Identification of a functional variant in SPLUNC1 associated with nasopharyngeal carcinoma susceptibility among Malaysian Chinese.
Nasopharyngeal carcinoma (NPC) is a multifactorial and polygenic disease with high incidence in Asian countries. Epstein-Barr virus infection, environmental and genetic factors are believed to be involved in the tumorigenesis of NPC. The association of single nucleotide polymorphisms (SNPs) in LPLUNC1 and SPLUNC1 genes with NPC was investigated by performing a two-stage case control association study in a Malaysian Chinese population. The initial screening consisted of 81 NPC patients and 147 healthy controls while the replication study consisted of 366 NPC patients and 340 healthy controls. The combined analysis showed that a SNP (rs2752903) of SPLUNC1 was significantly associated with the risk of NPC (combined P = 0.00032, odds ratio = 1.62, 95% confidence interval = 1.25-2.11). In the subsequent dense fine mapping of SPLUNC1 locus, 36 SNPs in strong linkage disequilibrium with rs2752903 (r(2) ≥ 0.85) were associated with NPC susceptibility. Screening of these variants by electrophoretic mobility shift and luciferase reporter assays showed that rs1407019 located in intron 3 (r(2)  = 0.994 with rs2752903) caused allelic difference in the binding of specificity protein 1 (Sp1) transcription factor and affected luciferase activity. This SNP may consequently alter the expression of SPLUNC1 in the epithelial cells. In summary, our study suggested that rs1407019 in intronic enhancer of SPLUNC1 is associated with NPC susceptibility in which its A allele confers an increased risk of NPC in the Malaysian Chinese population.
Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Tsurumi-ku, Yokohama, Japan.
Poh-Yin
PY
Yew
Taisei
T
Mushiroda
Kazuma
K
Kiyotani
Gopala Krishnan
GK
Govindasamy
Lee-Fah
LF
Yap
Soo-Hwang
SH
Teo
Paul Vey-Hong
PV
Lim
Selvaratnam
S
Govindaraju
Kananathan
K
Ratnavelu
Choon-Kook
CK
Sam
Yoke-Yeow
YY
Yap
Alan Soo-Beng
AS
Khoo
Kin-Choo
KC
Pua
Yusuke
Y
Nakamura
Ching-Ching
CC
Ng
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001324:Autoantigens; D002277:Carcinoma; D016022:Case-Control Studies; D002681:China / Q000208:ethnology; D024202:Electrophoretic Mobility Shift Assay; D050556:Fatty Acid-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D016017:Odds Ratio; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011897:Random Allocation; D055815:Young Adult
D001324:Autoantigens; C485599:BPIFA1 protein, human; C568077:BPIFB1 protein, human; D050556:Fatty Acid-Binding Proteins; D006023:Glycoproteins; D010750:Phosphoproteins; D011506:Proteins