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Nature and nurture on phenotypic variability of autosomal dominant polycystic kidney disease
Kidney International, Vol. 67 (2005), pp. 1630–1631
EDITORIAL
Nature and nurture on phenotypic variability of autosomal dominant polycystic kidney disease
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney, affecting all ethnic groups worldwide with an incidence of ∼1 in 500 to 1000 births. It is characterized by progressive formation and enlargement of renal cysts, typically leading to chronic renal failure by late middle age. Other manifestations of this disorder, such as cyst formation in nonrenal organs, hypertension, cardiac valvular defects, colonic diverticulosis, and intracranial arterial aneurysms, accompany the renal disease variably. Overall, ADPKD accounts for ∼5% to 8% of end-stage renal disease (ESRD) [1, 2]. Two disease genes (PKD1 and PKD2) have been identified and, respectively, account for ∼85% and ∼15% of cases in the Caucasian population [2]. Polycystin 1 and 2, the gene products of PKD1 and PKD2, are plasma membrane proteins that form components of a novel multifunctional signaling pathway [1]. Polycystin 1 is predicted to have a receptor-like structure, and may be involved in cell-cell and/or cell-matrix interaction. By contrast, polycystin 2 is thought to function as a subunit of a nonselective cation channel. Both proteins have been shown to interact in vitro through their cytoplasmic region, and transmit fluid-flow mediated mechanosensation by the primary cilium in renal epithelium [1, 3]. Disruption of the function of polycystin 1 or 2 may cause ADPKD, owing to the inability of the tubular epithelial cells to sense mechanical cues that normally regulate tissue morphogenesis [3]. A striking feature of ADPKD is its phenotypic variability. In particular, renal disease progression in ADPKD is highly variable, with the age of ESRD ranging from childhood to old age [1, 2]. Recent studies have shown that genomic deletion of PKD1 and TSC2, or bilineal inheritance of heterozygous PKD1 and PKD2 mutations, can result in earlier and more severe renal disease in a small number of patients [2]. For the majority of cases, however, the gene locus confers a major effect for interfamilial renal disease variability: patients from PKD1 families have Key words: heritability, renal disease progression, ADPKD. C
2005 by the International Society of Nephrology
an earlier onset of ESRD than patients from PKD2 families [median age at ESRD: 53 (95%CI: 51.2-54.8) vs. 69 (95%CI: 66.9-71.3)] years, respectively) [4]. A gender effect on renal survival (i.e., absence of ESRD) favoring the female patients is also evident in type 2, but in not type 1 ADPKD [4–6]. By contrast, a weak allelic effect (based on the 5’ vs. 3’ location of the germline mutations) on renal disease progression may exist for type 1 [5], but not type 2 ADPKD [6]. Additionally, significant intrafamilial renal disease variability has been well documented in both type 1 and 2 ADPKD [5–7]. These latter findings suggest that renal disease progression in ADPKD may be modified by genetic, environmental, and stochastic factors independent of the germline PKD mutations. The existence of modifier genes for ADPKD is further supported by a recent study documenting a larger intraclass correlation coefficient for the age of onset of ESRD in 9 monozygotic twin pairs compared to 56 sibships [8]. Nevertheless, the magnitude of the modifier gene effect for renal disease progression in ADPKD is not currently known. In this issue of Kidney International, Fain et al [9] reported their quantitative genetic analysis on a number of phenotypic traits from 315 affected relatives in 83 multiplex PKD1 families. Using the variance components analysis, they estimated the heritability (i.e., the proportion of variance due to modifier genes) of these traits. They found that inherited difference in modifier genes accounted for 18% to 59% of the variance of the traits examined. Importantly, they found that modifier genes accounted for ∼32% of the variance for creatinine clearance (Ccr) and 43% to 50% of the variance for age of ESRD. Additionally, modifier genes accounted for a significant proportion of the variances for other surrogate measures of renal and hepatic cystic disease. The main strengths of this study included the use of a robust research methodology for within-family comparisons in a well-characterized cohort of PKD1 families, which controlled for differences in age, gender, gene locus, and allelic effects. However, there were some limitations, as well. First, there was a selection bias for younger and less severely affected patients in this study. As a result, the median age of ESRD in the study cohort was older than that from 2 recent 1630
Editorial
PKD1 studies (61 vs. 53 and 54 years, respectively) [4, 5]. Consequent to the enrichment of younger patients whose disease has not been given a chance to manifest fully, the current study may underestimate the true magnitude of the modifier gene effect. Second, a number of trait values in the current study were not normally distributed. Violation of this assumption in the variance components analysis may impact the precision of the heritability estimates. Thus, the extreme kurtosis in the distribution of serum creatinine values could affect the reliability of its heritability estimate compared to other related traits, such as Ccr and age of ESRD. Nevertheless, the heritability estimates on Ccr and age of ESRD in the current study are generally concordant with another recent study of largely unselected PKD1 patients using similar study design [10]. While differences in methodology preclude direct comparisons between these 2 studies, they do support the notion that both genetic and environment modifiers play a significant role for renal disease progression of ADPKD. Where do we go from here? I believe that a formal and systematic search for genetic modifiers of renal disease progression in ADPKD is justifiable at this time. However, the identification of these modifier genes will be challenging because of the polygenic nature of this complex trait [11]. The best scenario that one can hope for is that a few moderately strong gene loci account for most of the modifier effect. Even under this scenario, a large patient and family resource will still be required to ensure adequate power in the study [9, 10], which underpins the need for large-scale international collaboration. The identification of major modifier genes in ADPKD is expected to improve our current understanding of the relevant molecular pathways, as well as environmental factors (for gene-environment interaction) that promote
1631
progression of this renal disease. Such knowledge is essential for future development of individualized patient risk prediction and mechanism-based therapeutics for ADPKD—a promise of molecular medicine. YORK PEI
Toronto, Ontario, Canada Correspondence to York Pei, M.D., Divisions of Nephrology and Genomic Medicine, University Health Network, 8N838, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2. E-mail: [email protected]
REFERENCES 1. IGARASHI P, SOMLO S: Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13:2384–2398, 2002 2. PEI Y: Molecular genetics of autosomal dominant kidney disease. Clin Invest Med 26:252–258, 2003 3. NAULI SM, ALENGHAT FJ, LUO Y, et al: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137, 2003 4. HATEBOER N, DIJK VAN MA, BOGDANOVA N, et al: Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 353:103–107, 1999 5. ROSSETTI S, BURTON S, STRMECKI L, et al: The position of the polycystic kidney disease 1 gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 13:1230–1237, 2002 6. MAGISTRONI R, HE N, WANG KR, et al: Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 14:1164–1174, 2003 7. HATEBOER N, LAZAROU LP, WILLIAMS AJ, et al: Familial phenotype differences in PKD1. Kidney Int 56:34–40, 1999 8. PERSU A, DUYME M, PIRSON Y, et al: Comparison between siblings and twins supports a role for modifier genes in ADPKD. Kidney Int 66:2132–2136, 2004 9. FAIN PR, MCFANN KK, TAYLOR MRG, et al: Modifier genes play a significant role in the phenotypic expression of PKD1. Kidney Int 67:1256–1267, 2005 10. PATERSON A, MAGISTRONI R, HE N, et al: Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol (in press) 11. DIPPLE K, MCCABE E: Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 71:43–50, 2000
EDITORIAL
Nature and nurture on phenotypic variability of autosomal dominant polycystic kidney disease
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney, affecting all ethnic groups worldwide with an incidence of ∼1 in 500 to 1000 births. It is characterized by progressive formation and enlargement of renal cysts, typically leading to chronic renal failure by late middle age. Other manifestations of this disorder, such as cyst formation in nonrenal organs, hypertension, cardiac valvular defects, colonic diverticulosis, and intracranial arterial aneurysms, accompany the renal disease variably. Overall, ADPKD accounts for ∼5% to 8% of end-stage renal disease (ESRD) [1, 2]. Two disease genes (PKD1 and PKD2) have been identified and, respectively, account for ∼85% and ∼15% of cases in the Caucasian population [2]. Polycystin 1 and 2, the gene products of PKD1 and PKD2, are plasma membrane proteins that form components of a novel multifunctional signaling pathway [1]. Polycystin 1 is predicted to have a receptor-like structure, and may be involved in cell-cell and/or cell-matrix interaction. By contrast, polycystin 2 is thought to function as a subunit of a nonselective cation channel. Both proteins have been shown to interact in vitro through their cytoplasmic region, and transmit fluid-flow mediated mechanosensation by the primary cilium in renal epithelium [1, 3]. Disruption of the function of polycystin 1 or 2 may cause ADPKD, owing to the inability of the tubular epithelial cells to sense mechanical cues that normally regulate tissue morphogenesis [3]. A striking feature of ADPKD is its phenotypic variability. In particular, renal disease progression in ADPKD is highly variable, with the age of ESRD ranging from childhood to old age [1, 2]. Recent studies have shown that genomic deletion of PKD1 and TSC2, or bilineal inheritance of heterozygous PKD1 and PKD2 mutations, can result in earlier and more severe renal disease in a small number of patients [2]. For the majority of cases, however, the gene locus confers a major effect for interfamilial renal disease variability: patients from PKD1 families have Key words: heritability, renal disease progression, ADPKD. C
2005 by the International Society of Nephrology
an earlier onset of ESRD than patients from PKD2 families [median age at ESRD: 53 (95%CI: 51.2-54.8) vs. 69 (95%CI: 66.9-71.3)] years, respectively) [4]. A gender effect on renal survival (i.e., absence of ESRD) favoring the female patients is also evident in type 2, but in not type 1 ADPKD [4–6]. By contrast, a weak allelic effect (based on the 5’ vs. 3’ location of the germline mutations) on renal disease progression may exist for type 1 [5], but not type 2 ADPKD [6]. Additionally, significant intrafamilial renal disease variability has been well documented in both type 1 and 2 ADPKD [5–7]. These latter findings suggest that renal disease progression in ADPKD may be modified by genetic, environmental, and stochastic factors independent of the germline PKD mutations. The existence of modifier genes for ADPKD is further supported by a recent study documenting a larger intraclass correlation coefficient for the age of onset of ESRD in 9 monozygotic twin pairs compared to 56 sibships [8]. Nevertheless, the magnitude of the modifier gene effect for renal disease progression in ADPKD is not currently known. In this issue of Kidney International, Fain et al [9] reported their quantitative genetic analysis on a number of phenotypic traits from 315 affected relatives in 83 multiplex PKD1 families. Using the variance components analysis, they estimated the heritability (i.e., the proportion of variance due to modifier genes) of these traits. They found that inherited difference in modifier genes accounted for 18% to 59% of the variance of the traits examined. Importantly, they found that modifier genes accounted for ∼32% of the variance for creatinine clearance (Ccr) and 43% to 50% of the variance for age of ESRD. Additionally, modifier genes accounted for a significant proportion of the variances for other surrogate measures of renal and hepatic cystic disease. The main strengths of this study included the use of a robust research methodology for within-family comparisons in a well-characterized cohort of PKD1 families, which controlled for differences in age, gender, gene locus, and allelic effects. However, there were some limitations, as well. First, there was a selection bias for younger and less severely affected patients in this study. As a result, the median age of ESRD in the study cohort was older than that from 2 recent 1630
Editorial
PKD1 studies (61 vs. 53 and 54 years, respectively) [4, 5]. Consequent to the enrichment of younger patients whose disease has not been given a chance to manifest fully, the current study may underestimate the true magnitude of the modifier gene effect. Second, a number of trait values in the current study were not normally distributed. Violation of this assumption in the variance components analysis may impact the precision of the heritability estimates. Thus, the extreme kurtosis in the distribution of serum creatinine values could affect the reliability of its heritability estimate compared to other related traits, such as Ccr and age of ESRD. Nevertheless, the heritability estimates on Ccr and age of ESRD in the current study are generally concordant with another recent study of largely unselected PKD1 patients using similar study design [10]. While differences in methodology preclude direct comparisons between these 2 studies, they do support the notion that both genetic and environment modifiers play a significant role for renal disease progression of ADPKD. Where do we go from here? I believe that a formal and systematic search for genetic modifiers of renal disease progression in ADPKD is justifiable at this time. However, the identification of these modifier genes will be challenging because of the polygenic nature of this complex trait [11]. The best scenario that one can hope for is that a few moderately strong gene loci account for most of the modifier effect. Even under this scenario, a large patient and family resource will still be required to ensure adequate power in the study [9, 10], which underpins the need for large-scale international collaboration. The identification of major modifier genes in ADPKD is expected to improve our current understanding of the relevant molecular pathways, as well as environmental factors (for gene-environment interaction) that promote
1631
progression of this renal disease. Such knowledge is essential for future development of individualized patient risk prediction and mechanism-based therapeutics for ADPKD—a promise of molecular medicine. YORK PEI
Toronto, Ontario, Canada Correspondence to York Pei, M.D., Divisions of Nephrology and Genomic Medicine, University Health Network, 8N838, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2. E-mail: [email protected]
REFERENCES 1. IGARASHI P, SOMLO S: Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13:2384–2398, 2002 2. PEI Y: Molecular genetics of autosomal dominant kidney disease. Clin Invest Med 26:252–258, 2003 3. NAULI SM, ALENGHAT FJ, LUO Y, et al: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137, 2003 4. HATEBOER N, DIJK VAN MA, BOGDANOVA N, et al: Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 353:103–107, 1999 5. ROSSETTI S, BURTON S, STRMECKI L, et al: The position of the polycystic kidney disease 1 gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 13:1230–1237, 2002 6. MAGISTRONI R, HE N, WANG KR, et al: Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 14:1164–1174, 2003 7. HATEBOER N, LAZAROU LP, WILLIAMS AJ, et al: Familial phenotype differences in PKD1. Kidney Int 56:34–40, 1999 8. PERSU A, DUYME M, PIRSON Y, et al: Comparison between siblings and twins supports a role for modifier genes in ADPKD. Kidney Int 66:2132–2136, 2004 9. FAIN PR, MCFANN KK, TAYLOR MRG, et al: Modifier genes play a significant role in the phenotypic expression of PKD1. Kidney Int 67:1256–1267, 2005 10. PATERSON A, MAGISTRONI R, HE N, et al: Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol (in press) 11. DIPPLE K, MCCABE E: Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 71:43–50, 2000