MyVisionTest News Archive
Aug 28, 2010
Hepatic lipase gene (LIPC) implicated in AMD
A genome-wide association study has identified a possible role of the hepatic lipase gene (LIPC) in advanced AMD, according to a new research report. These findings implicate a new biologic pathway in AMD and provide new avenues for prevention and treatment of AMD.
The role of the alternative complement pathway in disease pathogenesis was documented by the discovery and replication of the CFH association as well as reports of three additional risk loci in this pathway: CFB/C2 on chromosome 6, C3 on chromosome 19, and CFI on chromosome 4. Together with strongly associated variants in the ARMS2/HTRA1 region on chromosome 10, these multiple loci have been estimated to explain approximately one-half of the heritability of AMD, and combined with demographic, ocular, and environmental factors, they have potential predictive power.
To date, however, no large sample genome-wide association study (GWAS) has been undertaken to attempt to explain the remaining heritability of AMD and to identify other susceptibility loci. The current study represents just such a GWAS involving 979 cases of advanced AMD.
Methods and Results
A genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls).
Samples were genotyped on the Affymetrix 6.0 platform, which contains probes for 906,000 SNPs and an additional 946,000 SNP invariant probes to enhance copy-number variation (CNV) analysis; it captures 82% of the variation at an r2>=0.8 for Europeans in the 3.1 million SNPs of HapMap phase 2. Our study has uncovered several new AMD susceptibility loci. Intriguingly, the most significant, replicated association is a functional variation in the hepatic lipase gene (LIPC), a gene involved in triglyceride hydrolysis and high-density lipoprotein cholesterol (HDL) function, thus revealing another candidate pathway for AMD pathogenesis.
The discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09.
Weaker associations were observed with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component.
Discussion and Conclusions
The researchers found a significant association between advanced AMD and the LIPC locus in our GWAS. LIPC, which encodes hepatic triglyceride lipase, has been shown to catalyze hydrolysis of phospholipids, monoglycerides, diglycerides, triglycerides, and acyl-CoA thioesters, and is a critical enzyme in HDL metabolism.
The T allele of the LIPC SNP has been shown to increase HDL levels, and this study suggests that it decreases risk for AMD. In contrast, data from the genome-wide scan suggest that the HDL-raising alleles of ABCA1 and CETP may increase the risk of AMD, although these results are not currently genome-wide significant. Thus, the association between advanced AMD and LIPC may not represent a causal effect of serum HDL but could indicate a shared underlying biologic mechanism involving the cholesterol pathway.
Data regarding the association between serum HDL levels and AMD are conflicting. Some studies found no relationship, whereas others found that increased risk of AMD or a subphenotype was associated with increased HDL levels. Three studies have shown an inverse relationship with either decreased HDL levels in AMD cases or decreased incidence of advanced AMD with higher HDL.
If the relationship of the LIPC polymorphism to AMD is not mediated by variation in HDL levels, alternative mechanisms may play a role. Hepatic lipase has been shown to have an impact on atherogenesis, and cardiovascular risk factors are associated with AMD. The vascular intimae in atherosclerosis and Bruch's membrane in macular degeneration may undergo similar age-related changes. These diseases may represent parallel responses to tissue injury induced by multiple factors, including genetic variation, impaired immune responses, and oxidative stress. Whether LIPC genetic variation has parallel or distinct roles in AMD and atherogenesis remains to be determined.
Another possibility regarding the role of the LIPC polymorphism in AMD involves the role of HDL as the major lipoprotein transporter of lutein and zeaxanthin. Reduced dietary intake of these two carotenoids has been associated with an increased risk of AMD. Variation in the uptake and transport into the retina of carotenoids by HDL has been implicated in AMD pathogenesis. Changes in HDL-related efficiency of carotenoid delivery is another possible mechanism by which LIPC variation could impact the risk of AMD. It is also interesting to note that drusen also contain cholesterol deposits.
The LIPC locus may greatly enhance our biologic understanding by opening up another pathway for consideration in the pathogenesis of AMD. This finding could lead to insights regarding disease progression, ways to modify risk of AMD, and new treatments.
WHAT IT MEANS TO YOU: This exciting discovery opens the door to greater understanding of the factors that can lead to AMD. It is not clear yet precisely how hepatic lipase function influences AMD. It is possible that it has something to do with HDL ("good") cholesterol, because hepatic lipase plays an important role in HDL metabolism, but for now this is just speculation. We are confidant that additional research will clarify this question.
Read more...
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400. Epub 2010 Apr 12.
Tags: AMD, complement, fat, genetics
A genome-wide association study has identified a possible role of the hepatic lipase gene (LIPC) in advanced AMD, according to a new research report. These findings implicate a new biologic pathway in AMD and provide new avenues for prevention and treatment of AMD.The role of the alternative complement pathway in disease pathogenesis was documented by the discovery and replication of the CFH association as well as reports of three additional risk loci in this pathway: CFB/C2 on chromosome 6, C3 on chromosome 19, and CFI on chromosome 4. Together with strongly associated variants in the ARMS2/HTRA1 region on chromosome 10, these multiple loci have been estimated to explain approximately one-half of the heritability of AMD, and combined with demographic, ocular, and environmental factors, they have potential predictive power.
Methods and Results
A genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls).
Samples were genotyped on the Affymetrix 6.0 platform, which contains probes for 906,000 SNPs and an additional 946,000 SNP invariant probes to enhance copy-number variation (CNV) analysis; it captures 82% of the variation at an r2>=0.8 for Europeans in the 3.1 million SNPs of HapMap phase 2. Our study has uncovered several new AMD susceptibility loci. Intriguingly, the most significant, replicated association is a functional variation in the hepatic lipase gene (LIPC), a gene involved in triglyceride hydrolysis and high-density lipoprotein cholesterol (HDL) function, thus revealing another candidate pathway for AMD pathogenesis.
The discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09.
Weaker associations were observed with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component.
Discussion and Conclusions
The researchers found a significant association between advanced AMD and the LIPC locus in our GWAS. LIPC, which encodes hepatic triglyceride lipase, has been shown to catalyze hydrolysis of phospholipids, monoglycerides, diglycerides, triglycerides, and acyl-CoA thioesters, and is a critical enzyme in HDL metabolism.
The T allele of the LIPC SNP has been shown to increase HDL levels, and this study suggests that it decreases risk for AMD. In contrast, data from the genome-wide scan suggest that the HDL-raising alleles of ABCA1 and CETP may increase the risk of AMD, although these results are not currently genome-wide significant. Thus, the association between advanced AMD and LIPC may not represent a causal effect of serum HDL but could indicate a shared underlying biologic mechanism involving the cholesterol pathway.
Data regarding the association between serum HDL levels and AMD are conflicting. Some studies found no relationship, whereas others found that increased risk of AMD or a subphenotype was associated with increased HDL levels. Three studies have shown an inverse relationship with either decreased HDL levels in AMD cases or decreased incidence of advanced AMD with higher HDL.
If the relationship of the LIPC polymorphism to AMD is not mediated by variation in HDL levels, alternative mechanisms may play a role. Hepatic lipase has been shown to have an impact on atherogenesis, and cardiovascular risk factors are associated with AMD. The vascular intimae in atherosclerosis and Bruch's membrane in macular degeneration may undergo similar age-related changes. These diseases may represent parallel responses to tissue injury induced by multiple factors, including genetic variation, impaired immune responses, and oxidative stress. Whether LIPC genetic variation has parallel or distinct roles in AMD and atherogenesis remains to be determined.
Another possibility regarding the role of the LIPC polymorphism in AMD involves the role of HDL as the major lipoprotein transporter of lutein and zeaxanthin. Reduced dietary intake of these two carotenoids has been associated with an increased risk of AMD. Variation in the uptake and transport into the retina of carotenoids by HDL has been implicated in AMD pathogenesis. Changes in HDL-related efficiency of carotenoid delivery is another possible mechanism by which LIPC variation could impact the risk of AMD. It is also interesting to note that drusen also contain cholesterol deposits.
The LIPC locus may greatly enhance our biologic understanding by opening up another pathway for consideration in the pathogenesis of AMD. This finding could lead to insights regarding disease progression, ways to modify risk of AMD, and new treatments.
WHAT IT MEANS TO YOU: This exciting discovery opens the door to greater understanding of the factors that can lead to AMD. It is not clear yet precisely how hepatic lipase function influences AMD. It is possible that it has something to do with HDL ("good") cholesterol, because hepatic lipase plays an important role in HDL metabolism, but for now this is just speculation. We are confidant that additional research will clarify this question.
Read more...
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400. Epub 2010 Apr 12.
