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Rare Independent Mutations in Renal Salt Handling Genes Contribute to Blood Pressure Variation

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Rare Independent Mutations in Renal Salt Handling Genes Contribute to Blood Pressure Variation ARTICLES Rare independent mutations in renal salt handling genes contribute to blood pressure variation Weizhen Ji1,2,8, Jia Nee Foo1,2,8, Brian J O’Roak1, Hongyu Zhao1,3, Martin G Larson4,5, David B Simon1,2, Christopher Newton-Cheh4, Matthew W State1,6, Daniel Levy4,7 & Richard P Lifton1,2 The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes—SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)—causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, http://www.nature.com/naturegenetics genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits. Hypertension affects 1 billion people world-wide and is a major renal salt wasting and hypotension, often resulting in neonatal death. contributor to death from stroke, myocardial infarction, end-stage It is caused by recessive loss-of-function mutations in any of four renal disease and congestive heart failure. Although epidemiologic genes required for normal renal NaCl reabsorption12–15. These include studies have demonstrated high heritability of blood pressure variation the Na-K-2Cl cotransporter gene SLC12A1 and the inward rectifier Nature Publishing Group Group Nature Publishing 2 B 1 + 8 (h of long-term blood pressure 0.6) , identification of the respon- K channel gene KCNJ1. Gitelman’s syndrome is a less severe salt- sible genes has been difficult owing to the trait’s complexity. wasting disease caused by recessive loss-of-function mutations in the 200 Whether common variants or, alternatively, many independent rare Na-Cl cotransporter gene SLC12A3 (ref. 16). © mutations will account for the contributions of specific genes is The prevalences of Bartter’s and Gitelman’s syndromes (estimated unknown. Recent large genome-wide association studies have identi- at B1 per million and 1 per 40,000, respectively)16,17 suggest that fied a number of common variants that contribute to metabolic traits heterozygous disease alleles should be present in at least 1% of the including diabetes2–4, coronary artery disease5,6, and obesity7;notably, population (likely to be an underestimate, owing to early lethality of these collectively explain only a small fraction of interindividual risk2. Bartter’s syndrome), motivating evaluation of these genes in a large, These studies have thus far failed to identify any statistically significant well characterized cohort. We examined SLC12A1, SLC12A3 and loci for blood pressure or hypertension2,8, raising the possibility that KCNJ1 in the Framingham Heart Study (FHS) offspring cohort. rare independent variants account for a large fraction of blood This cohort, comprising 5,124 subjects (3,125 with DNA), has been pressure variation, as would be expected if trait alleles are under followed for up to 35 years with periodic evaluation of cardiovascular purifying selection9. risk factors and other traits, permitting stable assessments of quanti- The study of rare mendelian traits has identified more than 20 genes tative trait values over time. in which mutations impart large effects on blood pressure; these predominantly act by changing net renal salt reabsorption10,11.Several RESULTS of these disorders, exemplified by Bartter’s and Gitelman’s syndromes, Mutations in SLC12A3, SLC12A1 and KCNJ1 in FHS are recessive traits that lower blood pressure, raising the question of We screened all coding exons and flanking intronic sequences of whether the more prevalent heterozygous mutations in these genes SLC12A3, SLC12A1 and KCNJ1 for DNA sequence variants in the might commonly affect the trait. Bartter’s syndrome features massive 1,985 unrelated subjects and 1,140 relatives with available DNA 1Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA. 2Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA. 3Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, Connecticut 06510, USA. 4National Heart, Lung, and Blood Institute’s Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702, USA. 5Department of Mathematics and Statistics, Boston University, 111 Cummington Street, Boston, Massachusetts 02215, USA. 6Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, Connecticut 06520, USA. 7National Heart, Lung and Blood Institute, 31 Center Drive, Bethesda, Maryland 20892, USA. 8These authors contributed equally to this work. Correspondence should be addressed to R.P.L. ([email protected]). Received 2 November 2007; accepted 15 February 2008; published online 6 April 2008; corrected online 13 April 2008 (details online); doi:10.1038/ng.118 592 VOLUME 40 [ NUMBER 5 [ MAY 2008 NATURE GENETICS ARTICLES samples. This constituted evaluation of B24 Mb of diploid sequence. different disruptive mutations or missense mutations at highly con- The sensitivity of variant detection was high, as we detected all 18 served positions that accounted for 189 mutant alleles in subjects with validated SNPs in these genes and their allele frequencies in FHS were Gitelman’s syndrome. From these data we calculate that these criteria similar to previous frequency estimates (Supplementary Table 1 provide 77% sensitivity and 90% specificity for identification of online). In addition, eight subjects with Gitelman’s syndrome were functional mutations. Further, because 35 of the independent muta- blindly included in the screen and their 16 known mutations were tions in the Gitelman’s cohort were only found once, saturation for correctly identified. Variants were confirmed by two independent disease-causing mutations has not been approached. Similar results methods (Supplementary Fig. 1 online), and variants in the final were found for SLC12A1 and KCNJ1 (disruptive mutations or missense set were further verified by independent amplification of the original mutations at highly conserved positions were found in 86% and 65% sample. These variants recurred among siblings at expected mendelian of Bartter’s alleles, respectively). It is worth noting that we obtained frequencies (32 of 60 siblings), providing assurance of proper sample similar results if we confined the analysis to the 128 Gitelman’s tracking and indicating that few variants are de novo mutations. syndrome subjects of European ancestry (criteria showed 78% A total of 138 different coding sequence variants were found in sensitivity and 90% specificity), excluding a strong effect of 2,492 FHS subjects, whereas the remainder showed only wild-type genetic background on the spectrum of functional mutations. These sequence (Supplementary Table 2 online). The variants included findings provide direct experimental validation that these criteria 46 different synonymous substitutions found in 2,235 subjects, were sensitive and specific for identification of functional mutations 89 different missense variants found in 1,062 subjects, one nonsense mutation and two frameshift mutations. Table 1 Proven and inferred mutations in SLC12A3, SLC12A1 and KCNJ1 in FHS Given the rarity of Bartter’s and Gitelman’s Allele frequency Allele frequency Biochemical syndromes, the vast majority of these variants Phylogenetic conservation in unrelated in European-ancestry loss of must not cause loss of function. We first Variant of wild-type residue FHS subjects subjects with disease function18–22 SIFT/PolyPhen http://www.nature.com/naturegenetics looked for well documented disease-causing mutations that had been shown biochemi- SLC12A3 cally to cause loss of function of the encoded a cotransporter or channel18–22.Thisidentified E112X Disruptive 0.00025 0.0039 Yes NA ten different biochemically proven loss of L155F Complete 0.00025 0 Unknown ++/+ S188F Complete 0.00025 0 Unknown ++/++ function mutations found in 23 subjects A232T Complete 0.00050 0 Unknown ++/+ (Table 1). R261Ca Complete 0.00050 0 Unknown ++/++ We next sought to identify additional R399La Vertebrate 0.00025 0.0078 Yes ++/++ functional variants using phylogenetic con- G439Sa Complete 0.00050 0.0391 Yes ++/++ servation as an indication of amino acid F495L Complete 0.00025 0 Unknown ++/++ positions that are subject to purifying selec- P560Ha Complete 0.00025 0 Unknown ++/++ Nature Publishing Group Group Nature Publishing 8 tion. We characterized orthologs and para- G613Sa Complete 0.00025 0.0039 Yes ++/++ logs of each gene from diverse vertebrate and a 200 G741R Complete 0.00050 0.1211 Yes ++/++ © invertebrate species (10–12 orthologs and G779E Complete 0.00025 0 Unknown ++/++ 6–14 paralogs for each gene; see Methods) R861Ca Vertebrate 0.00025 0.0195 Unknown ++/+ and determined the conservation of each R964Qa Vertebrate 0.00025 0.0117 Yes ++/++ amino acid
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