ライフサイエンスコーパス: SLC30A8

1 enes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8.

2 ently described associations at HHEX/IDE and SLC30A8.

3 the impact of the type 2 diabetes-protective SLC30A8 allele (p.Lys34Serfs50*) and found that BLCs wit

4 we examined multiple variants that influence SLC30A8 allele-specific expression.

5 ificance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and

6 ur T2DM susceptibility loci (CDKAL1, MTNR1B, SLC30A8 and PAM) to emphasize how a holistic approach in

7 EndoC-betaH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves gluco

8 sted (ANPEP, CAMK2B, HMG20A, KCNJ11, NOTCH2, SLC30A8, and WFS1), with significant AEI confirmed for f

9 560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SN

10 y showing that loss-of-function mutations in SLC30A8 are protective against diabetes.

11 s to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified i

12 was likely due to effects of HLA-DQ2 and the SLC30A8 CC (RR) genotypes.

13 s) in 12 loci (e.g., TCF7L2, IDE/KIF11/HHEX, SLC30A8, CDKAL1, PKN2, IGF2BP2, FLJ39370, and EXT2/ALX4)

14 ype 2 diabetes-associated SNPs that truncate SLC30A8 confer protection from this disease, contradicti

15 a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%)

16 y, we generated mice with beta cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an une

17 ted an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance.

18 The impact of Slc30a8 deletion was examined in the context of the pure

19 tes that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation a

20 ecific modifier genes modulate the impact of Slc30a8 deletion.

21 SLC30A8 encodes a zinc transporter ZnT8 largely restrict

22 SLC30A8 encodes zinc transporter-8 (ZnT8), which deliver

23 A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is

24 udies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated

25 carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as asses

26 One of the latter (rs13266634) locates in an SLC30A8 exon, encoding a tryptophan-to-arginine substitu

27 that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency.

28 and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study

29 phan-to-arginine substitution that decreases SLC30A8 function, which is the canonical explanation for

30 of an overlapping enhancer and suggesting an SLC30A8 gain of function as the cause for the increased

31 al groups have examined the effect of global Slc30a8 gene deletion but the results have been highly v

32 The SLC30A8 gene encodes the islet-specific transporter ZnT-

33 e nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is asso

34 DKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions.

35 Correspondingly, polymorphisms in the SLC30A8 gene, encoding the secretory granule Zn(2)(+) tr

36 While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP

37 tions in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggest

38 Ps) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZ

39 ide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO

40 KN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated wit

41 A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loc

42 h patients due to different polymorphisms of SLC30A8, HLA-DQ, or both.

43 erve evidence that diabetes risk for CDKAL1, SLC30A8, IGF2BP2, and LOC387761 is specifically mediated

44 i including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birt

45 AL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression

46 To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 wa

47 ci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four

48 s of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes.

49 A polymorphic variant in SLC30A8 is associated with altered susceptibility to typ

50 Zinc transporter eight (SLC30A8) is a major target of autoimmunity in human type

51 Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin le

52 enotypic heterogeneity was observed in mouse Slc30a8 knockouts.

53 In contrast, female C57BL/6J Slc30a8 KO mice had reduced ( approximately 20%) fasting

54 Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance.

55 rs observed in male mixed genetic background Slc30a8 KO mice.

56 In human beta cells, loss of SLC30A8 leads to increased glucose responsiveness and re

57 idence for effect size heterogeneity for the SLC30A8 locus alone (RR(obese) 1.08 [1.01-1.15]; RR(nono

58 ered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.

59 Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D)

60 d an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associ

61 s at the solute carrier family 30, member 8 (SLC30A8) locus were nominally associated with decreased

62 sion of key beta cell genes, including Ins2, Slc30a8, MafA, Slc2a2, G6pc2, and Glp1r, was reduced aft

63 provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers.

64 the genotype of a common T2D-risk allele in SLC30A8, p.Arg325.

65 ions, which is spatially associated with the SLC30A8 promoter and additional neighboring genes.

66 tion variants in the zinc efflux transporter SLC30A8 reduce T2D risk.

67 Our results indicate that SLC30A8 regulates hepatic insulin clearance and that gen

68 nteraction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (be

69 ), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05].

70 ), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.

71 to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs44

72 The SLC30A8 SNP allele frequency (75% C and 25% T) varied li

73 Previous functional study of SLC30A8 suggested that reduced zinc transport increases

74 12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5.

75 ing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated re

76 Although common SLC30A8 variants, believed to reduce ZnT8 activity, incr

77 lc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in alpha-cells by cr

78 anking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of ne

79 ified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)

80 linkage between deleterious mutations in the SLC30A8 zinc transporter, which transports zinc into the

81 the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant.

82 etes autoantigens, such as insulin, IA-2 and Slc30a8 (ZnT8).