Tessier M-C, Qu H-Q, Fréchette R, Bacot F, Grabs R, Taback S P, Lawson M L, Kirsch S E, Hudson T J, Polychronakos C
Endocrine Genetics Laboratory, The McGill University Health Center, Montreal Children's Hospital, Montréal, Québec, Canada.
J Med Genet. 2006 Feb;43(2):129-32. doi: 10.1136/jmg.2005.035212. Epub 2005 Jul 13.
The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D).
We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7.
All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671.
We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.
2',5'-寡腺苷酸合成酶基因（OAS1、OAS2和OAS3）定位于人类12号染色体q24区域，编码一族对先天性抗病毒防御至关重要的酶。最近，发现一个改变剪接的OAS1单核苷酸多态性（SNP，rs10774671）的次要等位基因与酶活性增加相关，并且在一项病例-同胞对照研究中与1型糖尿病（T1D）相关。
我们通过传递不平衡检验（TDT；G:A = 386:329，p = 0.033）在784个核心家庭（父母双方和至少一个患病后代）中证实了这种T1D关联。然而，由于OAS1内部以及与其他两个OAS基因存在连锁不平衡，不能假定该关联是由这个SNP的功能所致。为了帮助回答这个问题，我们还对OAS1外显子3和7中的两个非同义SNP进行了基因分型。
所有三个SNP均显示出显著的传递失真。八个可能单倍型中的三个占亲本染色体的98.4%，其中两个在rs10774671处携带非易感性A等位基因。尽管在rs10774671处是纯合子，但这两个单倍型杂合的父母显示出显著的传递失真（p = 0.009）。
我们证实了T1D与rs10774671的关联，但我们得出结论，该关联不能（仅）归因于剪接变体rs10774671。OAS1外显子3中的丝氨酸/甘氨酸替换更可能是一个功能变体。
