👤 Antti Jula

We investigated the associations of genetic risk score for Alzheimer's disease (GRS-AD) with cardiometabolic risk from early childhood over a 20-year follow-up. The STRIP study included 1062 children at baseline. GRS-AD was calculated for 631 participants using 22 independent genetic risk variants, including APOE ε2 and ε4 alleles, and excluding them (non-APOE-GRS-AD). We repeatedly measured waist circumference, high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, triglycerides, glucose, insulin, and blood pressure. The data were analysed with generalised additive mixed models. GRS-AD was directly associated with serum LDL-C (unstandardised β = 0.140, 95% CI = 0.084 to 0.195) and inversely with HDL-C (β = -0.026, 95% CI = -0.044 to -0.009). GRS-AD was inversely associated with serum HDL-C in males (β = -0.044, 95% CI = -0.070 to -0.018) but not in females (β = -0.010, 95% CI = -0.032 to 0.012). The associations were diluted when the non-APOE-GRS-AD was applied. A genetic predisposition to AD may alter lipid metabolism from early childhood. While Alzheimer's disease and cardiometabolic diseases may have shared genetic determinants, the associations between genetic susceptibility for Alzheimer's disease and increased cardiometabolic risk from childhood to young adulthood are poorly understood. We investigated the associations of genetic risk score for Alzheimer's disease with cardiometabolic risk from early childhood over a 20-year follow-up. We found that a higher genetic risk score for Alzheimer's disease was associated with higher LDL cholesterol, non-HDL cholesterol, and ApoB, and with lower serum HDL cholesterol and ApoA1. These findings suggest that a genetic predisposition to Alzheimer's disease may alter lipid metabolism from early childhood. Show less

To investigate whether the systemic inflammatory response against inflammatory conditions in the periodontium is related to serum apolipoprotein B (ApoB) and A1 (ApoA1) concentrations. The study consisted of the Health 2000 Survey participants (n = 2709) aged 30-49 years. The inflammatory condition of the periodontium was assessed by means of the number of teeth with deepened (≥ 4 mm) and deep (≥ 6 mm) periodontal pockets. Systemic inflammation was measured by serum C-reactive protein (CRP) levels. The role of ApoB and ApoA1 was studied by performing regression analyses and stratified analyses (according to the median values). In logistic regression analyses, the number of teeth with deepened (≥ 4 mm) periodontal pockets was associated with serum CRP levels among those participants whose serum ApoB concentration was ≥ 1.12 g/L. When the participants' ApoB concentration was < 1.12 g/L, such an association between deepened periodontal pockets and CRP was not observed. The direction or strength of the association between periodontal pockets and CRP was not essentially different in the ApoA1 strata. Systemic response against poor periodontal condition varied between individuals. The variation appeared to be related more to the serum concentration of ApoB than ApoA1. Show less

Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass. Show less

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans. Show less

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less