Deka, Ranjan

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Background: Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar and non-lobar based on the location of the hemorrhage, with genetic variation contributing to risk of both subtypes. We report the first genome wide association study (GWAS) of this condition. Methods: The discovery phase included GWAS data (Illumina 610 or Affymetrix 6.0) from 6 ICH studies that enrolled subjects of European ancestry in the US and Europe. Cases were classified as lobar or non-lobar ICH based on head CT. ICH-free controls were selected from ambulatory clinics or by random digit dialing. Standard quality controls filters were applied and principal component analysis was used to account for population structure. Unobserved genotypes were inferred by imputation to 1000 genomes references panels. Association testing was carried out using logistic regression, assuming additive effects, and including age, gender and principal components in the model. Meta-analyses were completed using the inverse normal method, weighting by sample size. Replication of signals with p<1x10E-6 was pursued in an independent multi-ethnic study utilizing direct genotyping. Results: The discovery phase included 1545 cases (664 lobar and 881 non-lobar) and 1481 controls, and tested 5,358,103 SNPs. Two loci were identified: for lobar ICH, an intergenic region located on chromosome 12q21.1 (rs11179580: minor allele frequency [MAF] 0.22, OR 1.54, 95% CI 1.33 - 1.84; p = 6.7x10E-8); and for non-lobar ICH, a region on chromosome 1q22 encompassing the PMF1 and SLC25A44 genes (rs2984613: MAF 0.31, OR 1.45, 95% CI 1.2 - 1.64; p = 8.9x10E-9). Replication included 1256 cases (329 whites, 506 blacks and 421 Hispanics) and 760 controls (237 whites, 346 blacks and 177 Hispanics) and confirmed both loci: 12q21.1 (p = 0.037, meta-analysis p = 2.3x10E-8) and 1q22 (p = 3.0x10E-4, meta-analysis p = 2.2x10E-11). Conclusions: Two new susceptibility loci for ICH were identified, both showing location-specificity. These results confirm the presence of biological heterogeneity across ICH subtypes and highlight that different genetic risk factors may contribute to the small vessel diseases that underlie each ICH subtype.

Background and Purpose— Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. Methods— We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. Results— There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27]; P =0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22]; P =0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24], P =0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46]; P <0.001). Conclusions— In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.

Background and Purpose— The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA. Methods— White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking. Results— The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P =9.2×10 −5 ; allelic P =1.3×10 −5 ; OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA. Conclusion— Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.

Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P =0.03), 7 (LOD=4.1; P =0.01) and 12 (LOD=3.6; P =0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.