Recent progress in the genetics of diabetic microvascular complications

Table 1 Genome-wide linkage studies for diabetic nephropathy and retinopathy

Ethnicity and sample size	Type of diabetes	Phenotype definition	Linkage region (LOD score or P-value or MLS)	Ref.
Diabetic nephropathy
954 African American, 781 American Indians, 614 European American, 1611 Mexican Americans (FIND)	1 + 2	Estimated GFR	10p12.311 (LOD: 2.16), 1q431 (2.26), 2q31.3 (1.91), 3p12.1 (2.19), 7q11.22 (2.19), 10p141 (2.16), 15q12 (2.84), 20q11.111 (3.34)	[13]
218 African American, 335 American Indians, 119 European American, 469 Mexican Americans (FIND)	1 + 2	Urine ACR	7q21.3 (P = 8.6 x 10-5), 10p15.31 (1.29 x 10-5), 14q23.1 (7.8 x 10-4), 18q22.31 (2.17 x 10-3)	[14]
3972 Americans (African American, American Indians, European American, Mexican Americans) (FIND)	1 + 2	DN defined by macroalbuminuria or ESRD, ACR	DN: 1q431 (LOD: 2.00), 6p24.3 (2.84), 7p21.3 (2.81), 10p15.11 (2.10), 11p15.3 (2.28), 15q21.1 (2.04)ACR: 2q22.3 (2.04), 3p13 (2.76), 7q21.2 (2.96), 16q13 (2.31), 22q12.31 (2.29)	[23]
882 American (African American, American Indians, European American, Mexican Americans) (FIND)	1 + 2	eGFR	1q431 (LOD: 1.87), 7q36.1 (4.23), 8q13.3 (2.75), 15q22.3 (2.08), 18q23.3 (1.40)	[24]
100 United States sibling pairs (Joslin Study on Genetics of Diabetic Nephropathy)	1	Proteinuria or ESRD	1q441 (MLS: 1.6), 2q14.1 (2.1), 3p13 (0.6), 5q14.2 (2.7), 10q26.1 (2.4), 17p13.1 (1.9), 19q13.431 (3.1), 20p12.1 (1.8)	[15]
63 extended United States families (Joslin Study on Genetics of Diabetic Nephropathy)	2	GFR	2q33.3 (LOD: 4.1), 10q23.31 (3.1), 18p11.22 (2.2)	[19]
556 Finnish, Danish, and French (FinnDiane)	1	Macroalbuminuria or ESRD	3q21-251 (LOD: 0.76), 6p21 (2.31), 9p21.2, 16p12, 19q131 (1.61), 22q11 (2.78)	[16]
83 Finnish sibling pairs	1	Macroalbuminuria or ESRD	3q21.3-231 (MLS: 2.67)	[21]
18 Turkish family + 101 sibling pairs of Pima India	2	Macroalbuminuria	18q22.3-231 (max LOD:6.14)	[17]
201 Pima India sibling pairs	2	Macroalbuminuria or ESRD	3q26.11 (LOD: 1.48), 7q32.3 (2.04), 20p12.3 (1.83)	[18]
206 African American sibling pairs	2	ESRD	3q13.31 (LOD: 4.55), 7p21.1 (3.59), 18q22.11 (3.72)	[22]
691 West African	2	GFR	7p12.2 (LOD: 1.84), 16q24.1 (3.56), 17p13.2 (2.08)	[20]
Diabetic retinopathy
282 Mexican American sibling pairs	2	Non-proliferative DR and proliferative DR	3q12.3 (LOD: 2.41), 12p13.31 (2.47), 20q13.12 (4.47), 6p24.1 (2.28), 15q26.3 (2.53), 19q13.42 (2.21)	[45]
725 Pima Indian sibling pairs	2	Worse eye score	1p36.13 (LOD: 3.1)	[46]
210 Pima Indian sibling pairs	2	Hemorrhage, microaneurysm, and proliferative DR	3q26.31 (LOD: 1.36), 9q22.33 (1.46)	[18]

¹Overlapped region. MLS: Maximum LOD score; DN: Diabetic nephropathy; ESRD: End-stage renal disease; GFR: Glomerular filtration rate; ACR: Albumin-to-creatinine ratio; DR: Diabetic retinopathy.

Table 2 Genome-wide association studies for diabetic nephropathy, retinopathy, and neuropathy

Patients	Ethnic	Case	Control	Gene	Ref.	Replication studies	Non-replication studies
Diabetic nephropathy
T2DM	Japanese	459 DN	242	ELMO11	[25]	26, 27, 28, 29, 30	31, 32
T2DM	European	105 ESRD	102	PVT1	[33]
T2DM	African American	965 ESRD	1029	SASH1, RPS12,AUH, MSRB3, LIMK2-SKI1, APOL3-MYH91	[34]	35
T1DM	Caucasian (GoKinD, DCCT/EDIC)	820 ESRD	885	FRMD31, CARS, CPVL/CHN2, 13q3 between MYO16/IRS21	[39]	40, 41, 42	42, 30
T1DM	Caucasian	547 ESRD	549	ZMIZ1	[29]
T1DM	GENIE (UK-ROI, FinnDiane, GoKinUS) + 9 follow-up studies	Stage 1: 4315 ESRDStage 2: 1880 ESRD	Stage 1: 8568Stage 2: 6656	AFF3, RGMA/MCTP2, ERBB4	[43]
T1DM	Caucasian(FinnDiane + 7 follow-up studies)	5675 T1DMUrine albumin excretion rate		PSD3, SH2D4A	[44]
Diabetic retinopathy
T1DM	Caucasian (GoKinD and EDIC)	2829 PDR and macular edema	1856	AKT3/ZNF238, LEKR1/CCNL1, KRT18P34/VEPH1, A2BP1	[47]
T2DM	Taiwanese	174 NPDR and PDR	575	MYSM1, FSTL5, C5orfF21, PLXD2, ARHGAP22, HS6ST3	[48]
T2DM	Taiwanese	437 PDR	570	TBC1D4-COMMD6-UCHL3, LRP2-BBS5, and ARL4C-SH3BP4	[49]
T2DM	Mexican-American	103 severe DR	183	CAMK4, FMN1 genes	[50]
Diabetic neuropathy
United Kingdom	United Kingdom (GoDART)	572 diabetic neuropathic pain	2491	GFRA2	[51]

¹Loci that could be replicated in independent studies. T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; DN: Diabetic nephropathy; ESRD: End-stage renal disease; GFR: Glomerular filtration rate; DR: Diabetic retinopathy; NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative diabetic retinopathy.