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Genetic Factors Associated With Gout and Hyperuricemia

2006; Elsevier BV; Volume: 13; Issue: 2 Linguagem: Inglês

10.1053/j.ackd.2006.01.008

1548-5609

Anthony J. Bleyer, Thomas C. Hart,

Alcohol Consumption and Health Effects

Hyperuricemia and gout are common conditions that have long been known to have a heritable component. Obesity, diabetes, and chronic kidney failure are conditions with multifactorial inheritance that are associated with gout. In addition, social factors such as protein and alcohol intake affect serum uric acid levels. The current review discusses basic uric acid metabolism and the multigenetic inheritance of hyperuricemia. Several monogenic disorders affecting uric acid metabolism are reviewed. The genetics, pathophysiology, diagnosis, and treatment of familial juvenile hyperuricemic nephropathy/medullary cystic kidney disease, autosomal dominant disorders associated with hyperuricemia and progressive kidney failure, are described. Hyperuricemia and gout are common conditions that have long been known to have a heritable component. Obesity, diabetes, and chronic kidney failure are conditions with multifactorial inheritance that are associated with gout. In addition, social factors such as protein and alcohol intake affect serum uric acid levels. The current review discusses basic uric acid metabolism and the multigenetic inheritance of hyperuricemia. Several monogenic disorders affecting uric acid metabolism are reviewed. The genetics, pathophysiology, diagnosis, and treatment of familial juvenile hyperuricemic nephropathy/medullary cystic kidney disease, autosomal dominant disorders associated with hyperuricemia and progressive kidney failure, are described. Hyperuricemia is a classic example of a disorder with multifactorial inheritance. This article will review the basic pathophysiology of hyperuricemia, the polygenetic inheritance of hyperuricemia, and monogenic disorders classically associated with gout. It will focus on the primary genetic conditions associated with hyperuricemia due to kidney disease, including familial juvenile hyperuricemic nephropathy (FJHN)/medullary cystic kidney disease (MCKD). Uric acid is a key metabolite in nucleic acid metabolism (Fig 1). The uric acid pool is determined by endogenous uric acid production as well as uric acid formed from daily purine ingestion. Hyperuricemia leads to joint deposition of uric acid and the classic clinical manifestations of gout. Hyperuricemia may be considered the result of overproduction of uric acid or underexcretion of uric acid by the kidney. Overproduction of uric acid occurs through increased dietary intake of meats and seafood or endogenous defects in uric acid metabolism.1Choi H.K. Mount D.B. Reginato A.M. Pathogenesis of gout.Ann Int Med. 2005; 143: 499-516Crossref PubMed Scopus (760) Google Scholar Underexcretion of uric acid is the result of deficiencies of renal excretion of uric acid. Such deficiencies are most frequently the result of renal insufficiency or conditions associated with enhanced uptake of uric acid by the proximal tubule (ie, congestive heart failure, diuretic usage, and volume depletion). Therefore, from a general standpoint, genetic disorders resulting in hyperuricemia will cause either an overproduction of uric acid, with alterations in the enzymes regulating nucleic acid metabolism, or underexcretion of uric acid, in which renal handling of uric acid is affected. Specific enzyme defects in uric acid metabolism that have been identified are quite uncommon (hypoxanthine-guanine phosphoribosyl transferase [HPRT] deficiency and phosphoribosylpyrophosphate [PRPP] synthetase overactivity). Because proximal tubular transporters lead to uric acid reabsorption and because most genetic defects lead to loss of function rather than gain of function, specific genetic mutations in tubular transporters are likely to lead to hypouricemia rather than hyperuricemia.2Iwali N. Mino Y. Hosoyamada M. et al.A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese.Kidney Int. 2004; 66: 935-944Crossref PubMed Scopus (95) Google Scholar Therefore, in most individuals, hyperuricemia is the result of genetic disorders that indirectly affect uric acid metabolism or tubular handling of uric acid. However, there are specific genetic disorders of metabolism and kidney function that lead to hyperuricemia (see later). Mutations in the gene encoding the enzyme uricase (which converts uric acid to the very soluble allantoin, Fig 1) are present in all humans. Studies of the uricase gene have shown that at some point in man's history, the uricase gene common to all humans sustained 2 separate mutations that independently resulted in truncation of transcription of the uricase gene.1Choi H.K. Mount D.B. Reginato A.M. Pathogenesis of gout.Ann Int Med. 2005; 143: 499-516Crossref PubMed Scopus (760) Google Scholar The occurrence of these mutations must have resulted in extraordinary implications because all humankind subsequently possessed them. Speculations regarding the uricase gene mutations include that these changes somehow resulted in an increase in intelligence in affected species or increased antioxidant levels in the blood. Another theory is that uric acid production improved the ability of humans to retain salt. Such changes may have produced a distinct evolutionary advantage in a sodium-deficient environment. However, in today's salt-avid society, these changes could be detrimental and are now postulated to be important factors in the development of hypertension and potentially kidney failure.3Johnson R.J. Titte S. Cade J.R. et al.Uric acid, evolution and primitive cultures.Semin Nephrol. 2005; 25: 3-8Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Gout should be viewed as a classic multigenetic disorder. A primary defect in the uricase gene may be combined with another monogenic disorder (such as HPRT deficiency) to result in gout or a combination of genetic defects (eg, as may occur in diabetic nephropathy or obesity) together with the uricase mutation lead to gout. In addition, many environmental factors play a very important role in the development of gout, most notably differences in dietary protein intake4Choi H.K. Atkinson K. Karlson E.W. et al.Purine-rich foods, dairy and protein intake, and the risk of gout in men.N Engl J Med. 2004; 350: 1093-1103Crossref PubMed Scopus (821) Google Scholar and alcohol usage. Important factors include the following: 1Gender: in numerous studies, men have been found to have increased serum uric acid levels compared with women. Increased dietary protein intake and endogenous uric acid production are contributory. In addition, androgen-related factors appear to lead to decreased renal excretion of uric acid. Fractional excretion of uric acid decreases in adolescence in men5Stapleton F.B. Linshaw M.A. Hassanein K. et al.Uric acid excretion in normal children.J Pediatr. 1978; 92: 911-914Abstract Full Text PDF PubMed Scopus (101) Google Scholar but does not decrease similarly in females. For these reasons, gout is much more common in men than in women.2Obesity, also a genetically determined trait, is highly associated with hyperuricemia and gout because of increased uric acid production as well as decreased uric acid excretion.3Kidney failure leads to decreased excretion of uric acid, leading to a high predominance of hyperuricemia in patients with kidney disease. This hyperuricemia has been well described in inherited renal disorders such as polycystic kidney disease and glomerulonephritis. However, the mild, chronic renal insufficiency present in 10% of the general population likely leads to most cases of gout.4Alcohol intake is associated with an increase in endogenous uric acid production. Alcohol intake is determined by both social and genetic factors. All of these traits and characteristics lead to a high degree of heritability of gout in the general population. In 1823, Scudamore noted that the father was afflicted in 87% of patients with a positive family history of gout.6Talbott J.H. Gout. Grune and Stratton, New York, NY1964Google Scholar In 1955, Hauge and Harvald7Hauge M. Harvald B. Heredity in gout and hyperuricemia.Acta Med Scand. 1955; 152: 247-257Crossref PubMed Scopus (27) Google Scholar studied 32 gout patients and 261 relatives. These authors identified elevated mean serum uric acid levels in brothers and sisters of patients with gout compared with controls. These authors also noted that a single dominant gene did not appear to cause gout. In the limited number of familial studies of gout, there is very little information on what genetic or epigenetic factors are driving the familial incidence of hyperuricemia (eg, social status [with increased meat or alcohol intake], obesity, diabetes, or renal insufficiency). Grahame and Scott8Grahame R. Scott J.T. Clinical survey of 354 patients with gout.Ann Rheum Dis. 1970; 29: 461-468Crossref PubMed Scopus (167) Google Scholar studied 354 consecutive gout patients from a clinical practice in England. In this group of patients, 9.7% were women, 48% were more than 15% above their ideal weight, 37% consumed a minimum of 2 pints of beer or 2 double whiskies per day, and 25% had a blood urea nitrogen level of greater than 45 mg/dL. Of these individuals, 36% had at least 1 family member with gout, but it was unclear which factors were most likely to lead to the heredity of this disorder. In a study by Chen et al9Chen S.-Y. Chen C.-L. Shen M.-L. et al.Clinical features of familial gout and effects of probable genetic association between gout and its related disorders.Metabolism. 2001; 50: 1203-1207Abstract Full Text PDF PubMed Scopus (29) Google Scholar of a Taiwanese gout registry with 21,373 patients with gout, there was a similar body mass index, serum creatinine, and rate of diabetes mellitus between individuals with familial gout and nonfamilial gout. Hyperlipidemia and hypertriglyceridemia were more common in individuals with nonfamilial gout. There have been several studies examining specific genetic factors associated with gout. In a recent investigation, 2 single nucleotide polymorphisms in the enzyme xanthine oxidase and 2 in the uric acid transferase 1 transporter were associated with hyperuricemia and hypertension.10Rowder N.J. Rao F. Rana B.K. et al.Uric acid regulatory enzyme polymorphisms show significant effects on heritability of plasma uric acid, hypertension, and GFR in human twin pairs.J Am Soc Nephrol. 2005; 16: 368AGoogle Scholar In another study, the uncommon S2 allele variant of apoprotein CIII was found in 9 of 48 gout patients compared with 1 of 41 randomly selected individuals.11Ferns G.A. Lanham J. Dieppe P. et al.A DNA polymorphism of an apoprotein gene associates with the hypertriglyceridemia of primary gout.Hum Genet. 1988; 78: 55-59Crossref PubMed Scopus (35) Google Scholar There have been no subsequent investigations examining this relationship. Although many different genetic disorders are associated with hyperuricemia, there are 3 disorders that are particularly associated with a very high frequency of hyperuricemia and gout. These disorders are Lesch-Nyhan syndrome (HPRT deficiency), PRPP synthase overactivity, and familial juvenile hyperuricemic nephropathy/medullary cystic kidney disease. HPRT deficiency is an X-linked disorder characterized by uric acid overproduction resulting in precocious hyperuricemia, uric acid nephrolithiasis, spasticity, choreoathetosis, and mental retardation with self-mutilation.12Nyhan W.L. Inherited hyperuricemic disorders.Contrib Nephrol. 2005; 147: 22-34PubMed Google Scholar Some individuals with this disorder do not suffer from mental retardation and self-mutilation. The gene for HPRT is located on the long arm of the X chromosome. The gene contains 9 exons and 8 introns spanning 44 kb. Genetic mutations result in marked loss of HPRT function. HPRT is important in the recycling of hypoxanthine and guanine; the absence of HPRT results in excessive uric acid production (Fig 1). Two thirds of mutations result in truncated proteins. Patients who have conservative amino acid substitutions may have some HPRT activity. These patients still suffer from hyperuricemia and gout, but they are less likely to suffer from neurologic defects. Allopurinol therapy will prevent hyperuricemia and its metabolic complications but will not affect the changes found in the central nervous system. Patients who do not receive allopurinol therapy develop tophaceous gout, uric acid nephrolithiasis, and slowly progressive renal insufficiency as the result of interstitial urate deposition. PRPP synthetase catalyzes the first step in the de novo synthesis of purines (Fig 1). Increased activity of PRPP synthetase results in an increased production of purines and subsequently uric acid. Clinical characteristics include hyperuricemia and hyperuricosuria.13Cameron J.S. Moro F. Simmonds H.A. Gout, uric acid, and purine metabolism in pediatric nephrology.Pediatr Nephrol. 1993; 7: 105-118Crossref PubMed Scopus (150) Google Scholar Severely affected individuals may suffer from severe mental retardation, dysmorphic features, deafness, and pneumonia with death in infancy. There are 2 genes on the X chromosome that encode PRPP synthetase. PRPP synthetase overactivity has been associated with mutations in PRPP synthetase 1 gene at Xq22-24. Diagnostic testing includes measurement of PRPP synthetase function. Treatment with allopurinol is effective in controlling hyperuricemia and uric acid nephrolithiasis, although care must be taken to prevent the development of xanthine stones. Familial juvenile hyperuricemic nephropathy/MCKD) refers to a group of autosomal dominant disorders whose cardinal manifestations are precocious hyperuricemia and progressive chronic kidney disease. These conditions have been much better defined recently with genetic linkage.14Hart T.C. Gorry M.C. Hart P.S. et al.Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.J Med Genet. 2002; 39: 882-892Crossref PubMed Scopus (390) Google Scholar, 15Dahan K. Fuchshuber A. Adamis S. et al.Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2 Two facets of the same disease?.J Am Soc Nephrol. 2001; 12: 2348-2357PubMed Google Scholar, 16Dahan K. Devuyst O. Smaers M. et al.A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.J Am Soc Nephrol. 2003; 14: 2883-2893Crossref PubMed Scopus (181) Google Scholar At present, these conditions are best termed MCKD 1, MCKD 2, and MCKD 3. MCKD 1 has been linked to chromosome 1q21,17Stavrou C. Koptides M. Tombazos C. et al.Autosomal-dominant medullary cystic kidney disease type 1 Clinical and molecular findings in six large Cypriot families.Kidney Int. 2002; 62: 1385-1394Crossref PubMed Google Scholar and MCKD3 has been linked to 1q41.18Hodanova K. Kublova M. Vyletqal P. et al.Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.Kidney Int. 2005; 68: 1472-1482Crossref PubMed Scopus (30) Google Scholar MCKD and FJHN are the same disorders and are simply different names that have been used in the past by different researchers. Uromodulin-associated kidney disease is a term that has been used to describe MCKD 2, which results from a mutation in the uromodulin gene. Although medullary cystic kidney disease is the most commonly used term, it should be noted that most affected patients do not have medullary cysts on ultrasound. The predominant clinical characteristics are hypouricosuric hyperuricemia and chronic kidney failure. Hyperuricemia has been best characterized in MCKD type 2. In this disorder, hypouricosuric hyperuricemia starts early in childhood, although individuals do not usually present with gout until the teenage years.19Bleyer A.J. Woodard A.S. Shihabi Z. et al.Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene.Kidney Int. 2003; 64: 36-42Crossref PubMed Scopus (72) Google Scholar Most male individuals with the condition will suffer from gout, but many female individuals will suffer from hyperuricemia without gout. Gout may progress to the development of chronic tophi and crippling arthritis. Treatment with allopurinol will absolutely prevent the development of gout. Figure 2 shows the distribution of hyperuricemia in a family with MCKD2. Although many affected women are hyperuricemic, a significant number have normal serum uric acid levels. Younger women with preserved kidney function are more likely to have normal serum uric acid levels. In contrast, affected males all have hyperuricemia. However, they cannot be differentiated individually from unaffected male family members because a number of unaffected males will have hyperuricemia. Chronic kidney failure also develops in individuals with this condition, with a slow progressive decline in kidney function beginning in the late teens and steadily deteriorating until end-stage kidney disease develops. The age of onset of kidney disease is somewhat variable within and between families, with end-stage disease occurring anytime between the late thirties and early seventies. MCKD 1 has been linked to chromosome 1q21,17Stavrou C. Koptides M. Tombazos C. et al.Autosomal-dominant medullary cystic kidney disease type 1 Clinical and molecular findings in six large Cypriot families.Kidney Int. 2002; 62: 1385-1394Crossref PubMed Google Scholar and MCKD 3 has been linked to 1q41. Neither gene has yet been dentified.18Hodanova K. Kublova M. Vyletqal P. et al.Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.Kidney Int. 2005; 68: 1472-1482Crossref PubMed Scopus (30) Google Scholar Mutations in the uromodulin gene have been found to be the cause of MCKD 2. Mutations have been found in more than 40 families worldwide. Uromodulin is a very cysteine-rich protein, and these cysteine residues are extremely important in allowing uromodulin to assume its tertiary structure.20Serafini-Cessi F. Malagolini N. Cavallone D. Tamm-Horsfall glycoprotein Biology and clinical relevance.Am J Kidney Dis. 2003; 42: 658-676Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar All mutations found to date in the uromodulin gene occur in exon 4,5, or 6, and almost all mutations have been found to result in an exchange resulting in the loss or gain of a cysteine residue. MCKD 2 is best viewed as a dominant negative condition, where the mutated allele results in not only a loss of protein production from that allele but also a decrease in produced protein from the wild-type allele. Measurements of urinary uromodulin have documented a much more than 50% decrease in uromodulin excretion in affected individuals.21Bleyer A.J. Hart T.C. Shihabi Z. et al.Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein.Kidney Int. 2004; 66: 974-977Crossref PubMed Scopus (76) Google Scholar Uromodulin is a protein produced exclusively in the thick ascending limb and early distal convoluted tubule. The protein has an epidermal growth factor domain as well as a glycophosphatidyl inositol anchor. The function of uromodulin is unknown, but it has been postulated to be important in prevention of urinary tract infections, in the binding of cytokines, and in the maintenance of water impermeability of the thick ascending limb of Henle. However, individuals with mutations in the uromodulin gene do not suffer from an increased rate of urinary tract infections or renal calculi. Patients with MCKD 2 have mutations in the uromodulin gene that result in inabilities in the uromodulin achieving its appropriate tertiary structure. Many of the mutations involve the addition or deletion of a cysteine residue; cysteine is extremely important in cross-linking and the acquisition of the tertiary structure of the molecule. Misfolding of uromodulin is evidenced in the endoplasmic reticulum, where deposits of abnormal uromodulin occur.16Dahan K. Devuyst O. Smaers M. et al.A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.J Am Soc Nephrol. 2003; 14: 2883-2893Crossref PubMed Scopus (181) Google Scholar, 22Rampoldi L. Caridi G. Santon D. et al.Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.Hum Mol Genet. 2003; 12: 3369-3384Crossref PubMed Scopus (195) Google Scholar Immunohistochemical studies show these precipitants on light microscopic examination of the thick ascending limb. The thick ascending limb cells become apoptotic, and damage to these cells likely leads to cell death, nephron loss, and progressive chronic kidney failure culminating in the need for renal replacement therapy. The cause of hyperuricemia in individuals with uromodulin mutations is unknown. It is known that urate reabsorption occurs proximally, uromodulin knockout mice suffer from volume depletion,23Bachmann S. Mutig K. Bates J. et al.Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.Am J Physiol Renal Physiol. 2005; 288: F559-F567Crossref PubMed Scopus (122) Google Scholar and patients with MCKD2 have mild urinary concentrating defects. Based on these findings, one can conclude that absence of uromodulin in the thick ascending limb leads to changes in this area of the nephron that are communicated back to the proximal tubule and result in enhanced uric acid reabsorption. How these changes occur is at present unknown. There are three cardinal manifestations of MCKD: autosomal dominant inheritance, gout, and chronic kidney failure. Individuals may present with gout in their teenage years or incidentally noted renal insufficiency. Because of the autosomal dominant inheritance, there is frequently a very strong family history of both gout and kidney failure. Family members will have developed end-stage kidney disease with some variability between the fourth and seventh decades. The first diagnostic step is to take an accurate family history to determine the presence of a genetic condition and whether the inheritance is autosomal dominant, X-linked, or autosomal recessive. MCKD should be expected in autosomal dominant disease; nephronophthisis considered in recessive disease. A urinalysis should then be performed to determine if the family has an inherited glomerulonephritis or interstitial disease. The presence of high-grade proteinuria or hematuria suggests a familial glomerular disorder; low-grade proteinuria and bland urinary sediment suggests MCKD. An interstitial disorder with autosomal inheritance suggests a form of medullary cystic kidney disease. Ultrasound will rule out polycystic kidney disease, but the absence of medullary cysts is not helpful because many patients do not have cysts. Renal biopsy is characteristically not helpful because pathologic changes of tubular atrophy and dilatation are nonspecific, and patients are frequently misdiagnosed as having focal sclerosis. Immunohistochemical staining with antibody to uromodulin will show abnormal deposits in thick ascending limb cells, but this staining is not routinely performed and must be requested. If MCKD is expected, hyperuricemia will provide supportive but not definitive evidence. The initial testing should include a serum uric acid, serum creatinine, and urinary uric acid and creatinine. Hyperuricemia should be determined by age and gender-adjusted norms; simply relying on laboratory reference values will underdiagnose hyperuricemia. A fractional excretion of uric acid should be calculated and is usually quite low (<5%) in affected individuals with preserved kidney function. As renal insufficiency develops, the fractional excretion of uric acid will increase into the normal range for affected individuals. Individuals may have MCKD 1, 2, or 3 or another variant. Genetic testing for MCKD 2 can be performed through Athena Diagnostics, Worcester, MA. Athena currently screens exon 4 and 5 for mutations in the uromodulin gene. If a mutation in the uromodulin gene is not uncovered, there are several possibilities. One possibility is that a mutation may be present in another exon. Another possibility is that the patient suffers from MCKD 1 or MCKD 3. Urinary uromodulin excretion may be measured, which has been found to be low in MCKD 2 and MCKD 3. Unfortunately, such testing is not available by a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. In general, families with an autosomal dominant inherited kidney disease of unknown cause should be referred to a medical center for genetic linkage and further characterization. Allopurinol has been postulated to be beneficial in the slowing of progression of MCKD, although this remains controversial.24Fairbanks L. Cameron J. Venkata-Raman G. et al.Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.Q J Med. 2002; 95: 597-607Crossref Google Scholar Allopurinol will prevent the development of worsening, chronic gout and should be especially considered in young men with the condition. Kidney transplantation will result in a cure of the underlying disease because this condition appears limited to the kidney in all types. Studies for mutation in the uromodulin gene or genetic linkage will allow one to identify potential donors among family members.