Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.
Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).
We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.
Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.

The study aimed to explore additive interactions of CDKAL1 rs7747752 and GUDCA/DCA for GDM risk and whether the interactive effects on the risk of GDM was mediated via increasing lysophosphatidylcholines (LPC) 18:0 and/or saturated fatty acid (SFA) 16:0.
A 1:1 age-matched study nested in a prospective cohort of pregnant women (207 pairs) was organized in Tianjin, China. Additive interactions were used to test interaction effects while mediation analyses and Sobel tests were used to test mediation effects of LPC18:0 and SFA16:0 between copresence of rs7747752 and low GUDCA/DCA, and GDM risk.
The CDKAL1 rs7747752 was associated with GDM (P<0.05). The rs7747752 C polymorphism markedly enhanced ORs of low GUDCA from 4.04 (0.72-22.8) to 9.02 (1.63-49.7) and low DCA from 1.67 (0.68-4.11) to 4.24 (1.84-9.76), both with significant additive interactions. Further adjustment for LPC18:0 attenuated the interactive effects of rs7747752 and low DCA, with a significant mediation effect (P=0.003). High SFA16:0 did not mediate the interactive effects of rs7747752 and low DCA/GUDCA on GDM risk.
The CDKAL1 rs7747752 C carrier status and low GUDCA/DCA had significant additive interactions on the risk of GDM with the effect from interaction with DCA being partially mediated via increasing LPC18:0.

The understanding of the genetic basis of type 2 diabetes mellitus (T2DM) has progressed rapidly, but the interactions among common genetic variants and metabolic risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and metabolic environments on the risk of T2DM. Obesity is emerging as an independent risk factor for T2DM and arterial stiffness. Here, we examined the effect of the rs9356744 polymorphism in the body mass index (BMI) gene CDKAL1 on the risk of T2DM in East Asians and particularly assessed the interactions between this polymorphism and other metabolic risk factors. A total of 1975 subjects in whom the rs9356744 polymorphism had been detected in the CDKAL1 gene were enrolled in this study. The height, weight, blood pressure and relevant markers, including glucose, lipids, liver and renal function, of the participants were successfully measured. Pulse wave velocity (PWV) was measured using an automatic wave form analyzer. At baseline, we found a significant association between BMI and rs9356744 genotypes (CC, CT, TT) (P = 0.048). After adjusting for confounding factors, including sex, age and BMI, participants carrying the T allele of rs9356744 showed a lower incidence of T2DM. Further adjustment for blood pressure and lipids did not appreciably change the results (P = 0.019, 0.009, 0.015, respectively). We found significant interactions between the rs9356744 polymorphism and high-density lipoprotein (HDL), serum uric acid (SUA) and carotid-femoral pulse wave velocity (cf-PWV) in relation to T2DM incidence (P for interaction = 0.007, 0.002, 0.004, respectively), especially in the group with the lowest SUA level and the group with the highest HDL and cf-PWV levels (P for trend = 0.006, 0.008, 0.018, respectively). Furthermore, we found a significant interaction between the rs9356744 polymorphism and cf-PWV in relation to the level of 2-h plasma glucose in the oral glucose tolerance test (OGTT) (P for interaction = 0.0341). In summary, the T allele of rs9356744 was an independent protective factor for T2DM. There were significant interactions between rs9356744 and HDL, SUA, and cf-PWV in relation to T2DM risk.