Functional variants in cytochrome b5 type A (CYB5A) are enriched in Southwest American Indian individuals and associate with obesity.
Functional variants in cytochrome b5 type A (CYB5A) are enriched in Southwest American Indian individuals and associate with obesity.
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DOI：
10.1002/oby.23359
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发表时间：
2022-03
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本研究旨在确定西南美洲印第安人(SWAI)个体中丰富的与BMI相关的遗传变异。使用全基因组测序数据(n=296)来识别在SWAI个体中常见的潜在功能变异(次要等位基因频率≥为10%)，但在其他种族中很少见(次要等位基因频率为0.1%)。在5870名SWAI个体中测试了富含变异与体重指数的相关性。使用荧光素酶报告基因研究了一个变异，并分析了包括该变异的单倍型与各种肥胖指标(n=917-5,870)、24小时能量消耗(24小时能量消耗；n=419)和骨骼肌活检表达数据(n=207)的相关性。细胞色素b5A型(Cyb5A)的5‘非翻译区变异rs548402150符合浓缩标准，并与体重指数增加相关(β=2%，p=0.004)。在功能上，rs548402150使荧光素酶的表达减少30%(p=0.003)，并与骨骼肌细胞色素B5A的表达降低相关(β=−0.5SD，p=0.0008)。结合rs548402150和CyB5A中的两个剪接数量性状基因座，发现了一个几乎仅在SWAI个体中携带的单倍型，该单倍型与体重指数增加(β=3%，p=0.0003)和CyB5A表达降低有关，而所有种族中最常见的单倍型与较低的体重指数和体脂百分比、24小时EE增加和CyB5A表达增加有关。进一步研究CyB5A对24小时EE和BMI的影响可能会为肥胖相关的生理学提供更深入的了解。
This study aimed to identify genetic variants enriched in Southwest American Indian (SWAI) individuals that associate with BMI. Whole genome sequencing data (n = 296) were used to identify potentially functional variants that are common in SWAI individuals (minor allele frequency ≥10%) but rare in other ethnic groups (minor allele frequency < 0.1%). Enriched variants were tested for association with BMI in 5,870 SWAI individuals. One variant was studied using a luciferase reporter, and haplotypes that included this variant were analyzed for association with various measures of obesity (n = 917‐5,870), 24‐hour energy expenditure (24‐h EE; n = 419), and skeletal muscle biopsy expression data (n = 207). A 5′ untranslated region variant in cytochrome b5 type A (CYB5A), rs548402150, met the enrichment criteria and associated with increased BMI (β = 2%, p = 0.004). Functionally, rs548402150 decreased luciferase expression by 30% (p = 0.003) and correlated with decreased skeletal muscle CYB5A expression (β = −0.5 SD, p = 0.0008). Combining rs548402150 with two splicing quantitative trait loci in CYB5A identified a haplotype carried almost exclusively in SWAI individuals that associated with increased BMI (β = 3%, p = 0.0003) and decreased CYB5A expression, whereas the most common haplotype in all ethnic groups associated with lower BMI and percentage of body fatness, increased 24‐h EE, and increased CYB5A expression. Further studies on the effects of CYB5A on 24‐h EE and BMI may provide insights into obesity‐related physiology.
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