Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis

Abstract

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland’s population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.

Genome-wide association study of varicose veins identifies a protective missense variant in GJD3 enriched in the Finnish population

“…The missense variant rs201955556-T in GDJ3 was associated with a substantially lower VV risk and showed no pleiotropy in a phenome-wide scan of >1700 disease endpoints highlighting the potential of connexin modulation as a therapy for VV. Overall our results support the use of samples from isolated populations for increased statistical power to, first, gain insight into the etiology of complex diseases [21][22][23][24][25][26][27][28] such as VV and, second, in finding therapeutic target genes.…”

“…For most of the identified VV-loci the putative causal gene nevertheless remains unknown hence complicating the translation of the genetic findings into therapeutic strategies. However, for several complex traits the study of low-frequency protein-coding variation potentially enriched in population isolates such as Finns has yielded novel loci pointing directly to a likely causal gene and identifying possible intervention opportunities 21 , 22 .…”

“…Population isolates, such as Finns, show an enrichment of protein-coding variants compared to admixed populations [23][24][25][26][27][28] . Genetic studies of population isolates thus boost the statistical power to detect associations between phenotypes and proteincoding variants and have identified novel associations between variants and phenotypes 21,22,[24][25][26]28,29 . Studies of genotyped individuals coupled with comprehensive healthcare records have the potential to identify disease etiology and likely causal relationships between traits.…”

FinnGen provides genetic insights from a well-phenotyped isolated population

“…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 .…”

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin

“…Knockdown of MFGE8 in coronary smooth muscle cell and monocytes inhibited proliferation, indicating MFGE8 as the causal gene for CAD-associated at this locus[43]. Splice variants of MFGE8 have been associated with reduced risk of atherosclerosis in FinnGen, a large Finnish biobank study[44]. However, an in vivo role for MFGE8 has not been established.…”