Frequency of rare allelic variation in candidate genes among individuals with low and high urinary calcium excretion

Our study investigated the association of rare allelic variants with extremes of 24-hour urinary calcium excretion because higher urinary calcium excretion is a dominant risk factor for calcium-based kidney stone formation. We resequenced 40 candidate genes potentially related to urinary calcium exc...

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Published in:PloS one 2013-08, Vol.8 (8), p.e71885
Main Authors: Toka, Hakan R, Genovese, Giulio, Mount, David B, Pollak, Martin R, Curhan, Gary C
Format: Article
Language:English
Subjects:
Adult
Aged
Alleles
Biology
Calcium
Calcium (urinary)
Calcium - urine
Chi-Square Distribution
Claudins - genetics
Cohort Studies
Deoxyribonucleic acid
DNA
DNA sequencing
Enrichment
Excretion
Female
Follow-Up Studies
Gene Frequency
Gene sequencing
Genes
Genetic Predisposition to Disease - genetics
Haplotypes
Humans
Kidney Calculi - genetics
Kidney Calculi - urine
Kidney stones
Kidneys
Male
Medical personnel
Medicine
Middle Aged
Multiplexing
Mutation
Next-generation sequencing
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Risk Factors
Rodents
Sequence Analysis, DNA
Single-nucleotide polymorphism
Urine
Womens health
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cited_by cdi_FETCH-LOGICAL-c526t-5398a81fcd2a07b83dac0d7fad098d59356801c55b3c1b8de529b3648372e69a3
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description Our study investigated the association of rare allelic variants with extremes of 24-hour urinary calcium excretion because higher urinary calcium excretion is a dominant risk factor for calcium-based kidney stone formation. We resequenced 40 candidate genes potentially related to urinary calcium excretion in individuals from the Nurses' Health Studies I & II and the Health Professionals Follow-up Study. A total of 960 participants were selected based on availability of 24-hour urine collection data and level of urinary calcium excretion (low vs. high). We utilized DNA sample pooling, droplet-based target gene enrichment, multiplexing, and high-throughput sequencing. Approximately 64% of samples (n = 615) showed both successful target enrichment and sequencing data with >20-fold deep coverage. A total of 259 novel allelic variants were identified. None of the rare gene variants (allele frequencies
doi_str_mv 10.1371/journal.pone.0071885
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We resequenced 40 candidate genes potentially related to urinary calcium excretion in individuals from the Nurses' Health Studies I &amp; II and the Health Professionals Follow-up Study. A total of 960 participants were selected based on availability of 24-hour urine collection data and level of urinary calcium excretion (low vs. high). We utilized DNA sample pooling, droplet-based target gene enrichment, multiplexing, and high-throughput sequencing. Approximately 64% of samples (n = 615) showed both successful target enrichment and sequencing data with &gt;20-fold deep coverage. A total of 259 novel allelic variants were identified. None of the rare gene variants (allele frequencies &lt;2%) were found with increased frequency in the low vs. high urinary calcium groups; most of these variants were only observed in single individuals. Unadjusted analysis of variants with allele frequencies ≥ 2% suggested an association of the Claudin14 SNP rs113831133 with lower urinary calcium excretion (6/520 versus 29/710 haplotypes, P value = 0.003). Our data, together with previous human and animal studies, suggest a possible role for Claudin14 in urinary calcium excretion. Genetic validation studies in larger sample sets will be necessary to confirm our findings for rs113831133. 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subjects Adult
Aged
Alleles
Biology
Calcium
Calcium (urinary)
Calcium - urine
Chi-Square Distribution
Claudins - genetics
Cohort Studies
Deoxyribonucleic acid
DNA
DNA sequencing
Enrichment
Excretion
Female
Follow-Up Studies
Gene Frequency
Gene sequencing
Genes
Genetic Predisposition to Disease - genetics
Haplotypes
Humans
Kidney Calculi - genetics
Kidney Calculi - urine
Kidney stones
Kidneys
Male
Medical personnel
Medicine
Middle Aged
Multiplexing
Mutation
Next-generation sequencing
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Risk Factors
Rodents
Sequence Analysis, DNA
Single-nucleotide polymorphism
Urine
Womens health
title Frequency of rare allelic variation in candidate genes among individuals with low and high urinary calcium excretion
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