Genetic variant in SPDL1 reveals novel mechanism linking pulmonary fibrosis risk and cancer protection

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a rare disease with poor prognosis. By contrast, cancer is common in any elderly population and a leading killer, but is now often curable. Of note, whereas IPF is driven by cellular senescence, cancer is characterized by uncontrolled cell division. Using data available from two large biobank-based studies (Finnish FinnGen study and UK biobank), we conducted a comprehensive analysis of the shared genetic background of IPF and cancer. In a population sample of 218,792 Finns with complete longitudinal health histories, we estimated the effect of individual genetic variants to the lifetime risk of IPF and cancer. We extend the analysis from IPF-GWAS to pan-cancer meta-analysis over FinnGen and UK Biobank and finally to the identification of genetic drivers of somatic chromosomal alterations. We detected six loci (SPDL1, MAD1L1, MAP2K1, RTEL1-STMN3, TERC-ACTRT3, OBFC1) associated with both IPF and cancer, all closely related to cellular division. However, each individual signal is found with opposite effects over the two diseases, termed as antagonistic pleiotropy. Several of these loci (TERC-ACTRT3, RTEL1-STMN3, OBFC1) are among the strongest inherited factors for constitutive telomere length variation and consistently indicate that shorter telomere length would increase the risk for IPF but protect from malignancy. However, a Finnish enriched SPDL1 missense variant and a common MAD1L1 intronic variant had no effect on telomere length but were shown to protect individuals from accumulation of somatic mutations. The decreased risk of cancer in SPDL1 and MAD1L1 variant carriers might result from a lower number of chromosomal alterations accumulated over time, conversely leading to fibrosis in the lung due to cellular senescence-induced inflammation. We hypothesize that the SPDL1 missense variant functions as gain-of-function mutation, leading to cellular senescence, a barrier to cancer and a driver of fibrosis in IPF. If translated to therapy, these findings might not only be able to offer relief to individuals with IPF, but also to protect from onset of cancer.

FinnGen provides genetic insights from a well-phenotyped isolated population

“…One such new observation is a missense variant (p.Arg20Gln; AF = 3%, gnomAD NFSEE = 0.7%) in SPDL1 with a pleiotropic association. It is associated with a strongly increased risk of idiopathic pulmonary fibrosis (OR = 3.1, P = 1.0 × 10 −15 ) but protective with an end point that combines all cancers (OR = 0.82, P = 2.1 × 10 −15 ) 32 . Other associations between variants and disease described in separate manuscripts include the following: an inframe deletion in MFGE8 and coronary atherosclerosis (p.Asn239dup; AF = 2.9%, gnomAD NFSEE = 0%, OR = 0.74, P = 5.4 × 10 −15 ) 33 ; a frameshift variant in MEPE (p.Lys101IlefsTer26; AF = 0.3%, gnomAD NFSEE = 0.07%, OR = 18.9, P = 1.5 × 10 −11 ) and otosclerosis 34 ; and a missense variant in ANGPTL7 (p.Arg220Cys; AF = 4.2%, gnomAD NFSEE = 0.06%, OR = 0.7, P = 7.2 × 10 −16 ) and glaucoma 35 .…”

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

“…In 15/23 non-suspicious loci harboring a nonsynonymous variant, the nonsynonymous variant had the highest PIP. These included known missense variants such as rs116483731 (p.Arg20Gln) in SPDL1 for idiopathic pulmonary fibrosis (IPF) 61,62 and rs28929474 (p.Glu366Lys) in SERPINA1 for chronic obstructive pulmonary disease (COPD) 63,64 . In addition, we observed successful fine-mapping in 2 novel loci for asthma, i) rs41286560 (p.Pro558Thr) in RTL1 , a missense variant known for decreasing height 65,66 and ii) rs34187696 (p.Gly337Val) in ZSCAN5A , a known missense variant for increasing monocyte count 30 .…”

Leveraging global multi-ancestry meta-analysis in the study of Idiopathic Pulmonary Fibrosis genetics

“…Fine-mapping suggested deleterious coding causal variants at three loci. In addition to the previously reported coding variants in TERT and SPDL1 4,6 , fine-mapping identified a coding variant in KIF15 (predicted missense, rs138043992, AF = 0.29%, OR[95% CI] = 1.71[1.39-2.10], PIP = 0.24), enriched 2.6-fold in the Finnish population compared to non-Finnish non-Estonian Europeans (NFEE, gnomAD v2.1.1) and predicted as probably damaging by Polyphen and deleterious by SIFT.…”

“…As IPF has, by definition, no identifiable cause, genome-wide approaches are especially attractive as they may provide insight into underlying causes, pathogenesis, and might potentially reveal novel therapeutic avenues. Genome-wide association studies (GWAS) of IPF have thus far reported at least 23 associated loci [2][3][4][5][6][7][8][9][10][11] highlighting genes involved with telomere maintenance 12 , cell adhesion, airway clearance, and innate immunity. These studies have mainly been restricted to individuals of European descent and common variants, and have identified few associations to conclusively functional variants.…”