Dataset Information

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

ABSTRACT: Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.

SUBMITTER: Van Dijck E

PROVIDER: S-EPMC9601648 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Rare Heterozygous <i>PCSK1</i> Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

Van Dijck Evelien E Beckers Sigri S Diels Sara S Huybrechts Tammy T Verrijken An A Van Hoorenbeeck Kim K Verhulst Stijn S Massa Guy G Van Gaal Luc L Van Hul Wim W

Genes 20220927 10

Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolesc ...[more]

PMID: 36292633

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Project description:Common PCSK1 variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common PCSK1 variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (P?=?0.006) and obesity (P?=?0.018) but also increased the obesity incidence during the 20 years of follow-up (HR?=?1.53 [1.07-2.19], P?=?0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (P?=?0.028) and obesity (P?=?0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR?=?1.23 [1.05-1.45], P?=?9.5×10(-3)). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (P?=?4.2×10(-3)) and obesity (P?=?3.4×10(-3)) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (P?=?0.756 and P?=?0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full PCSK1 locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings.

Project description:Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR. Methods Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment. Conclusions Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Project description:BackgroundAlpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world.MethodsA systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article.ResultsOf the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once.ConclusionAATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.

Dataset Information

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

Publications

Rare Heterozygous <i>PCSK1</i> Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

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