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Genome-Wide Association Study Identifies Genetic Loci Associated With Fat Cell Number and Overlap With Genetic Risk Loci for Type 2 Diabetes
Diabetes ( IF 6.2 ) Pub Date : 2022-03-23 , DOI: 10.2337/db21-0804
Agné Kulyté 1 , Alisha Aman 2 , Rona J Strawbridge 3, 4 , Peter Arner 1 , Ingrid A Dahlman 1
Affiliation  

Interindividual differences in generation of new fat cells determine body fat and type 2 diabetes risk. In the GENetics of Adipocyte Lipolysis (GENiAL) cohort, which consists of participants who have undergone abdominal adipose biopsy, we performed a genome-wide association study (GWAS) of fat cell number (n = 896). Candidate genes from the genetic study were knocked down by siRNA in human adipose-derived stem cells. We report 318 single nucleotide polymorphisms (SNPs) and 17 genetic loci displaying suggestive (P < 1 × 10−5) association with fat cell number. Two loci pass threshold for GWAS significance, on chromosomes 2 (lead SNP rs149660479-G) and 7 (rs147389390-deletion). We filtered for fat cell number–associated SNPs (P < 1.00 × 10−5) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified SPATS2L and KCTD18 as regulators of cell proliferation consistent with the genetic data. Furthermore, 30 reported type 2 diabetes–associated SNPs displayed nominal and consistent associations with fat cell number. In functional follow-up of candidate genes, RPL8, HSD17B12, and PEPD were identified as displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion, findings presented herein identify SPATS2L, KCTD18, RPL8, HSD17B12, and PEPD of potential importance in controlling fat cell numbers (plasticity), the size of body fat, and diabetes risk.

中文翻译:

全基因组关联研究确定了与脂肪细胞数量相关的遗传位点,并与 2 型糖尿病的遗传风险位点重叠

新脂肪细胞生成的个体差异决定了身体脂肪和 2 型糖尿病的风险。在由接受过腹部脂肪活检的参与者组成的脂肪细胞脂解遗传学 (GENiAL) 队列中,我们对脂肪细胞数量 (n = 896) 进行了全基因组关联研究 (GWAS)。来自基因研究的候选基因被人脂肪来源的干细胞中的 siRNA 敲低。我们报告了 318 个单核苷酸多态性 (SNP) 和 17 个显示与脂肪细胞数量相关的暗示性 (P < 1 × 10-5) 基因座。2 号染色体(前导 SNP rs149660479-G)和 7 号染色体(rs147389390-缺失)上的两个位点通过了 GWAS 显着性阈值。我们使用基因型特异性表达的证据过滤脂肪细胞数量相关的 SNP (P < 1.00 × 10-5)。在观察到这一点的地方,我们选择了用于后续调查的基因,并特此将 SPATS2L 和 KCTD18 确定为与遗传数据一致的细胞增殖调节因子。此外,30 个报告的 2 型糖尿病相关 SNP 显示与脂肪细胞数量名义上和一致的关联。在候选基因的功能追踪中,RPL8、HSD17B12 和 PEPD 被鉴定为显示出与遗传关联和基因表达发现一致的对细胞增殖的影响。总之,本文提出的研究结果确定了 SPATS2L、KCTD18、RPL8、HSD17B12 和 PEPD 在控制脂肪细胞数量(可塑性)、体脂大小和糖尿病风险方面具有潜在重要性。30 个报告的 2 型糖尿病相关 SNP 显示与脂肪细胞数量名义上和一致的关联。在候选基因的功能追踪中,RPL8、HSD17B12 和 PEPD 被鉴定为显示出与遗传关联和基因表达发现一致的对细胞增殖的影响。总之,本文提出的研究结果确定了 SPATS2L、KCTD18、RPL8、HSD17B12 和 PEPD 在控制脂肪细胞数量(可塑性)、体脂大小和糖尿病风险方面具有潜在重要性。30 个报告的 2 型糖尿病相关 SNP 显示与脂肪细胞数量名义上和一致的关联。在候选基因的功能追踪中,RPL8、HSD17B12 和 PEPD 被鉴定为显示出与遗传关联和基因表达发现一致的对细胞增殖的影响。总之,本文提出的研究结果确定了 SPATS2L、KCTD18、RPL8、HSD17B12 和 PEPD 在控制脂肪细胞数量(可塑性)、体脂大小和糖尿病风险方面具有潜在重要性。
更新日期:2022-03-23
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