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A SNP in the ABCC11 gene is the determinant of human earwax type

Abstract

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G → A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G → A SNP is the first example of DNA polymorphism determining a visible genetic trait.

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Acknowledgements

We are grateful to all volunteers, especially to Nagasaki University Administration Officers, for their participation in this study and are grateful to S. Horai, P. Duanchang, S. Pookajorn, A. Soemantri, W. Settheetham-Ishida, P.G. Babu, R. Kimura, P.N. Tongol-Rivera, K. Tajim, L.H. Sulaiman and K. Na-Bangchang for assistance in collecting samples. We also thank N. Yanai and Y. Noguchi for their technical assistance and S.M. Kennedy for correction of the manuscript. This study was supported in part by CREST from the Japan Science and Technology Agency (JST) and Grants-in-Aid for Scientific Research (Category S, No. 13854024; Priority Area 'Applied Genomics' No. 17019055; Category C, No. 17590288) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Koh-ichiro Yoshiura.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Three-locus genotypes of 118 and 126 Japanese whose earwax types were self-declared and diagnosed otologically, and who underwent the first- and second-step association analyses, respectively. (PDF 47 kb)

Supplementary Table 2

Genotypes at the rs17822931 site and frequencies of alleles “A” and Δ27 in ABCC11 and of dry cerumen among different human populations. (PDF 78 kb)

Supplementary Table 3

Inferred haplotypes' frequencies at three polymorphic loci (rs17822931-rs6500380-ss49784070) in the Japanese (Nagasaki inhabitants), Southern Han Chinese (Changsha inhabitants), Native Americans, Native Bolivians, and the CEPH families of European origin. (PDF 51 kb)

Supplementary Table 4

Primer sequences for 24 SNPs that were used for haplotyping in a 600-kb interval and its flanking region. (PDF 64 kb)

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Figure 1: Four genes, ABCC12, ABCC11, LONPL and SIAH1, and 31 polymorphic DNA markers located in the 600-kb region between B81540 and IMS-JST141676.
Figure 2: Linkage disequilibrium (LD) analysis of candidate region.
Figure 3: Pedigree analysis of an individual showing phenotype-genotype discrepancy (at rs17822931).
Figure 4: Worldwide frequency of allele A (open portion in each circle).
Figure 5: ABCC11 expression and cGMP transport in LLC-PK1 cells transfected with allele A and those with allele G.