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Am J Nephrol. 2018;47(5):304-316. doi: 10.1159/000488946. Epub 2018 May 18.

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study.

Author information

1
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
3
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
4
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5
Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan.
6
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
7
Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
8
Department of Health Science, Shiga University of Medical Science, Otsu, Japan.
9
Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
10
Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
11
Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
12
Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan.
13
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
14
Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan.
15
Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
16
Department of Preventive Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.

Abstract

BACKGROUND:

Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide.

METHODS:

We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects.

RESULTS:

In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations.

CONCLUSION:

Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

KEYWORDS:

Chronic kidney disease; Genome-wide association study; Population-based cohort

PMID:
29779033
DOI:
10.1159/000488946

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