Role Of Low-frequency Variants Research Articles

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

414. The role of low-frequency variants in pre-eclampsia: Recent findings in a Finnish population

The genetic basis of pre-eclampsia and its link with increased lifetime risk of cardiovascular diseases in women with a history of pre-eclampsia and children born from pre-eclamptic pregnancies are incompletely understood. Genetic factors have been shown to account for 55% of the liability of pre-eclampsia with 35% attributed to the maternal genetic effects and 20% to the fetal genetic effects (Cnattingius et al. Am J Med Genet 2004). Genome-wide association screening in offspring from pre-eclamptic pregnancies performed by a collaboration between research groups has already proven a successful approach in finding a common sequence variant near the fms related tyrosine kinase gene (FLT1) associated with pre-eclampsia (McGinnis et al. Nat Genet 2017). The sequencing approach enables identification of both common and rare variants, but is challenging in common complex disorders like pre-eclampsia. An isolated population may offer a major advantage for genetic discovery. In Finland a strong founding bottleneck has been shown to cause enrichment of some low-frequency variants (Lim et al. PLOS Genet 2014). Centrally collected registers with lifelong medical histories can be used together with genetic data to better understand diseases associated with pre-eclampsia. We designed a targeted sequencing study to screen the coding and splicing areas of genes of interest in pre-eclampsia and found maternal low-frequency variants in FLT1 which may protect from pre-eclampsia (Lokki et al. Hypertension 2017). Using data from health registers we found that the same variants may also protect from heart failure later in life. Future studies are needed to improve our understanding of the genetic background pre-eclampsia and its links to other diseases. Any new gene discovery will highlight a known pathway or reveal a new biochemical pathway in the pathogenic process leading to pre-eclampsia and may also help in prediction and in identifying individuals with higher risk for later cardiovascular disease.

A low-frequency GLIS3 variant associated with resistance to Japanese type 1 diabetes

The role of low-frequency variants in type 1 diabetes (T1D) susceptibility still remains to be clarified. In the present study, we analyzed low-frequency variants of the T1D candidate genes in Japanese. We first screened for protein-changing variants of 24 T1D candidate genes in 96 T1D patients and 96 control subjects, and then the association with T1D was tested in 706 T1D patients and 863 control subjects recruited from the collaborating institutions in Japan. In total, 56 protein-changing variants were discovered; among them, 34 were low-frequency variants (allele frequency<5%). The association analysis of the low-frequency variants revealed that only the A908V variant of GLIS3 was strongly associated with resistance to T1D (Haldane’s odds ratio=0.046, p=8.21×10−4, and pc=2.22×10−2). GLIS3 is a zinc finger transcription factor that is highly expressed in pancreatic beta cells, and regulates beta cell development and insulin gene expression. GLIS3 mRNA is also moderately expressed in the human thymus. The precise mechanism responsible for the association is unclear at present, but the A908V variant may affect autoimmunity to the GLIS3 protein itself; the 908V containing epitope may induce central or peripheral tolerance more efficiently than that of 908A.