Associations between endothelial nitric oxide synthase polymorphisms and risk of diabetic nephropathy: an updated meta-analysis

Figures & data

Figure 1. Flowchart of the study selection process.

Table 1. Characteristics of studies included in the meta-analysis.

Author	Year	Polymorphism	DM type	Ethnicity	Group	Sample size	Criteria	Gender	Age	DM durations	BMI	HbA1C	Language
Shoukry11	2012	T786C, G894T, 4b/4a	2	Egypt	DN	200	ACR > 300 mg/g	108/92	55.3 ± 5.8	14.5 ± 4.3	27.4 ± 3.2	7.5 ± 1.4	English
				(African)	DM	200	ACR < 30 mg/g	116/84	54.6 ± 5.2	13.8 ± 3.2	27.9 ± 3.7	7.3 ± 1.5
Santos12	2011	T786C, G894T, 4b/4a	2	Brazil	DN	376	AER > 20 mcg/min	215/161	60.4 ± 9.7	15.0 ± 9.1	28.7 ± 5.0	NA	English
				(Whites)	DM	268	AER < 20 mcg/min	85/156	62.0 ± 9.4	16.7 ± 6.8	28.2 ± 4.4	NA
Ahluwalia13	2008	T786C, G894T, 4b/4a	2	India	DN	195	Overt proteinuria	68/127	60.0 ± 6.15	16.45 ± 6.37	28.01 ± 3.95	NA	English
				(E. Asians)	DM	255	Normoalbuminuria	105/150	60.47 ± 5.76	15.62 ± 5.25	23.95 ± 2.95	NA
Ezzidi14	2008	T786C, G894T, 4b/4a	2	Tunisia	DN	515	AER > 30 mg/24 h	235/278	59.6 ± 10.8	13.5 ± 6.3	27.4 ± 5.0	9.9 ± 3.9	English
				(African)	DM	402	AER < 30 mg/24 h	169/233	59.1 ± 11.2	11.5 ± 6.2	11.5 ± 6.2	9.2 ± 3.7
					HC	748	Healthy Tunisians	373/375	58.7 ± 8.7	NA	24.7 ± 3.0	5.1 ± 0.7
Zanchi15	2000	T786C, 4b/4a	1	USA	Case 1	74	AER > 200 mcg/mg	30/44	35.5 ± 7.3	24.9 ± 9.0	NA	9.2 ± 1.5	English
				(Whites)	Case 2	78	AER > 200 mcg/mg	38/40	35.7 ± 6.5	24.5 ± 6.8	NA	9.4 ± 0.9
					DM	195	AER < 20 mcg/mg	101/94	36.5 ± 7.6	23.7 ± 6.3	NA	8.2 ± 1.1
Liao16	2006	T786C, 4b/4a	2	China	DN	85	AER ≥ 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA	Chinese
				(E. Asians)	DM	65	AER < 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA
Liao16	2006	T786C, 4b/4a	2	Malaysia	DN	51	AER ≥ 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA	Chinese
				(S.E. Asians)	DM	20	AER < 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA
Liao16	2006	T786C, 4b/4a	2	India	DN	26	AER ≥ 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA	Chinese
				(S. Asians)	DM	11	AER < 30 mg/24 h	NA	61.0 ± 14.5	>10yrs	NA	NA
Asakimori17	2002	T786C	NA	Japan	DN	84	NA	42/42	63.4 ± 11.0	NA	NA	NA	English
				(E. Asians)	DM	168	NA	101/67	59.6 ± ± 16.6	NA	NA	NA
					HC	187	Healthy Japanese	44/143	42.1 ± 12.2	NA	NA	NA
Rahimi18	2012	G894T	2	Iran	Case 1	72	Microalbuminuria	26/46	55.3 ± 8.6	8.58 ± 5.18	27.61 ± 4.18	7.94 ± 1.56	English
				(W. Asians)	Case 2	68	Macroalbuminuria	33/35	57.1 ± 8.7	11.12 ± 6.43	26.61 ± 4.45	7.73 ± 1.69
					DM	72	Normoalbuminuria	23/49	54.4 ± 7.9	7.65 ± 5.43	26.90 ± 4.13	7.87 ± 1.50
Rao19	2012	G894T	2	China	DN	49	AER ≥ 20 mg/2 4h	29/20	58.46 ± 8.56	12.35 ± 2.24	23.52 ± 4.11	7.64 ± 1.84	Chinese
				(E. Asians)	DM	39	AER < 20 mg/24 h	22/17	57.33 ± 8.12	12.54 ± 2.42	24.10 ± 3.98	7.42 ± 1.79
Dai20	2012	G894T	2	China	DN	60	AER ≥ 20 mg/24 h	23/37	48.4 ± 6.6	11.7 ± 0.9	NA	NA	Chinese
				(E. Asians)	DM	60	AER < 20 mg/24 h	38/22	45.4 ± 8.2	10.8 ± 1.1	NA	NA
					HC	60	Healthy Chinese	32/28	38.7 ± 7.4	NA	NA	NA
Tiwari21	2009	G894T	2	North India	DN	90	DM > 2 yrs + Cr > 2 mg/dl	78/12	53.56 ± 10.99	9.62 ± 6.84	NA	10.4 ± 7.7	English
				(S. Asians)	DM	75	DM > 10 yrs + Cr < 2 mg/dl	40/35	61.03 ± 8.88	15.39 ± 8.168	NA	7.3 ± 1.0
Tiwari21	2009	G894T	2	South India	DN	106	DM > 2 yrs + Cr > 2 mg/dl	81/25	55.97 ± 11.502	13.97 ± 6.452	NA	7.3 ± 1.1	English
				(S. Asians)	DM	149	DM > 10 yrs + Cr < 2 m g/dl	101/48	60.45 ± 11.472	15.45 ± 6.913	NA	7.2 ± 1.4
Tamemoto22	2008	G894T	NA	Japan	DN	124	Microalbuminuria	NA	NA	NA	NA	NA	English
				(E. Asians)	DM	211	Normoalbuminuria	NA	61.1 ± 10.8	11.0 ± 10.8	23.8 ± 3.9	NA
Ma23	2006	G894T	2	China	Case 1	76	Microalbuminuria	40/36	62.79 ± 8.68	10.79 ± 5.44	24.14 ± 3.65	8.99 ± 1.98	Chinese
				(E. Asians)	Case 2	43	Macroalbuminuria	18/25	60.65 ± 7.45	12.33 ± 4.70	25.46 ± 3.09	9.09 ± 1.75
					Case 3	48	ESRD with DM	23/25	61.08 ± 9.30	10.84 ± 5.49	24.80 ± 3.53	8.54 ± 1.60
					DM	132	AER < 30 mg/24 h	66/66	61.27 ± 8.51	11.98 ± 5.28	25.23 ± 3.36	8.98 ± 1.79
					HC	100	Healthy Chinese	57/43	59.37 ± 10.34	NA	NA	NA
Dong24	2005	G894T, 4b/4a	2	China	DN	69	AER ≥ 20 mg/24 h	26/44	63.1 ± 7.3	15.3 ± 3.1	NA	NA	Chinese
				(E. Asians)	DM	64	AER < 20 mg/24 h	25/39	63.4 ± 6.0	14.9 ± 2.6	NA	NA
					HC	85	Healthy Chinese	35/50	61.3 ± 6.8	NA	NA	NA
Fu25	2007	G894T	2	China	DN	61	20 < AER < 200 µg/min	24/37	63.89 ± 7.82	14.12 ± 2.61	NA	NA	English
				(E. Asians)	DM	78	AER < 20 µg/min	30/48	64.13 ± 6.58	14.07 ± 2.12	NA	NA
					HC	63	Healthy Chinese	24/39	64.11 ± 7.21	NA	NA	NA
Shin Shin26	2004	G894T	2	Korea	Case 1	35	Microalbuminuria	16/19	62.9 ± 10.9	16 (12–20)	24.5 ± 4.4	8.9 ± 1.9	English
				(E. Asians)	Case 2	83	Overt proteinuria	38/45	58.8 ± 9.7	16 (11–20)	23.1 ± 3.1	7.8 ± 2.0
					DM	59	Normoalbuminuria	15/44	61.6 ± 11.7	12 (10–16)	23.3 ± 2.9	9.0 ± 2.2
					HC	129	Healthy Koreans	64/65	51.6 ± 9.3	NA	NA	NA
Li27	2004	G894T	2	China	DN	86	20 < AER < 200 µg/min	NA	65.89 ± 6.70	11.69 ± 3.32	24.39 ± 2.30	NA	Chinese
				(E. Asians)	DM	80	AER <20 µg/min	38/42	66.27 ± 7.89	10.21 ± 2.09	24.05 ± 2.53	NA
Lv28	2003	G894T	2	China	DN	45	20 < AER < 200 µg/min	NA	65.9 ± 6.7	11.69 ± 3.32	24.39 ± 2.30	NA	Chinese
				(E. Asians)	DM	52	AER <20 µg/min	20/32	66.3 ± 7.9	10.21 ± 2.09	24.05 ± 2.53	NA
Lv29	2002	G894T	2	China	DN	79	AER >20 mcg/min	30/49	63.4 ± 7.03	14.3 ± 4.42	NA	NA	Chinese
				(E. Asians)	DM	64	AER <20 mcg/min	25/39	63.38 ± 5.95	13.7 ± 3.5	NA	NA
					HC	85	Healthy Chinese	35/50	61.2 ± 6.75	NA	NA	NA
Möllsten30	2006	G894T, 4b/4a	1	Sweden	DN	150	AER > 20 mcg/min	76/74	48.7 ± 10.2	35 (11–65)	NA	146.7 ± 26.7	English
				(Whites)	DM	197	AER <20 mcg/min	88/109	43.8 ± 11.4	30 (20–57)	NA	141.9 ± 22.1
Möllsten30	2006	G894T, 4b/4a	1	Finland	DN	805	AER >20 mcg/min	475/330	38.7 ± 19.2	27.3 (5–47)	NA	148.0 ± 25.3	English
				(Whites)	DM	358	AER <20 mcg/min	140/218	41.3 ± 9.4	27.4 (20–51)	NA	134.5 ± 19.8
Möllsten31	2009	G894T	1	Sweden	DN	458	AER > 300 mg/ 24 h	180/278	42.0 ± 10.4	27 (7–65)	NA	9.3 (5.4–14.0)	English
				(Whites)	DM	319	AER <30 mg/24 h	175/144	43.7 ± 11.0	23 (15–63)	NA	8.3 (5.7–11.5)
Cai32	1998	G894T	2	Australia	DN	116	Microalbuminuria	NA	62.4 ± 0.5	NA	NA	NA	English
				(Whites)	DM	284	Normoalbuminuria	NA	62.4 ± 0.5	NA	NA	NA
Bessa33	2011	G894T	2	Egypt	DN	40	AER >30 mg/24 h	21/19	58.8 ± 12.5	19.4 ± 4.2	NA	10.4 ± 2.5	English
				(African)	DM	40	AER <30 mg/24 h	17/23	55.4 ± 8.8	15.3 ± 3.7	NA	6.6 ± 0.4
					HC	20	Staff and blood donors	10/10	54.1 ± 8.3	NA	NA	4.2 ± 0.3
Li34	2011	G894T	2	China	Case 1	81	Microalbuminuria	NA	58.3 ± 12.1	10.7 ± 3.1	NA	NA	Chinese
				(E. Asians)	Case 2	143	Macroalbuminuria	NA	58.3 ± 12.1	10.7 ± 3.1	NA	NA
					DM	102	Normoalbuminuria	NA	58.3 ± 12.1	10.7 ± 3.1	NA	NA
					HC	215	Healthy Chinese	109/106	54.5 ± ± 12.6	NA	NA	NA
Wang35	2004	G894T	2	China	DN	61	20 < AER <200 µg/min	32/29	60.2 ± 10.1	12.01 ± 2.51	25.12 ± 3.41	8.59 ± 1.33	Chinese
				(E. Asians)	DM	77	AER <20 µg/min	39/38	58.5 ± 8.54	11.04 ± 2.48	25.68 ± 3.01	8.48 ± 1.34
					HC	100	Healthy China	47/53	57.5 ± 9.72	NA	29.94 ± 4.28	NA
Nagase36	2003	G894T, 4b/4a	NA	Japan	DN	71	NA	48/23	62.0 ± 9.2	NA	NA	NA	English
				(E. Asians)	HC	248	Healthy Japanese	179/69	49.3 ± 8.8	NA	NA	NA
Thaha37	2008	G894T	NA	Japan	DN	39	ESRD with DM	NA	NA	NA	NA	NA	English
				(E. Asians)	HC	100	Healthy Japanese	NA	NA	NA	NA	NA
Suzuki38	2000	G894T	NA	Japan	DN	48	NA	NA	62.9 ± 11.1	NA	NA	NA	English
				(E. Asians)	HC	270	Healthy Japanese	NA	49.3 ± 8.8	NA	NA	NA
Guo39	2011	4b/4a	2	China	DN	69	AER ≥30 mg/24 h	NA	64.33 ± 9.68	15.17 ± 6.51	24.45 ± 3.97	7.44 ± 1.47	Chinese
				(E. Asians)	DM	75	AER <30 mg/24 h	NA	62.17 ± 11.23	13.40 ± 5.44	23.89 ± 3.81	6.97 ± 1.34
					HC	63	Healthy Chinese	NA	58.80 ± 10.76	NA	24.10 ± 3.33	4.81 ± 0.66
Dong40	2007	4b/4a	2	China	DN	130	AER ≥ 30 mg/24 h	NA	60.0 ± 12.3	>10yrs	NA	NA	Chinese
				(E. Asians)	DM	107	AER < 30 mg/24 h	NA	60.0 ± 12.3	>10yrs	NA	NA
Zhang41	2005	4b/4a	2	China	Case 1	123	30 < UA1b < 300 mg/24h	NA	54 ± 15	NA	21 ± 7	NA	Chinese
				(E. Asians)	Case 2	57	UA1b≥300 mg/24 h	NA	54 ± 15	NA	21 ± 7
					DM	154	UA1b<30 mg/24 h	NA	54 ± 15	NA	21 ± 7	NA
					HC	166	Healthy Chinese	82/84	55 ± 11	NA	21 ± 5	NA
Xing42	2004	4b/4a	2	China	Case 1	42	Microalbuminuria	18/24	62.1 ± 10.6	9.9 ± 5.4	24.5 ± 3.7	8.45 ± 4.45	Chinese
				(E. Asians)	Case 2	88	Microalbuminuria	38/50	63.6 ± 8.2	12.9 ± 6.7	24.5 ± 3.4	9.07 ± 4.50
					DM	136	Without DN	61/75	58.8 ± 12.2	10.9 ± 5.4	24.1 ± 3.3	9.20 ± 5.07
Sun43	2004	4b/4a	2	China	Case 1	140	20 < AER < 200 µg/min	NA	59.81 ± 9.53	5.28 ± 6.24	NA	NA	Chinese
				(E. Asians)	Case 2	35	AER > 200 µg/min	NA	59.81 ± 9.53	5.28 ± 6.24	NA	NA
					Case 3	13	ESRD	NA	59.81 ± 9.53	5.28 ± 6.24	NA	NA
					DM	114	AER < 20 mg/24 h	NA	59.81 ± 9.53	5.28 ± 6.24	NA	NA
					HC	113	Healthy Chinese	53/60	56.02 ± 9.29	NA	NA	NA
Luo44	2003	4b/4a	2	China	Case 1	29	Microalbuminuria	NA	62 ± 10	9 ± 6	NA	NA	Chinese
				(E. Asians)	Case 2	20	Macroalbuminuria	NA	64 ± 9	10 ± 6	NA	NA
					DM	35	Normoalbuminuria	NA	56 ± 11	2 ± 3	NA	NA
					HC	32	Healthy Chinese	NA	56 ± 11	NA	NA	NA
Shimiz45	2002	4b/4a	2	Japan	Case 1	107	Overt proteinuria	75/32	63.1 ± 10.6	15.5 ± 11.0	22.8 ± 2.7	7.5 ± 1.4	English
				(E. Asians)	Case 2	124	Advanced nephropathy	93/31	65.1 ± 8.8	19.8 ± 7.8	21.8 ± 2.9	6.8 ± 1.4
					DM	203	Normoalbuminuria	132/71	63.7 ± 8.8	18.6 ± 7.8	21.9 ± 2.9	7.0 ± 1.1
Li46	2002	4b/4a	2	China	DN	79	AER = 164 ± 32.8 μg/min	30/49	63.41 ± 7.03	14.28 ± 4.45	NA	NA	Chinese
				(E. Asians)	DM	64	AER = 15.6 ± 3.4 μg/min	25/39	63.38 ± 5.95	13.66 ± 5.99	NA	NA
Lin47	2002	4b/4a	2	China	DN	79	With DN	44/36	59.94 ± 11.16	11.66 ± 6.99	NA	NA	Chinese
				(E. Asians)	DM	48	Normoalbuminuria	22/26	53.5. ± 9.70	4.23 ± 3.32	NA	NA
					HC	70	Healthy staff	34/36	38.63 ± 10.45	NA	NA	NA
Taniwaki48	2001	4b/4a	2	Japan	Case 1	44	Microalbuminuria	26/18	60.5 ± 8.5	10.9 ± 7.4	23.2 ± 2.5	8.8 ± 1.7	English
				(E. Asians)	Case 2	22	Overt proteinuria	15/7	59.0 ± 10.5	12.8 ± 6.5	22.9 ± 2.5	8.5 ± 2.2
					Case 3	20	Overt proteinuria	10/10	64.2 ± 7.8	19.1 ± 9.7	23.9 ± 2.1	7.0 ± 1.4
					DM	69	Normoalbuminuria	41/28	60.1 ± 9.8	7.4 ± 4.5	23.1 ± 2.6	8.9 ± 2.6
Lv49	2001	4b/4a	2	China	DN	79	UAE > 20 μg/min	30/49	46–75 (63.41)	10-30(14.28)	NA	NA	Chinese
				(E. Asians)	DM	64	UAE < 20 μg/min	25/39	49–77 (63.38)	10-20(13.66)	NA	NA
					HC	85	Healthy volunteers	35/50	46–77 (61.22)	NA	NA	NA
Asakimori50	2001	4b/4a	NA	Japan	DN	295		168/127	62.9 ± 11.1	NA	NA	NA	English
				(E. Asians)	DM	710		390/320	58.9 ± 13.8	NA	NA	NA
					HC	189		44/145	42.1 ± 12.3	NA	NA	NA
Fujita51	2000	4b/4a	2	Japan	DN	102	AER > 200 mcg/min	61/41	61.0 ± 21.0	NA	22.6 ± 2.9	7.6 ± 2.1	English
				(E. Asians)	DM	65	AER < 20 mcg/min	30/35	62.0 ± 10.0	NA	22.6 ± 2.9	7.6 ± 2.1
Neugebauer52	2000	4b/4a	2	Japan	Case 1	94	AER = 20–200 mg/g Cr	49/55	59.0 ± 11.1	13.8 ± 5.1	23.4 ± 3.15	8.3 ± 1.1	English
				(E. Asians)	Case 2	39	AER > 200 mg/g Cr	10/29	59.0 ± 8.6	15.2 ± 4.5	23.9 ± 2.3	8.0 ± 1.5
					DM	82	AER < 20 mg/g Cr	29/53	56.0 ± 8.6	13.3 ± 4.5	23.5 ± 2.85	7.8 ± 1.2
Shestakova53	2006	4b/4a	1	Russia	DN	63	AER > 300 mg/24 h	30/33	25.7 ± 6.4	12.6 ± 2.8	NA	NA	English
				(Whites)	DM	66	AER < 30 mg/24 h	24/42	40.8 ± 10.2	26.8 ± 6.9	NA	NA
Rippin54	2003	4b/4a	1	UK	DN	464	Overt proteinuria	NA	NA	NA	NA	NA	English
				(Whites)	DM	396	Normoalbuminuria	NA	NA	NA	NA	NA
Ksiazek55	2003	4b/4a	2	Poland	DN	178	With DN	86/92	57.9 ± 8.2	8.7 ± 3.1	29.1 ± 4.2	9.1 ± 1.1	English
				(Whites)	DM	232	Without DN	118/114	58.3 ± 6.8	8.0 ± 2.6	28.9 ± 3.6	8.4 ± 1.6
Frost56	2003	4b/4a	1	Germany	DN	22	AER ≥ 20 µg/min	NA	14–44	NA	NA	NA	English
				(Whites)	DM	125	AER ≤ 20 µg/min	NA	14–44	NA	NA	NA
Degen57	2001	4b/4a	1	Germany	DN	130	AER > 30 mg/24 h	NA	NA	>10yrs	NA	NA	English
				(Whites)	DM	194	AER < 30 mg/24 h	NA	NA	>10yrs	NA	NA
Degen57	2001	4b/4a	2	Germany	DN	197	AER > 30 mg/24 h	NA	NA	>10yrs	NA	NA	English
				(Whites)	DM	217	AER < 30 mg/24 h	NA	NA	>10yrs	NA	NA
Rahimi58	2013	4b/4a	2	Iran	Case 1	63	Microalbuminuria	23/40	55.7 ± 8.7	8.4 ± 5.3	27.9 ± 4.1	8.04 ± 1.58	English
				(S.W. Asians)	Case 2	58	Macroalbuminuria	26/32	57.8 ± 8.4	11.3 ± 6.6	26.8 ± 4.5	8.04 ± 1.58
					DM	52	Normoalbuminuria	15/37	54.5 ± 8.8	7.8 ± 5.6	27.3 ± 4.8	7.8 ± 1.57
Lamnissou59	2004	4b/4a	NA	Greece	DN	77	NA	48/29	68.19	NA	NA	NA	English
				(Whites)	HC	295	NA	NA	NA	NA	NA	NA
Bellini60	2007	4b/4a	NA	Brazil	DN	37	NA	NA	NA	NA	NA	NA	English
				(Whites)	HC	94	NA	52/42	52.7 ± 14.9	NA	NA	NA

Notes: DN, diabetic nephropathy; DM, diabetes mellitus; HC, healthy controls; ESRD, end-stage renal disease; NA, not applicable; Case 1, microalbuminuria; Case 2, macroalbuminuria; Case 3, ESRD with DM; ACR, albumin/creatinine ratio; AER, albumin excretion rate; UAE, urinary albumin excretion; BMI, body mass index; HbA1C, hemoglobin A1c.

Table 2. Distribution of eNOS polymorphisms and frequency of allele for studies.

		Distribution of genotype			Frequency of allele
		DN/DM/HC			DN/DM/HC		DM/HC
Author	Year	TT	TC	CC	T	C	HWE p value
(A) Distribution of the T786C polymorphism
Shoukry	2012	57/84	89/83	54/33	203/251	197/149	0.112
Santos	2011	140/93	160/104	76/44	440/290	312/192	0.122
Ezzidi	2008	261/224/436	215/139/264	34/32/36	737/587/1136	283/203/336	0.119/0.623
Ahluwalia	2008	121/165	62/87	41976	304/417	86/93	0.021
Liao	2006	138/77	24/19	0/0	300/173	24/19	0.282
Asakimori	2002	50/121/159	24/42/28	0/5/0	124/284/346	24/52/28	0.565/0.268
Zanchi	2000	58/75	64/100	30/20	180/250	124/140	0.111
		GG	GT	TT	G	T
(B) Distribution of the G894T polymorphism
Dai	2012	31/44/43	29/16/17	0/0/0	91/104/103	29/16/17	0.233/0.201
Rahimi	2012	68/39	45/17	13/7	181/95	71/31	0.03
Rao	2012	22/38	17/11	0/0	61/87	17/11	0.376
Li	2011	173/85/171	50/17/33	1/0/1	396/187/375	52/17/35	0.359/0.659
Tiwari (NI)	2009	62/56	24/16	4/1	148/128	32/18	0.906
Tiwari (SI)	2009	82/91	21/43	3/13	185/225	27/69	0.024
Ahluwalia	2008	82/125	81/105	32/25	245/355	145/155	0.669
Tamemoto	2008	104/181	18/27	2/3	226/389	22/33	0.103
Fu	2007	33/64/51	28/14/12	0/0/0	94/142/114	28/14/12	0.384/0.403
Ma	2006	125/115/86	42/17/14	0/0/0	292/247/186	42/17/14	0.429/0.452
Dong	2005	39/49/63	30/15/21	0/0/0	108/113/147	30/15/21	0.288/0.19
Li	2004	57/85	37/15	0/0	151/185	37/15	0.417
Shin Shin	2004	95/52/116	23/7/13	0/0/0	213/111/245	23/7/13	0.628/0.547
Wang	2004	32/55/81	29/22/19	0/0/0	93/132/181	29/22/19	0.144/0.294
Lv	2003	27/42	18/10	0/0	72/94	18/10	0.443
Lv	2002	44/49/63	34/15/21	0/0/0	122/113/147	34/15/21	0.288/0.19
Santos	2011	176/118	166/95	32/22	518/331	230/139	0.651
Möllsten	2009	224/150	188/128	46/41	636/428	280/210	0.103
Möllsten (S)	2006	82/100	53/76	14/19	217/276	81/114	0.418
Möllsten (F)	2006	410/168	312/156	75/32	1132/492	462/220	0.622
Cai	1998	65/148	44/109	7/27	174/405	58/163	0.295
Shoukry	2012	66/99	94/77	40/24	226/275	174/125	0.141
Bessa	2011	10/17/12	18/19/7	12/4	38/53/31	42/27/9	0.694/0.987
Ezzidi	2008	185/165/335	247/195/334	81/41/69	617/525/1004	409/277/472	0.131/0.274
Nagase	2003	38//250	8//18	2//2	84//518	12//22	/0.016
Thaha	2008	7//72	31//26	1//2	45//170	33//30	/0.845
Suzuki	2000	38//250	8//18	2//2	84//518	12//22	/0.016
		4b	4ba	4a	4b	4a
(C) Distribution of the 4b/4a polymorphism
Rahimi	2013	86/38/73	32/14/28	3/0/0	204/90/174	38/14/28	0.262/0.106
Guo	2011	56/70/60	7/0/1	6/3/2	119/140/121	19/6/5	p < 0.001
Ahluwalia	2008	146/189	28/61	21/5	320/439	70/71	0.976
Dong	2007	108/86	17/21	3/0	233/193	23/21	0.26
Zhang	2005	159/131/145	21/21/20	0/2/1	339/283/310	21/25/22	0.287/0.734
Dong	2005	43/53/62	27/11/22	0/0/0	113/117/146	27/11/22	0.452/0.167
Xing	2004	110/128	16/8	4/0	236/264	24/8	0.724
Sun	2004	136/101/93	48/11/18	4/2/2	320/213/204	56/15/22	0.022/0.32
Liao (M)	2004	45/17	5/3	0/0	95/37	5/3	0.717
Liao (C)	2004	66/56	14/9	3/0	146/121	20/9	0.549
Liao (I)	2004	18/7	7/4	1/0	43/18	9/4	0.461
Luo	2003	20/23/34	2/4/1	27/8/2	42/50/69	56/20/5	p < 0.001
Shimizu	2002	180/156	44/44	6/3	404/356	56/50	0.959
Li	2002	50/53/64	29/11/6	0/0/0	129/117/134	29/11/6	0.452/0.708
Lin	2002	71/41/64	8/6/6	0/1/0	150/88/134	8/8/6	0.208/0.708
Taniwaki	2001	63/50	21/19	2/0	147/119	25/19	0.184
Lv	2001	49/53/62	30/11	0/0/0	128/117/146	30/11/22	0.452/0.167
Neugebauer	2000	101/71	26/10	6/1	228/152	38/12	0.361
Fujita	2000	81/55	21/10	0/0	183/120	21/10	0.502
Santos	2011	237/168	99/59	11/5	573/395	121/69	0.946
Möllsten (S)	2006	103/147	40/46	7/4	246/340	54/54	0.857
Shestakova	2006	14/34	48/31	1/1	76/99	50/33	0.04
Möllsten (F)	2006	553/242	208/99	32/15	1314/583	272/129	0.236
Ksiazek	2003	105/147/252	58/66/74	15/19/4	268/360/578	88/104/82	0.006/0.58
Frost	2003	21/70	10/35	2/9	52/175	14/53	0.136
		DN/DM/HC			DN/DM/HC		DM/HC
Author	Year	4b	4ba	4a	4b	4a	HWE p value
Rippin	2003	344/297	108/90	12/9	796/684	132/108	0.485
Degen (Type 1)	2001	87/136	41/55	2/3	215/327	45/61	0.331
Degen (Type 2)	2001	142/161	53/50	2/6	337/372	57/62	0.384
Zanchi	2000	80/144	27/47	37/4	187/335	101/55	0.943
Shoukry	2012	124/131	64/60	12/9	312/322	88/78	0.53
Ezzidi	2008	314/234/511	162/143/217	29/21/20	790/611/1239	220/185/257	0.889/0.594
Bellini	2007	16//60	15//29	6//5	47//149	27//39	/0.549
Lamnissou	2004	57//205	17//80	3//10	131//490	23//100	/0.528
Nagase	2003	58//201	13//47	0//0	129//449	13//47	/0.099
Asakimori	2001	225/541/163	67/157/26	3/12/0	517/1239/352	73/181/26	0.875/0.310

Notes: DN, diabetic nephropathy; DM, Diabetes mellitus; HC, Healthy controls; HWE, Hardy–Weinberg equilibrium.

Figure 2. Forest plots for the allelic model of eNOS-T786C by ethnicity in DN/DM group.

Table 3. Meta-analysis for eNOS-T786C Polymorphism.

	Group	Studies	OR	95% CI	p-Value	Model	PQ	I^2 (%)
(A) DN versus DM
Allele	Global	7	1.19	1.06–1.33	0.003	Fixed	0.31	15
Dominant	Global	7	1.18	1.02–1.37	0.03	Fixed	0.41	3
Recessive	Global	7	1.48	0.93–2.38	0.1	Random	0.01	66
Codominant (CC)	Global	7	1.58	0.97–2.57	0.06	Random	0.02	64
Codominant (TC)	Global	7	1.13	0.97–1.32	0.13	Fixed	0.34	11
(B) DN versus HC
Allele	Global	2	1.65	0.92–2.96	0.09	Random	0.05	74
Dominant	Global	2	1.82	0.95–3.48	0.07	Random	0.05	74
Recessive	Global	2	1.39	0.86–2.25	0.18	Random	NA	NA
Codominant (CC)	Global	2	1.58	0.96–2.58	0.07	Random	NA	NA
Codominant (TC)	Global	2	1.81	0.92–3.53	0.08	Random	0.04	76
(B) DM versus HC
Allele	Global	2	1.57	0.82–2.98	0.17	Random	0.01	84
Dominant	Global	2	1.50	0.77–2.93	0.23	Random	0.02	81
Recessive	Global	2	1.93	1.20–3.10	0.007	Fixed	0.18	45
Codominant (CC)	Global	2	3.08	0.47–20.22	0.24	Random	0.15	51
Codominant (TC)	Global	2	1.36	0.72–2.57	0.34	Random	0.03	79

Notes: DN, diabetic nephropathy; DM, Diabetes mellitus; HC, Healthy controls.

Figure 3. Funnel plots for the allelic model by ethnicity in DN/DM group: A, B and C for T786C, G894T and 4b/4a, respectively.

Table 4. Meta-analysis for eNOS-G894T Polymorphism.

	Group	Studies	OR	95% CI	p-Value	Model	PQ	I^2(%)
(A) DN versus DM (ethnicity)
Allele	Asians	15	1.64	1.29–2.08	p < 0.0001	Random	0.0007	61
	Whites	4	0.92	0.83–1.03	0.17	Random	0.81	0
	African	3	1.52	1.15–2.03	0.004	Random	0.1	57
	Global	22	1.37	1.17–1.61	0.0001	Random	0.00001	72
Dominant	Asians	15	1.84	1.40–2.42	p < 0.0001	Random	0.0005	62
	Whites	4	0.92	0.80–1.06	0.25	Random	0.69	0
	African	3	1.6	1.08–2.37	0.02	Random	0.11	55
	Global	22	1.49	1.23–1.81	p < 0.0001	Random	p < 0.00001	71
Recessive	Asians	15	1.23	0.82–1.86	0.32	Fixed	0.18	34
	Whites	4	0.88	0.69–1.12	0.29	Fixed	0.77	0
	African	3	1.81	1.32–2.47	0.0002	Fixed	0.44	0
	Global	22	1.17	0.99–1.39	0.07	Fixed	0.03	45
Codominant (TT)	Asians	15	1.14	0.55–2.37	0.72	Random	0.11	44
	Whites	4	0.85	0.66–1.10	0.22	Random	0.84	0
	African	3	2.19	1.44–3.32	0.0002	Random	0.28	22
	Global	22	1.2	0.87–1.65	0.27	Random	0.004	57
Codominant (GT)	Asians	15	1.85	1.42–2.40	p < 0.00001	Random	0.002	58
	Whites	4	0.94	0.80–1.09	0.39	Random	0.58	0
	African	3	1.4	0.98–2.01	0.07	Random	0.17	43
	Global	22	1.47	1.22–1.78	p < 0.0001	Random	p < 0.00001	67
(B) DN versus DM (type of DM)
Allele	Type 1	2	0.91	0.79–1.03	0.14	Random	0.99	0
	Type 2	20	1.5	1.26–1.79	p < 0.00001	Random	p < 0.0001	65
	Total	22	1.37	1.17–1.61	0.0001	Random	p < 0.00001	72
Dominant	Type 1	2	0.88	0.74–1.04	0.13	Random	0.88	0
	Type 2	20	1.66	1.34–2.04	p < 0.00001	Random	p < 0.0001	64
	Total	22	1.49	1.23–1.81	p < 0.0001	Random	p < 0.00001	71
Recessive	Type 1	2	0.91	0.68–1.21	0.51	Fixed	0.58	0
	Type 2	20	1.36	1.09–1.69	0.006	Fixed	0.06	43
	Total	22	1.17	0.99–1.39	0.07	Fixed	0.03	45
Codominant (TT)	Type 1	2	0.86	0.64–1.16	0.32	Random	0.76	0
	Type 2	20	1.38	0.92–2.07	0.12	Random	0.02	54
	Total	22	1.2	0.87–1.65	0.27	Random	0.004	57
Codominant (GT)	Type 1	2	0.88	0.73–1.06	0.17	Random	0.67	0
	Type 2	20	1.63	1.33–2.00	p < 0.00001	Random	0.0003	59
	Total	22	1.47	1.22–1.78	p < 0.001	Random	p < 0.00001	67
(C) Microalbuminuria versus macroalbuminuria
Allele	Total	4	0.69	0.35–1.37	0.30	Random	0.03	66
Dominant	Total	4	0.65	0.29–1.43	0.28	Random	0.02	69
Recessive	Total	4	0.86	0.29–2.51	0.78	Fixed	0.8	0
Codominant (TT)	Total	4	0.72	0.24–2.19	0.56	Fixed	0.81	0
Codominant (GT)	Total	4	0.64	0.29–1.44	0.28	Random	0.02	69
(D) DN versus HC
Allele	Total	13	2.25	1.76–2.86	p < 0.00001	Random	0.003	59
Dominant	Total	13	2.63	1.95–3.54	p < 0.00001	Random	0.001	63
Recessive	Total	13	1.99	1.44–2.75	p < 0.0001	Fixed	0.46	0
Codominant (TT)	Total	13	2.41	1.71–3.39	p < 0.00001	Fixed	0.34	12
Codominant (GT)	Total	13	2.53	1.86–3.45	p < 0.00001	Random	0.0007	65
(E) DM versus HC
Allele	Total	10	1.11	0.96–1.28	0.17	Fixed	0.94	0
Dominant	Total	10	1.14	0.95–1.36	0.15	Fixed	0.91	0
Recessive	Total	10	1.12	0.75–1.67	0.57	Fixed	0.82	0
Codominant (TT)	Total	10	1.23	0.81–1.87	0.32	Fixed	0.73	0
Codominant (GT)	Total	10	1.14	0.95–1.36	0.18	Fixed	0.93	0

Notes: DN, diabetic nephropathy; DM, diabetes mellitus; HC, healthy controls.

Table 5. Meta-analysis for eNOS-4b/4a polymorphism.

	Group	Studies	OR	95% CI	p-Value	Model	PQ	I^2 (%)
(A) DN versus DM (ethnicity)
Allele	Asians	18	1.50	1.19–1.89	0.0006	Random	0.0002	61
	Whites	8	1.28	1.01–1.62	0.04	Random	p < 0.0001	77
	African	2	1.00	0.80–1.24	0.98	Random	0.26	22
	Global	28	1.35	1.16–1.57	p < 0.0001	Random	p < 0.00001	68
Dominant	Asians	18	1.44	1.12–1.86	0.005	Random	0.0005	59
	Whites	8	1.27	1.03–1.56	0.03	Random	0.01	57
	African	2	0.96	0.73–1.27	0.79	Random	0.24	28
	Global	28	1.31	1.13–1.53	0.0005	Random	p < 0.0001	58
Recessive	Asians	18	2.35	1.39–3.96	0.001	Random	0.25	18
	Whites	8	1.43	0.76–2.70	0.27	Random	0.0008	68
	African	2	1.17	0.72–1.89	0.53	Random	0.69	0
	Global	28	1.68	1.16–2.44	0.006	Random	0.002	50
Codominant (4a/4a)	Asians	18	2.37	1.43–3.91	0.0007	Random	0.31	13
	Whites	8	1.52	0.80–2.86	0.20	Random	0.001	68
	African	2	1.13	0.69–1.85	0.62	Random	0.57	0
	Global	28	1.72	1.19–2.49	0.004	Random	0.003	48
Codominant (4b/4a)	Asians	18	1.27	0.96–1.66	0.09	Random	0.0004	60
	Whites	8	1.15	0.98–1.36	0.09	Random	0.19	27
	African	2	0.93	0.71–1.22	0.60	Random	0.27	18
	Global	28	1.18	1.02–1.37	0.03	Random	0.0006	51
(B) DN versus DM (type of DM)
Allele	Type 1	6	1.36	0.96–1.95	0.09	Random	p < 0.00001	84
	Type 2	22	1.48	1.06–2.08	0.02	Random	p < 0.00001	86
	Total	28	1.43	1.12–1.84	0.004	Random	p < 0.00001	85
Dominant	Type 1	6	1.35	0.98–1.85	0.07	Random	0.002	71
	Type 2	22	1.34	1.10–1.62	0.003	Random	0.0006	55
	Total	28	1.33	1.14–1.56	0.0004	Random	p < 0.0001	58
Recessive	Type 1	6	1.77	0.71–4.43	0.22	Random	0.0004	76
	Type 2	22	1.72	1.16–2.55	0.007	Random	0.12	29
	Total	28	1.77	1.21–2.58	0.003	Random	0.002	50
Codominant (4a/4a)	Type 1	6	1.9	0.76–4.77	0.17	Random	0.0004	76
	Type 2	22	1.73	1.18–2.52	0.005	Random	0.16	24
	Total	28	1.81	1.24–2.63	0.002	Random	0.004	48
Codominant (4b/4a)	Type 1	6	1.16	0.90–1.50	0.25	Random	0.06	50
	Type 2	22	1.21	0.99–1.49	0.06	Random	0.0007	55
	Total	28	1.2	1.02–1.40	0.03	Random	0.0004	52
(C) Microalbuminuria versus macroalbuminuria
Allele	Total	7	0.76	0.56–1.03	0.07	Fixed	0.23	26
Dominant	Total	7	0.78	0.55–1.12	0.18	Fixed	0.57	0
Recessive	Total	7	0.57	0.28–1.17	0.13	Fixed	0.3	18
Codominant (4a/4a)	Total	7	0.59	0.28–1.23	0.16	Fixed	0.37	7
Codominant (4b/4a)	Total	7	0.86	0.59–1.26	0.43	Fixed	0.57	0
(D) Macroalbuminuria versus advanced nephropathy
Allele	Total	3	0.84	0.52–1.35	0.46	Fixed	0.7	0
Dominant	Total	3	0.76	0.44–1.29	0.30	Fixed	0.84	0
Recessive	Total	3	1.32	0.32–5.45	0.70	Fixed	0.75	0
Codominant (4a/4a)	Total	3	1.24	0.30–5.13	0.76	Fixed	0.73	0
Codominant (4b/4a)	Total	3	0.7	0.40–1.23	0.22	Fixed	0.94	0
(D) DN versus HC
Allele	Total	15	1.76	1.33–2.31	p < 0.0001	Random	p < 0.00001	75
Dominant	Total	15	1.72	1.31–2.27	0.0001	Random	p < 0.0001	67
Recessive	Total	15	3.19	2.20–4.61	p < 0.00001	Fixed	0.08	42
Codominant (4a/4a)	Total	15	3.44	2.37–4.99	p < 0.00001	Fixed	0.05	47
Codominant (4b/4a)	Total	15	1.43	1.24–1.65	p < 0.00001	Fixed	0.02	48
(E) DM versus HC
Allele	Total	12	1.36	1.02–1.80	0.03	Random	0.002	63
Dominant	Total	12	1.30	0.97–1.74	0.08	Random	0.009	56
Recessive	Total	12	2.95	1.89–4.59	p < 0.00001	Fixed	0.44	0
Codominant (4a/4a)	Total	12	3.24	2.08–5.07	p < 0.00001	Fixed	0.39	6
Codominant (4b/4a)	Total	12	1.32	1.12–1.55	0.0009	Fixed	0.05	43

Notes: DN, diabetic nephropathy; DM, diabetes mellitus; HC, healthy controls.

Table 6. Scale for quality assessment.

Criteria	Score
Representativeness of cases
Consecutive/randomly selected form case population  with clearly defined sampling frame	2
Consecutive/randomly selected form case population  without clearly defined sampling frame or with extensive	1
Not described	0
Source of controls
Healthy- or population-based	2
Hospital-bases	1
Not described	0
Hardy–Weinberg equilibrium in controls
Hardy–Weinberg equilibrium	2
Hardy–Weinberg disequilibrium	1
Genotyping examination
Genotyping done under “blinded” condition	1
Unblinded done or not mentioned	0
Association assessment
Assess association between genotypes and head and neck  cancer squamous cell carcinoma with appropriate  statistics and adjustment for confounders	2
Assess association between genotypes and head and neck  cancer squamous cell carcinoma with appropriate  statistics and without adjustment for confounders	1
Inappropriate statistics used	0
Total sample size
≥200	2
>100 but <200	1
≤100	0

Table 7. Search History by example of the PubMed.

Search	Query
#12	#11 and #12
#11	#6 or #7 or #8 or #9
#10	#1 or #2 or #3 or #4 or #5
#9	Search Diabetic Kidney Disease [Title]
#8	Search Diabetic Nephropath* [Title]
#7	Search Diabetic Nephropathies/genetics [MeSH Terms]
#6	Search Diabetic Nephropathies/etiology [MeSH Terms]
#5	Search eNOS [Title]
#4	Search ENOS Enzyme [Title]
#3	Search Nitric Oxide Synthase, Type III [Title]
#2	Search Endothelial Nitric Oxide Synthase [Title]
#1	Search “Nitric Oxide Synthase Type III” [Mesh]

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