P740 Age determines the risk of familial IBD: A nationwide case–control study

Background A family history of inflammatory bowel disease (IBD) is a proxy for an individual’s genetic and, in part, environmental risk of developing IBD, and is one of the strongest known risk factors for developing IBD. Although a familial aggregation is a well-established concept, data on its strength and nature are sparse. Therefore, to provide precise estimates of the familial aggregation, we performed a nation-wide, case-control study and examined the relative risk for patients with IBD (vs. population controls) to have a first-degree relative (FDR) with IBD, by age of onset, type of family history, and IBD subtype. Methods Individuals diagnosed with IBD between 1 January 2003 and 31 December 2017 with at least one first degree relative (FDR) were identified from Swedish national registers and compared with non-IBD controls, with at least one FDR, from the general population. We used logistic regression to calculate odds ratios (ORs) as estimates of relative risk for IBD in FDRs taking age at IBD onset, sex, county, and year of IBD diagnosis into account. Results We identified 50,667 incident cases with IBD (CD, n = 14,927; UC, n = 27,221 and IBD-U, n = 8519) and 506,720 controls, matched for age, sex, birth year and county of residence. The overall familial relative risk estimate of IBD for siblings (OR 3.6 [95% CI 3.4–3.8]) was similar to that between generations (OR 3.5 [95% CI 3.3–3.7] for mothers and OR 3.5 [95% CI 3.3–3.7] for fathers). Half-siblings conferred a lower yet elevated relative risk (OR 2.0 [95% 1.8–2.2]). The familial relative risk estimates of IBD increased with number of affected FDRs (Figure 1). Pronounced differences were seen between subtypes of IBD in the index case and also across age of onset in the index case and in the FDR (Figure 2). Lowest odds ratios were seen for having an FDR with elderly onset IBD among cases who were diagnosed with elderly onset Crohn’s disease (OR 1.9 [95% CI 1.4–2.5]) or ulcerative colitis (OR 1.9 [95% CI 1.5–2.3]). Highest odds ratios were seen for having an FDR with paediatric onset IBD among cases who were diagnosed with paediatric Crohn’s disease (OR 10.6 [95% CI 8.2–13.5]) or paediatric ulcerative colitis (OR 8.4 [95% CI 6.4–10.9]). Conclusion The relative risk of familial IBD varies by IBD subtype as well as by age of onset in the index patient with IBD and the FDR, pointing to differences in genetic predisposition and environmental risks between different phenotypes of IBD.

Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk

Sud and colleagues interrogated the familial risk of hematological malignancy in association with over 150 000 patients. The majority of hematological malignancies showed increased familial relative risk, most prominently in association with B-cell malignancies.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Other cancers in lung cancer families are overwhelmingly smoking-related cancers

Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology.We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking.The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found.Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor.