Zhao Lue Ping, Alshiekh Shehab, Zhao Michael, Carlsson Annelie, Larsson Helena Elding, Forsander Gun, Ivarsson Sten A, Ludvigsson Johnny, Kockum Ingrid, Marcus Claude, Persson Martina, Samuelsson Ulf, Örtqvist Eva, Pyo Chul-Woo, Nelson Wyatt C, Geraghty Daniel E, Lernmark Åke
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
Diabetes. 2016 Mar;65(3):710-8. doi: 10.2337/db15-1115. Epub 2016 Jan 6.
The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1-18 years with islet autoantibody-positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB103:01:01 was affected by DRB301:01:02 and DRB302:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB113:01:01 was affected by DRB301:01:02 to increase the risk and by DRB302:02:01 to maintain a negative association. DRB401:03:01 was strongly associated with type 1 diabetes (P = 10(-36)), yet its association was extensively affected by DRB1 alleles from protective (DRB104:03:01) to high (DRB104:01:01) risk, but its association with DRB104:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.
HLA - DRB3、- DRB4和 - DRB5等位基因对1型糖尿病风险以及对胰岛素自身抗体（IAA）、谷氨酸脱羧酶65（GAD自身抗体[GADA]）、胰岛抗原2（IA - 2A）或锌转运体8针对325位的三种氨基酸变体R、W或Q（分别为ZnT8RA、ZnT8WA和ZnT8QA）在临床诊断时的影响尚不清楚。采用新一代测序（NGS）来确定1 - 18岁连续诊断的胰岛自身抗体阳性1型糖尿病患者（n = 970）和对照受试者（n = 448）中的所有DRB等位基因。检测DRB3、DRB4或DRB5等位基因与自身抗体、1型糖尿病或两者的DRB1风险之间的关联。1型糖尿病与DRB103:01:01之间的关联受DRB301:01:02和DRB302:02:01影响。这些DRB3等位基因与GADA呈正相关，但与ZnT8WA、IA - 2A和IAA呈负相关。1型糖尿病与DRB113:01:01之间的负相关受DRB301:01:02影响而增加风险，受DRB302:02:01影响而维持负相关。DRB401:03:01与1型糖尿病强烈相关（P = 10⁻³⁶），但其关联受到DRB1等位基因从保护性（DRB104:03:01）到高风险（DRB104:01:01）的广泛影响，但其与DRB104:05:01的关联降低了风险。HLA - DRB3、- DRB4和 - DRB5影响1型糖尿病风险和胰岛自身抗体。采用NGS进行HLA分型对于选择预防或干预试验的参与者应是有用的。
