PCSK9 genetic variants and cognitive abilities: a large-scale Mendelian randomization study

IntroductionPCSK9 inhibitors lower low-density lipoprotein (LDL) cholesterol and are efficacious at reducing vascular disease, however questions remain about potential effects on cognitive function.MethodsWe examined the association of genetic variants in PCSK9 with continuous measures of cognitive ability in UK Biobank. Six independent polymorphisms in PCSK9 were used in up to 337,348 individuals.ResultsThe PCSK9 allele score was associated with a lower risk of CHD, and weakly with worse log reaction time.ConclusionsWe are unable to rule out meaningful associations of PCSK9 genetic variants with cognition, emphasising the potential need for continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.     

Association of FTO and IRX3 genetic variants to obesity risk in north India

Abstract

Objective: Validation of body adiposity index (BAI) in a paediatrics sample; and to develop, if necessary, a valid BAI for paediatrics (i.e. BAI_p).

Methods: A total of 1615 children (52% boys) aged 5–12 years underwent anthropometry. Their body composition was assessed using a foot-to-foot bioimpedance. The validity of BAI?=?(Hip circumference/Height^1.5)???18 was tested by combining correlation and agreement statistics. Then, the sample was split into two sub-samples for the construction of BAI_p. A regression was used to compute the prediction equation for BAI_p-based percentage of body fat (%BF).

Results: The initial BAI over-estimated the %BF of children by 49% (29.6?±?4.2% versus 19.8?±?6.8%; p?<?0.0001). The original methodology led to a BAI_p?=?(Hip circumference/Height^0.8) ? 38 in children. When compared to BAI, BAI_p showed both better correlation (r?=?0.57; p?<?0.01 versus r?=?0.74; p?<?0.0001) and agreement (ICC?=?0.34; [95% CI?=??0.19–0.65] versus ICC?=?0.83; [95% CI?=?0.81–0.84]). However, there were some systematic biases between the two values of %BF as exemplified by the large 95% limit of agreement [?9.1%; 8.8%] obtained.

Conclusion: BAI over-estimates the %BF in children. In contrast, BAI_p appears as a new index for children’s body fatness, with acceptable accuracy. In its current form, this index is valid only for large-scale studies.     

Sequence variants of ACE, AGT, AT1R, and PAI-1 as genetic risk factors for vascular dementia

Sequence variants of angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) T235M, angiotensin II type 1 receptor (AT1R) A1166C, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G were analyzed to see their genetic associations with vascular dementia as its candidate genetic risk factors involving renin-angiotensin and fibrin systems. While the ACE I/D, AT1R A1166C, and PAI-1 4G/5G did not contribute to the genetic susceptibility to vascular dementia (P>0.05), a significant association with vascular dementia was shown in the T235M polymorphism of AGT. The frequency of the M allele in patients was higher than in controls with the odds ratio (OR) estimate of 1.51 (P<0.05). In a dominant model, the TM+MM genotypes increased the risk of vascular dementia compared to the TT genotype (OR=2.01; P<0.001). The current results suggested that AGT T235M polymorphism might be a risk factor of vascular dementia.     

Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.     

Gene variants as risk factors for gastroschisis

In a population‐based case‐control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (OR_h) or homozygous variants (OR_v) genotypes. These included NOS3 (rs1036145) OR_h = 0.4 (95% CI: 0.2–0.7); NOS3 (rs10277237) OR_v = 2.7 (95% CI: 1.3–6.0); ADD1 (rs12503220) OR_h = 2.9 (95% CI: 1.6–5.4), GNB3 (rs5443) OR_h = 0.2 (95% CI: 0.1–0.5), OR_v = 0.4 (95% CI: 0.2–0.9); ICAM1 (rs281428) OR_v = 6.9 (95% CI: 2.1–22.9), ICAM1 (rs3093030) OR_v = 2.6 (95% CI: 1.2–5.6); ICAM4 (rs281438) OR_v = 4.9 (95% CI: 1.4–16.6), ICAM5 (rs281417) OR_h = 2.1 (95% CI: 1.1–4.1), OR_v = 4.8 (95% CI: 1.7–13.6); ICAM5 (rs281440) OR_h = 23.7 (95% CI: 5.5–102.5), OR_v = 20.6 (95% CI: 3.4–124.3); ICAM5 (rs2075741) OR_v = 2.2 (95% CI: 1.1–4.4); NAT1 OR_v = 0.3 (95% CI: 0.1–0.9). There were additional associations between several gene variants and gastroschisis among women aged 20–24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.

     

Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

ABSTRACT: BACKGROUND: Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. METHODS: A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. RESULTS: Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. CONCLUSIONS: To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.     

Association of genetic variants of ABCA1 with Alzheimer's disease risk.

ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE epsilon4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C-14T and C-477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C-14T polymorphism modified the risk of AD in an APOE epsilon4 allele-dependent fashion: in APOE epsilon4 carriers, homozygous for the ABCA1 -14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 -14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (-14T) in concert with the APOE epsilon4 allele.     

Increased genetic risk for obesity in premature coronary artery disease

There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRS_BMI significantly (P=2.12 × 10⁻¹²) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042–1.076). The addition of GRS_BMI to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82–21.26%, P<0.0001). To test whether GRS_BMI explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRS_BMI plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD.     

PD-1基因遗传变异与上皮性卵巢癌发病风险的关联

目的探讨细胞程序性死亡受体-1(PD-1)基因遗传变异与上皮性卵巢癌发病风险的关系。方法用聚合酶连接酶检测反应技术(PCR-LDR)检测分析620例上皮性卵巢癌患者和620名对照妇女PD-1.1 A/G和PD-1.5 C/T两个单核苷酸多态位点的基因型和等位基因频率。结果 PD-1.1 A/G多态的AA、AG、GG 3种基因型频率在病例组和对照组中具有显著差异(P0.05)。比较AA基因型携带者,AG和GG基因型携带者显著降低上皮性卵巢癌的发病风险(OR=0.71,95%CI=0.54~0.94和OR=0.68,95%CI=0.50~0.94)。病例组中G等位基因频率明显低于对照组(P0.05)。与A等位基因相比,G等位基因显著降低妇女上皮性卵巢癌的发病风险(OR=0.83,95%CI=0.71~0.97)。PD-1.5 C/T多态C和T等位基因频率在2组间具有统计学意义,病例组中T等位基因频率明显低于对照组(P0.05)。与C等位基因相比,T等位基因显著降低妇女上皮性卵巢癌的发病风险(OR=0.82,95%CI=0.69~0.98)。结论 PD-1.1 A/G和PD-1.5 C/T两个单核苷酸多态位点可能是中国北方妇女上皮性卵巢癌发病风险的分子标志物。     

Death from pulmonary thromboembolism in severe obesity: lack of association with established genetic and clinical risk factors

 Several clinical and environmental conditions are causally related to sudden death from acute pulmonary thromboembolism (APT). Morbid obesity, despite its frequency and association with adverse health effects, is usually considered at most only an additive risk factor for APT. We reviewed protocols and histories from 7227 consecutive autopsies performed between 1985 and 1996 at the Mayo Clinic, including all deaths from APT where no clinical or environmental risk factor could be identified in the study. Body mass indices (BMI) were calculated and compared with those of age- and sex-matched controls who had died suddenly and naturally without evidence of APT. Resistance to activated protein C is the most common molecular clotting defect predisposing to APT, and it is caused by a point mutation in the factor V gene (R⁵⁰⁶Q). Genomic DNA was extracted from archival tissues of all cases and controls, and the R⁵⁰⁶Q status was determined by polymerase chain reaction amplification, restriction endonuclease digestion, and direct sequencing. APT was found as the immediate cause of death in 433 patients, with 36 (8%) having no previously established risk factors. Twenty-four of these persons (67%) were morbidly obese (BMI >30 kg/m²), compared with only five controls (14%, P<0.0001). Four patients in both groups, each with a BMI <30 kg/m², had at least one allele positive for R⁵⁰⁶Q. Morbid obesity is an independent risk factor in cases of sudden death from APT after the exclusion of previously established clinical, environmental, and molecular risk factors. Received: 6 November 1998 / Accepted: 25 January 1999     

Five common gene variants identify elevated genetic risk for coronary heart disease

PurposeBecause multiple genetic variants influence risk for coronary heart disease, we combined multiple variants that had been associated with coronary heart disease in several studies into a genetic risk score and asked whether a high genetic risk score would be significantly associated with coronary heart disease after accounting for traditional risk factors.MethodsWe considered five variants that were associated with coronary heart disease in two studies and confirmed in the Atherosclerosis Risk in Communities study: rs20455 (KIF6), rs3900940 (MYH15), rs7439293 (PALLD), rs2298566 (SNX19), and rs1010 (VAMP8). We calculated a genetic risk score for each Atherosclerosis Risk in Communities study participant and estimated the hazard ratio for incident coronary heart disease of a high genetic risk score (compared with not-high) in Cox models that adjusted for traditional risk factors during a median of 13 years of follow-up.ResultsFor white participants with a high genetic risk score (4% of the 9129 whites), compared with those without a high genetic risk score, the hazard ratio for incident coronary heart disease was 1.57 (95% confidence interval 1.21–2.04; P = 0.001). Internal validation using bootstrap samples estimated that a hazard ratio of 1.43 could be expected in external populations.ConclusionsAfter adjusting for traditional risk factors, those with a high genetic risk score had a 57% increased risk of incident coronary heart disease in the Atherosclerosis Risk in Communities study.     

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10⁻⁴). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an ‘extreme genetics'' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.     

The role of common genetic risk variants in Parkinson disease

Despite the discovery of at least five pathogenic genes in Parkinson disease (PD), the genetic etiology in the vast majority of PD remains to be clarified. Common genetic variants could act as susceptibility risk factors. Our previous meta-analysis of PD genetic association studies, over a 30-year period yielded four genes (N-acetylcysteine 2, monoamine oxidase B, glutathione transferase, and mitochondrial tRNA), as their common variants were found to be associated with PD. More recently, international collaborative studies and meta-analysis have identified the S18Y variant of ubiquitin carboxy-terminal hydrolase L1, Rep 1 variant of alpha-synuclein and tau H1 haplotype to be genetic susceptibility risk/protective factors. However, the most significant, common genetic risk factor in PD has been its association with the leucine-rich repeat kinase-2 (LRRK2) G2385R variant. We conducted an analysis of independent studies involving 2205 PD and 1817 controls and found the average carrier rate of G2385R variant to be about 9% in PD and 4% in controls (p < 0.001; odds ratio: 2.27; 95% confidence interval: 1.78-2.9). A higher frequency of G2385R carriers has been observed in familial PD when compared with sporadic patients. Based on current evidence, certain common genetic variants are likely to modulate the risk of PD.     

TOMM40 and APOE common genetic variants are not Parkinson's disease risk factors

Polymorphic, deoxythymidine-tract in intron 6 of the TOMM40 gene has been associated with Alzheimer's disease. We have investigated the impact of this polymorphism on Parkinson's disease risk and age of onset, independently and in combination with apolipoprotein E alleles, in a group of 407 PD patients and 305 control subjects. No significant association was observed at the single allele, genotype, or haplotype levels. Our data suggest that the polymorphism is not a risk factor for Parkinson's disease in the Polish population.