AU - Haines, Jonathan L.

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N2 - PURPOSE. Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported. METHODS. The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families. RESULTS. TWO protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases ∼13%, in controls ∼20%, P = 0.001; P2 frequency in cases ∼5%, in controls ∼8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction). CONCLUSIONS. Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.

AB - PURPOSE. Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported. METHODS. The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families. RESULTS. TWO protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases ∼13%, in controls ∼20%, P = 0.001; P2 frequency in cases ∼5%, in controls ∼8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction). CONCLUSIONS. Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.

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